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Gong J, Chan KS, Rajesh A, Droho S, Lavine JA. Adrb2 Expression in Ocular-Infiltrating Macrophages Is Necessary for Interleukin-6 Expression and Choroidal Neovascularization. Invest Ophthalmol Vis Sci 2025; 66:43. [PMID: 40434345 DOI: 10.1167/iovs.66.5.43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2025] Open
Abstract
Purpose Effective therapies for treatment resistant neovascular age-related macular degeneration (nAMD) remain an unmet need. Beta-adrenergic receptor (AR) blockers can decrease laser-induced choroidal neovascularization (CNV) size in mice. We have shown that monocyte-derived macrophages (MDMs) and interleukin-6 (IL-6) are necessary for beta-AR blockers to inhibit CNV. However, the specific beta-AR and the mechanism of this pathway are not fully elucidated. We hypothesized that beta2-AR (Adrb2) signaling on MDMs increases IL-6 production and stimulates CNV. Methods Previously published single-cell RNA-sequencing data was reanalyzed to determine which mononuclear phagocytes express beta-ARs. Adrb2flox/flox: Cx3cr1CreER/+ mice (Adrb2ΔMacs) or Adrb2flox/flox (Adrb2flox) controls were given tamoxifen injections at either four weeks before or at the time of laser-induced CNV to knockout Adrb2 in tissue resident or all macrophages, respectively. Mice underwent laser induced-CNV, and eyes were collected for choroidal wholemount immunofluorescence imaging to measure CNV area, multiparameter flow cytometry to analyze macrophage heterogeneity, and ELISAs to quantitate IL-6 levels. Results Adrb2 was the predominantly expressed beta-AR and was found on microglia, macrophages, and monocytes. Adrb2 deletion in tissue resident macrophages had no effect upon CNV area. Adrb2 deletion in all macrophages decreased CNV area by 1.4-fold. Adrb2ΔMacs posterior eye cups demonstrated similar levels of pro-angiogenic CD11c+ macrophages compared to Adrb2flox controls, but Ly6CnegCD11cneg macrophages were significantly increased. IL-6 levels increased with laser in Adrb2flox controls, but IL-6 levels in Adrb2ΔMacs posterior eye cups were unchanged. Conclusions Beta2-AR deletion in ocular-infiltrating macrophages decreases laser-induced CNV area. Beta2-AR expression regulates IL-6 expression in monocyte-derived macrophages.
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Affiliation(s)
- Joyce Gong
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Kyle S Chan
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Amrita Rajesh
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Steve Droho
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
| | - Jeremy A Lavine
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
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2
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Wang Z, Han X, Xu J, Zhang W, Patel K, Zheng J, Wan M, Zheng J, Cao X. Hypothalamus Regulates Anabolic Metabolism of Articular Cartilage Superficial Chondrocytes through PGE2 Skeletal Interoception. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2501039. [PMID: 40138204 PMCID: PMC12097074 DOI: 10.1002/advs.202501039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/11/2025] [Indexed: 03/29/2025]
Abstract
Degeneration of articular cartilage is the key underlying cause of most joint-related diseases and yet little is known about its regeneration. Here, we report that skeletal interoception induces anabolic synthesis of superficial membrane by tuning down sympathetic norepinephrine (NE). Specifically, the superficial membrane is consumed during animal activity and anabolically renewed by the underneath chondrocytes in the superficial zone (SFZ). Notably, by stereotactic knockdown of sympathetic NE synthesis in the paraventricular nucleus, articular cartilage thickness increases. Moreover, deletion of the gene encoding the prostaglandin E2 (PGE2) receptor, EP4, in sensory nerves for ascending interoceptive pathway induces damage of superficial membrane and articular cartilage degeneration. In contrast, increase of interoceptive signaling by elevation of local PGE2 reduces sympathetic outflow to promote the anabolic renewal of superficial membrane. Importantly, inducible knockout of the β-2-adrenergic-receptor (Adrb2) in the SFZ chondrocytes damages superficial membrane and treadmill running aggravates the damage. Mechanistically, NE-mediated activation of Adrb2 induces internalization of Adrb2 and TGF-β type II receptor as a complex, thereby regulating TGF-β activity for articular cartilage homeostasis regeneration. Together, physical activity induces an anabolic renewal of the superficial membrane by downregulation hypothalamic NE for optimized thickness and integrity of articular cartilage.
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Affiliation(s)
- Ziyi Wang
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Xuequan Han
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Jiawen Xu
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
- Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Weixin Zhang
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Kalp Patel
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Jinjian Zheng
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Mei Wan
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
- Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Junying Zheng
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
| | - Xu Cao
- Center for Musculoskeletal ResearchDepartment of OrthopedicJohns Hopkins University School of MedicineBaltimoreMD21205USA
- Department of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreMD21205USA
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3
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Le LHD, Feidler AM, Rodriguez LC, Cealie M, Plunk E, Li H, Kara-Pabani K, Lamantia C, O'Banion MK, Majewska AK. Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors. Brain Behav Immun 2025; 128:307-322. [PMID: 40245958 DOI: 10.1016/j.bbi.2025.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 04/07/2025] [Accepted: 04/12/2025] [Indexed: 04/19/2025] Open
Abstract
Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer's disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain's resident immune cells, via their β2 adrenergic receptors (β2ARs). Here, we investigate the role of microglial β2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated β2AR expression early in amyloid pathology. Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology. Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.
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Affiliation(s)
- L H D Le
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - A M Feidler
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - L Calcines Rodriguez
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - M Cealie
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - E Plunk
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA; Department of Environmental Medicine, University of Rochester, Rochester, NY, USA
| | - H Li
- Medical Scientist Training Program, University of Rochester, Rochester NY, USA
| | - K Kara-Pabani
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - C Lamantia
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - M K O'Banion
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA
| | - A K Majewska
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY, USA; Center for Visual Science, University of Rochester, Rochester NY, USA.
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Berggren S, Dahlgren J, Andersson O, Bergman S, Roswall J. Osteocalcin in Infancy and Early Childhood and Its Correlation With Later Growth and Body Composition: A Longitudinal Birth Cohort Study. Clin Endocrinol (Oxf) 2025; 102:427-437. [PMID: 39727029 PMCID: PMC11874053 DOI: 10.1111/cen.15187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Osteocalcin is a metabolic active hormone, which correlates positively with bone formation and inversely with body mass index and waist circumference in adults. OBJECTIVES To investigate whether osteocalcin in infancy and early childhood were related to childhood growth or body composition. METHODS A Swedish longitudinal birth cohort with blood samples from 551 children from birth until 5 years of age. Regular anthropometric measurements were carried out up to 8 years of age and dual-energy X-ray absorptiometry (DXA) scans were also performed at 8 years. The results included p-values and Spearman's rho (ρ). RESULTS Osteocalcin at 4 months of age correlated inversely and consecutively with weight from 4 to 24 months and to waist circumference from 6 to 24 months in boys. The correlations for girls were limited to weight at 4 months and waist circumference at 6 and 18 months (ρ < 0.3, p = 0.001 to 0.048). The boys' osteocalcin levels at 5 years correlated positively with their height and weight at 5 and 6.5 years (ρ < 0.3, p < 0.01). Meanwhile, the girls' osteocalcin at 3 years showed positive correlations to all weight and height measurements until 8 years of age (ρ < 0.3, p = 0.003 to 0.023). DXA data showed that the boys' osteocalcin at 5 years correlated with the fat-free mass index (FFMI) (ρ 0.212, p = 0.026) but not the fat mass index (FMI) at 8 years. The opposite was seen for the girls' osteocalcin at 3 years, which correlated with FMI (ρ 0.222, p = 0.020) but not FFMI. CONCLUSION Early levels of osteocalcin showed inverse correlations with later weight, height and body composition in infancy and positive correlations during childhood. The weak but consistent correlations suggest that osteocalcin carries information about future growth. Girls with high osteocalcin at 3 and 5 years had a larger fat mass at 8 years, while boys, in contrast, had a larger lean mass. These sex differences need to be further explored.
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Affiliation(s)
- Sara Berggren
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Health Centre HyltebrukHyltebrukSweden
| | - Jovanna Dahlgren
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of Pediatrics, Västra Götaland CountyQueen Silvia Children's HospitalGothenburgSweden
| | - Ola Andersson
- Department of Clinical SciencesLund UniversityLundSweden
| | - Stefan Bergman
- Primary Health Care Unit, Department of Public Health and Community MedicineInstitute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Spenshult Research and Development CentreHalmstadSweden
| | - Josefine Roswall
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Department of PediatricsHalland Hospital HalmstadHalmstadSweden
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Fnu T, Shi P, Zhang W, Chung SS, Damoci CB, Fang Y, Chen QY, Saqi A, Huang Y, Wu X, Lu C, Yang D, Wang TC, Que J. Sympathetic Neurons Promote Small Cell Lung Cancer through the β2-Adrenergic Receptor. Cancer Discov 2025; 15:616-632. [PMID: 39513738 PMCID: PMC11875942 DOI: 10.1158/2159-8290.cd-24-0718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 10/04/2024] [Accepted: 11/06/2024] [Indexed: 11/15/2024]
Abstract
SIGNIFICANCE SCLC is highly aggressive, with limited effective treatment options. We show that ablating sympathetic nerves or inhibiting the ADRB2 receptor slows SCLC progression and prolongs survival in mice. Additionally, ADRB2 inhibition reduces the growth of human SCLC organoids and xenografts by disrupting PKA signaling, identifying a new therapeutic target.
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Affiliation(s)
- Tala Fnu
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Peiguo Shi
- Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of System Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Wanwei Zhang
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Sanny S.W. Chung
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Christopher B Damoci
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Yinshan Fang
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Qi-Yue Chen
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Anjali Saqi
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Yuefeng Huang
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Xuebing Wu
- Cardiometabolic Genomics Program, Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of System Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Chao Lu
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Dian Yang
- Department of System Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
- Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Timothy C. Wang
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Jianwen Que
- Columbia Center for Human Development, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
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Xu H, Luo Y, An Y, Wu X. The mechanism of action of indole-3-propionic acid on bone metabolism. Food Funct 2025; 16:406-421. [PMID: 39764708 DOI: 10.1039/d4fo03783a] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2025]
Abstract
Indole-3-propionic acid (IPA), a metabolite produced by gut microbiota through tryptophan metabolism, has recently been identified as playing a pivotal role in bone metabolism. IPA promotes osteoblast differentiation by upregulating mitochondrial transcription factor A (Tfam), contributing to increased bone density and supporting bone repair. Simultaneously, it inhibits the formation and activity of osteoclasts, reducing bone resorption, possibly through modulation of the nuclear factor-κB (NF-κB) pathway and downregulation of osteoclast-associated factors, thereby maintaining bone structural integrity. Additionally, IPA provides indirect protection to bone health by regulating host immune responses and inflammation via activation of receptors such as the Aryl hydrocarbon Receptor (AhR) and the Pregnane X Receptor (PXR). This review summarizes the roles and signaling pathways of IPA in bone metabolism and its impact on various bone metabolic disorders. Furthermore, we discuss the therapeutic potential and limitations of IPA in treating bone metabolic diseases, aiming to offer novel strategies for clinical management.
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Affiliation(s)
- Huimin Xu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Yingzhe Luo
- Department of Oncology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yi An
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
| | - Xi Wu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
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Šestan M, Raposo B, Rendas M, Brea D, Pirzgalska R, Rasteiro A, Aliseychik M, Godinho I, Ribeiro H, Carvalho T, Wueest S, Konrad D, Veiga-Fernandes H. Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis. Science 2025; 387:eadi3624. [PMID: 39818880 DOI: 10.1126/science.adi3624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 04/02/2024] [Accepted: 11/08/2024] [Indexed: 01/19/2025]
Abstract
The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.
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Affiliation(s)
- Marko Šestan
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Bruno Raposo
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Miguel Rendas
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - David Brea
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Roksana Pirzgalska
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Ana Rasteiro
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Maria Aliseychik
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Inês Godinho
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Hélder Ribeiro
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Tania Carvalho
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Henrique Veiga-Fernandes
- Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research. Lisbon, Portugal
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8
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Liu Z, Mao Y, Yang K, Wang S, Zou F. A trend of osteocalcin in diabetes mellitus research: bibliometric and visualization analysis. Front Endocrinol (Lausanne) 2025; 15:1475214. [PMID: 39872315 PMCID: PMC11769813 DOI: 10.3389/fendo.2024.1475214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 12/16/2024] [Indexed: 01/30/2025] Open
Abstract
Background Osteocalcin has attracted attention for its potential role in diabetes management. However, there has been no bibliometric assessment of scientific progress in this field. Methods We analysed 1680 articles retrieved from the Web of Science Core Collection (WoSCC) between 1 January 1986 and 10 May 2024 using various online tools. Result These papers accumulated 42,714 citations,with an average of 25.43 citations per paper. Publication output increased sharply from 1991 onwards. The United States and China are at the forefront of this research area. Discussion The keywords were grouped into four clusters: 'Differential and functional osteocalcin genes', 'Differential expression of osteocalcin genes in relation to diabetes mellitus', 'Role of osteocalcin in the assessment of osteoporosis and diabetes mellitus', and 'Indirect involvement of osteocalcin in metabolic processes'. Analysis using the VoS viewer suggests a shift in research focus towards the correlation between osteocalcin levels and diabetic complications, the clinical efficacy of therapeutic agents or vitamins in the treatment of osteoporosis in diabetic patients, and the mechanisms by which osteocalcin modulates insulin action. The proposed focus areas are "osteocalcin genes", "insulin regulation and osteoporosis ", "different populations", "diabetes-related complications" and "type 2 diabetes mellitus","effect of osteocalcin expression on insulin sensitivity as well as secretion","osteocalcin expression in different populations of diabetic patients and treatment-related studies".
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Affiliation(s)
- Zixu Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- The First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Yuchen Mao
- The First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Kangping Yang
- The Second Clinical Medicine School, Nanchang University, Nanchang, China
| | - Shukai Wang
- The First Clinical Medicine School, Nanchang University, Nanchang, China
| | - Fang Zou
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Channuwong P, Speight V, Yuan Y, Yao S, Yoshimura M, Bauermann FV, Ranjan A, Adisakwattana S, Cheng H. Hyperglycemia from Diabetes Potentiates Uncarboxylated Osteocalcin-Stimulated Insulin Secretion in Rat INS-1 Pancreatic β-Cells. Nutrients 2024; 16:2384. [PMID: 39125265 PMCID: PMC11313777 DOI: 10.3390/nu16152384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/16/2024] [Accepted: 07/20/2024] [Indexed: 08/12/2024] Open
Abstract
Uncarboxylated osteocalcin (ucOC) is a hormone secreted by osteoblasts that strengthens bone during mineralization and is a biomarker for ongoing bone formation. It also regulates glucose homeostasis by stimulating insulin secretion from pancreatic β-cells. However, its effect on β-cells under hyperglycemic diabetic conditions is unclear. The objective of this study was to investigate ucOC's effect on insulin secretion in β-cells maintained under high glucose conditions. We hypothesized that hyperglycemia potentiates insulin secretion in response to ucOC stimulation. Using INS-1 cells, we performed insulin secretion experiments, intracellular calcium recordings, and RT-qPCR to determine ucOC's effect on glucose-stimulated insulin secretion (GSIS)-related genes. The results reveal that ucOC significantly increased insulin secretion under hyperglycemic conditions compared to lower glucose levels. High glucose conditions also potentiated the effect of ucOC on calcium signals, which enhanced insulin secretion. The increase in intracellular calcium was due to an influx from the extracellular space via voltage-dependent calcium channels (VDCCs). Interestingly, the treatment of cells with NPS-2143, a GPRC6A blocker, failed to abolish the calcium signals. Uncarboxylated osteocalcin upregulated the expression of GSIS-related genes under high glucose conditions (450 mg/dL) compared to cells under standard culture conditions (200 mg/dL). In conclusion, hyperglycemia potentiates ucOC-induced insulin secretion in β-cells by opening VDCCs and upregulating GSIS genes. These findings provide a better understanding of ucOC's mechanism in the diabetic state and could lead to alternative treatments to stimulate insulin secretion.
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Affiliation(s)
- Pilailak Channuwong
- Center of Excellence in Phytochemical and Functional Food for Clinical Nutrition, Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Victoria Speight
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Yuanying Yuan
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Shaomian Yao
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Masami Yoshimura
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Fernando V. Bauermann
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
| | - Ashish Ranjan
- Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sirichai Adisakwattana
- Center of Excellence in Phytochemical and Functional Food for Clinical Nutrition, Department of Nutrition and Dietetics, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Henrique Cheng
- Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA
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10
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Mei G, Wang J, Wang J, Ye L, Yi M, Chen G, Zhang Y, Tang Q, Chen L. The specificities, influencing factors, and medical implications of bone circadian rhythms. FASEB J 2024; 38:e23758. [PMID: 38923594 DOI: 10.1096/fj.202302582rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 05/14/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Physiological processes within the human body are regulated in approximately 24-h cycles known as circadian rhythms, serving to adapt to environmental changes. Bone rhythms play pivotal roles in bone development, metabolism, mineralization, and remodeling processes. Bone rhythms exhibit cell specificity, and different cells in bone display various expressions of clock genes. Multiple environmental factors, including light, feeding, exercise, and temperature, affect bone diurnal rhythms through the sympathetic nervous system and various hormones. Disruptions in bone diurnal rhythms contribute to the onset of skeletal disorders such as osteoporosis, osteoarthritis and skeletal hypoplasia. Conversely, these bone diseases can be effectively treated when aimed at the circadian clock in bone cells, including the rhythmic expressions of clock genes and drug targets. In this review, we describe the unique circadian rhythms in physiological activities of various bone cells. Then we summarize the factors synchronizing the diurnal rhythms of bone with the underlying mechanisms. Based on the review, we aim to build an overall understanding of the diurnal rhythms in bone and summarize the new preventive and therapeutic strategies for bone disorders.
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Affiliation(s)
- Gang Mei
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Jinyu Wang
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Jiajia Wang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Lanxiang Ye
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Ming Yi
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Guangjin Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Yifan Zhang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, China
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11
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Shi H, Chen M. The brain-bone axis: unraveling the complex interplay between the central nervous system and skeletal metabolism. Eur J Med Res 2024; 29:317. [PMID: 38849920 PMCID: PMC11161955 DOI: 10.1186/s40001-024-01918-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 06/03/2024] [Indexed: 06/09/2024] Open
Abstract
The brain-bone axis has emerged as a captivating field of research, unveiling the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This comprehensive review delves into the current state of knowledge surrounding the brain-bone axis, exploring the complex mechanisms, key players, and potential clinical implications of this fascinating area of study. The review discusses the neural regulation of bone metabolism, highlighting the roles of the sympathetic nervous system, hypothalamic neuropeptides, and neurotransmitters in modulating bone remodeling. In addition, it examines the influence of bone-derived factors, such as osteocalcin and fibroblast growth factor 23, on brain function and behavior. The therapeutic potential of targeting the brain-bone axis in the context of skeletal and neurological disorders is also explored. By unraveling the complex interplay between the CNS and skeletal metabolism, this review aims to provide a comprehensive resource for researchers, clinicians, and students interested in the brain-bone axis and its implications for human health and disease.
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Affiliation(s)
- Haojun Shi
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China
| | - Min Chen
- Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, Macau SAR, China.
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12
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Arif E, Solanki AK, Rahman B, Wolf B, Schnellmann RG, Nihalani D, Lipschutz JH. Role of the β 2-adrenergic receptor in podocyte injury and recovery. Pharmacol Rep 2024; 76:612-621. [PMID: 38668812 PMCID: PMC11126448 DOI: 10.1007/s43440-024-00594-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/28/2024] [Accepted: 04/03/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Podocytes have a remarkable ability to recover from injury; however, little is known about the recovery mechanisms involved in this process. We recently showed that formoterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, induced mitochondrial biogenesis (MB) in podocytes and led to renoprotection in mice. However, it is not clear whether this effect was mediated by formoterol acting through the β2-AR or if it occurred through "off-target" effects. METHODS We genetically deleted the β2-AR specifically in murine podocytes and used these mice to determine whether formoterol acting through the podocyte β2-AR alone is sufficient for recovery of renal filtration function following injury. The podocyte-specific β2-AR knockout mice (β2-ARfl/fl/PodCre) were generated by crossing β2-AR floxed mice with podocin Cre (B6.Cg-Tg(NPHS2-cre)295Lbh/J) mice. These mice were then subjected to both acute and chronic glomerular injury using nephrotoxic serum (NTS) and adriamycin (ADR), respectively. The extent of injury was evaluated by measuring albuminuria and histological and immunostaining analysis of the murine kidney sections. RESULTS A similar level of injury was observed in β2-AR knockout and control mice; however, the β2-ARfl/fl/PodCre mice failed to recover in response to formoterol. Functional evaluation of the β2-ARfl/fl/PodCre mice following injury plus formoterol showed similar albuminuria and glomerular injury to control mice that were not treated with formoterol. CONCLUSIONS These results indicate that the podocyte β2-AR is a critical component of the recovery mechanism and may serve as a novel therapeutic target for treating podocytopathies.
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Affiliation(s)
- Ehtesham Arif
- Department of Medicine, Nephrology Division, Medical University of South Carolina, Clinical Science Building 822N, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA
| | - Ashish K Solanki
- Department of Medicine, Nephrology Division, Medical University of South Carolina, Clinical Science Building 822N, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA
| | - Bushra Rahman
- Department of Medicine, Nephrology Division, Medical University of South Carolina, Clinical Science Building 822N, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA
| | - Bethany Wolf
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Rick G Schnellmann
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA
- Southern Arizona VA Health Care System, Tucson, AZ, USA
| | - Deepak Nihalani
- Department of Medicine, Nephrology Division, Medical University of South Carolina, Clinical Science Building 822N, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA
| | - Joshua H Lipschutz
- Department of Medicine, Nephrology Division, Medical University of South Carolina, Clinical Science Building 822N, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA.
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13
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Nowicki JK, Jakubowska-Pietkiewicz E. Osteocalcin: Beyond Bones. Endocrinol Metab (Seoul) 2024; 39:399-406. [PMID: 38803289 PMCID: PMC11220208 DOI: 10.3803/enm.2023.1895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/23/2024] [Accepted: 01/31/2024] [Indexed: 05/29/2024] Open
Abstract
Apart from basic roles such as supporting the body, protecting internal organs, and storing calcium, the skeletal system also performs hormonal functions. In recent years, several reports have been published on proteins secreted by bones and their impact on the homeostasis of the entire body. These proteins include fibroblast growth factor 23, sclerostin, lipocalin 2, and osteocalcin. Osteocalcin, the most abundant non-collagenous protein in bone tissue, is routinely measured as a clinical marker for diagnosing bone metabolism disorders. Its molecule undergoes numerous transformations, with decarboxylation being the critical process. Decarboxylation occurs in the acidic environment typical of bone resorption, facilitating the release of the molecule into the bloodstream and enabling its hormonal action. Decarboxylated osteocalcin promotes insulin secretion and stimulates the proliferation of pancreatic islet β-cells. It also plays a role in reducing the accumulation of visceral fat and decreasing fat storage in the liver. Furthermore, decarboxylated osteocalcin levels are inversely correlated with fasting serum glucose levels, total body fat, visceral fat area, and body mass index. Apart from its role in energy metabolism, osteocalcin affects testosterone production and the synthesis of glucagon-like peptide-1. It is also actively involved in muscle-bone crosstalk and influences cognitive function.
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Affiliation(s)
- Jakub Krzysztof Nowicki
- Department of Pediatrics, Neonatal Pathology and Metabolic Bone Diseases, Medical University of Lodz, Lodz, Poland
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14
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Jahn D, Knapstein PR, Otto E, Köhli P, Sevecke J, Graef F, Graffmann C, Fuchs M, Jiang S, Rickert M, Erdmann C, Appelt J, Revend L, Küttner Q, Witte J, Rahmani A, Duda G, Xie W, Donat A, Schinke T, Ivanov A, Tchouto MN, Beule D, Frosch KH, Baranowsky A, Tsitsilonis S, Keller J. Increased β 2-adrenergic signaling promotes fracture healing through callus neovascularization in mice. Sci Transl Med 2024; 16:eadk9129. [PMID: 38630849 DOI: 10.1126/scitranslmed.adk9129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 03/27/2024] [Indexed: 04/19/2024]
Abstract
Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β2-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene-related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.
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Affiliation(s)
- Denise Jahn
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Paul Richard Knapstein
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Ellen Otto
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Paul Köhli
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, 13353 Berlin, Germany
| | - Jan Sevecke
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Frank Graef
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, 13353 Berlin, Germany
| | - Christine Graffmann
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Melanie Fuchs
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Shan Jiang
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Mayla Rickert
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Cordula Erdmann
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Jessika Appelt
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Lawik Revend
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
| | - Quin Küttner
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
| | - Jason Witte
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Adibeh Rahmani
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Georg Duda
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Weixin Xie
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Antonia Donat
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Thorsten Schinke
- University Medical Center Hamburg-Eppendorf, Department of Osteology and Biomechanics, 20251 Hamburg, Germany
| | - Andranik Ivanov
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, 10117 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Mireille Ngokingha Tchouto
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, 10117 Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, 10117 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
| | - Karl-Heinz Frosch
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Anke Baranowsky
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
| | - Serafeim Tsitsilonis
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany
| | - Johannes Keller
- University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany
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Sharma D, Kohlbach KA, Maples R, Farrar JD. The β2-adrenergic receptor (ADRB2) entrains circadian gene oscillation and diurnal responses to virus infection in CD8 + T cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.12.584692. [PMID: 38559276 PMCID: PMC10980027 DOI: 10.1101/2024.03.12.584692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Adaptive immune cells are regulated by circadian rhythms (CR) under both steady state conditions and during responses to infection. Cytolytic CD8 + T cells display variable responses to infection depending upon the time of day of exposure. However, the neuronal signals that entrain these cyclic behaviors remain unknown. Immune cells express a variety of neurotransmitter receptors including nicotinic, glucocorticoid, and adrenergic receptors. Here, we demonstrate that the β2-adrenergic receptor (ADRB2) regulates the periodic oscillation of select core clock genes, such as Per2 and Bmal1 , and selective loss of the Adrb2 gene dramatically perturbs the normal diurnal oscillation of clock gene expression in CD8 + T cells. Consequently, their circadian-regulated anti-viral response is dysregulated, and the diurnal development of CD8 + T cells into variegated populations of cytolytic T cell (CTL) effectors is dramatically altered in the absence of ADRB2 signaling. Thus, the Adrb2 directly entrains core clock gene oscillation and regulates CR-dependent T cell responses to virus infection as a function of time-of-day of pathogen exposure. One Sentence Summary The β2-adrenergic receptor regulates circadian gene oscillation and downstream daily timing of cytolytic T cell responses to virus infection.
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16
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Majewska A, Le L, Feidler A, Li H, Kara-Pabani K, Lamantia C, O'Banion MK. Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors. RESEARCH SQUARE 2024:rs.3.rs-3976896. [PMID: 38464247 PMCID: PMC10925421 DOI: 10.21203/rs.3.rs-3976896/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/12/2024]
Abstract
Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer's disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain's resident immune cells, via their β2 adrenergic receptors (β2ARs). Here, we investigate the role of microglial β2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated β2AR gene expression early in amyloid pathology. Importantly, dampening microglial β2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial β2AR signaling attenuated amyloid pathology. Our results suggest that microglial β2AR could be explored as a potential therapeutic target to modify AD pathology.
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Affiliation(s)
| | | | | | - Herman Li
- University of Rochester Medical Center
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17
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Le L, Feidler AM, Li H, Kara-Pabani K, Lamantia C, O'Banion MK, Majewska KA. Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial β2 adrenergic receptors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.01.569564. [PMID: 38106167 PMCID: PMC10723313 DOI: 10.1101/2023.12.01.569564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
In Alzheimer's disease (AD) pathophysiology, plaque and tangle accumulation trigger an inflammatory response that mounts positive feed-back loops between inflammation and protein aggregation, aggravating neurite damage and neuronal death. One of the earliest brain regions to undergo neurodegeneration is the locus coeruleus (LC), the predominant site of norepinephrine (NE) production in the central nervous system (CNS). In animal models of AD, dampening the impact of noradrenergic signaling pathways, either through administration of beta blockers or pharmacological ablation of the LC, heightened neuroinflammation through increased levels of pro-inflammatory mediators. Since microglia are the resident immune cells of the CNS, it is reasonable to postulate that they are responsible for translating the loss of NE tone into exacerbated disease pathology. Recent findings from our lab demonstrated that noradrenergic signaling inhibits microglia dynamics via β2 adrenergic receptors (β2ARs), suggesting a potential anti-inflammatory role for microglial β2AR signaling. Thus, we hypothesize that microglial β2 adrenergic signaling is progressively impaired during AD progression, which leads to the chronic immune vigilant state of microglia that worsens disease pathology. First, we characterized changes in microglial β2AR signaling as a function of amyloid pathology. We found that LC neurons and their projections degenerate early and progressively in the 5xFAD mouse model of AD; accompanied by mild decrease in the levels of norepinephrine and its metabolite normetanephrine. Interestingly, while 5xFAD microglia, especially plaque-associated microglia, significant downregulated β2AR gene expression early in amyloid pathology, they did not lose their responsiveness to β2AR stimulation. Most importantly, we demonstrated that specific microglial β2AR deletion worsened disease pathology while chronic β2AR stimulation resulted in attenuation of amyloid pathology and associated neuritic damage, suggesting microglial β2AR might be used as potential therapeutic target to modify AD pathology.
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Affiliation(s)
- L Le
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - A M Feidler
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - H Li
- Medical Scientist Training Program, University of Rochester, Rochester NY
| | - K Kara-Pabani
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - C Lamantia
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - M K O'Banion
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
| | - K A Majewska
- Department of Neuroscience, Del Monte Institute for Neuroscience, University of Rochester, Rochester, NY
- Center for Visual Science, University of Rochester, Rochester NY
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18
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Viswanath A, Vidyasagar S, Amrutha Sukumar C. Osteocalcin and Metabolic Syndrome. Clin Med Insights Endocrinol Diabetes 2023; 16:11795514231206729. [PMID: 37954481 PMCID: PMC10634259 DOI: 10.1177/11795514231206729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 09/20/2023] [Indexed: 11/14/2023] Open
Abstract
Introduction Metabolic syndrome which is a syndrome complex that is associated with insulin resistance. Osteocalcin (OC), a bone derived protein has been found to decrease insulin resistance and stimulate production of insulin from the pancreas. Serum osteocalcin levels correlate with body mass index (BMI) and waist circumference. Thus, serum osteocalcin levels in metabolic syndrome could potentially be a new area to explore therapeutically. However, its role in clinical practice needs to be established. Methods We conducted a cross-sectional study on patients, who visited Kasturba Hospital, Manipal between September 2018 and September 2020, to study the relationship between Serum Osteocalcin and the parameters of metabolic syndrome. All patients above the age of 18 years who satisfied the NCEP-ATP III guidelines (Asian adaptation) for metabolic syndrome were considered for the study. Patients who had thyroid and parathyroid disorders, bone malignancies, osteoporosis, liver failure and renal dysfunction were excluded. Results A total of 115 subjects were analyzed. As serum osteoclacin increased, there was a significant decrease in fasting blood glucose levels (r = -.748, P < .05) and a significant increase in serum HDL levels (r = .617, P < .01). There was no correlation found between serum osteocalcin and BMI/waist circumference in this study. Finally, it was observed that individuals with fewer components of metabolic syndrome had a significantly higher serum osteocalcin when compared with individuals with a higher number of components of metabolic syndrome (P < .01). Conclusion This data further confirmed the association between serum OC and parameters of metabolic syndrome such as FBS and serum HDL. It also found that increased serum OC was associated with fewer components of the metabolic syndrome indicating that OC could have a positive metabolic impact and may prevent atherosclerotic risk.
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Affiliation(s)
- Aaditya Viswanath
- Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Sudha Vidyasagar
- Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Cynthia Amrutha Sukumar
- Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
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Remark J, Tong J, Lin MJ, Concepcion A, Mareedu S, Babu GJ, Feske S, Lu CP. Neurotransmitter signaling specifies sweat gland stem cell fate through SLN-mediated intracellular calcium regulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.10.557066. [PMID: 37745514 PMCID: PMC10515797 DOI: 10.1101/2023.09.10.557066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
Sympathetic nerves co-develop with their target organs and release neurotransmitters to stimulate their functions after maturation. Here, we provide the molecular mechanism that during sweat gland morphogenesis, neurotransmitters released from sympathetic nerves act first to promote sweat duct elongation via norepinephrine and followed by acetylcholine to specify sweat gland stem cell fate, which matches the sequence of neurotransmitter switch. Without neuronal signals during development, the basal cells switch to exhibit suprabasal (luminal) cell features. Sarcolipin (SLN), a key regulator of sarcoendoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA), expression is significantly down-regulated in the sweat gland myoepithelial cells upon denervation. Loss of SLN in sweat gland myoepithelial cells leads to decreased intracellular Ca 2+ over time in response to ACh stimulation, as well as upregulation of luminal cell features. In cell culture experiments, we showed that contrary to the paradigm that elevation of Ca 2+ promote epidermal differentiation, specification of the glandular myoepithelial (basal) cells requires high Ca 2+ while lowering Ca 2+ level promotes luminal (suprabasal) cell fate. Our work highlights that neuronal signals not only act transiently for mature sweat glands to function, but also exert long-term impact on glandular stem cell specification through regulating intracellular Ca 2+ dynamics.
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20
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Jahn D, Knapstein PR, Otto E, Köhli P, Sevecke J, Graef F, Graffmann C, Fuchs M, Jiang S, Rickert M, Erdmann C, Appelt J, Revend L, Küttner Q, Witte J, Rahmani A, Duda G, Xie W, Donat A, Schinke T, Ivanov A, Tchouto MN, Beule D, Frosch KH, Baranowsky A, Tsitsilonis S, Keller J. Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.14.548550. [PMID: 37502964 PMCID: PMC10369985 DOI: 10.1101/2023.07.14.548550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone. Abstract Figure
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21
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Tschaffon-Müller MEA, Kempter E, Steppe L, Kupfer S, Kuhn MR, Gebhard F, Pankratz C, Kalbitz M, Schütze K, Gündel H, Kaleck N, Strauß G, Vacher J, Ichinose H, Weimer K, Ignatius A, Haffner-Luntzer M, Reber SO. Neutrophil-derived catecholamines mediate negative stress effects on bone. Nat Commun 2023; 14:3262. [PMID: 37277336 DOI: 10.1038/s41467-023-38616-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 05/09/2023] [Indexed: 06/07/2023] Open
Abstract
Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific β2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with β2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance.
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Affiliation(s)
| | - Elena Kempter
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Lena Steppe
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Sandra Kupfer
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Melanie R Kuhn
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Florian Gebhard
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
| | - Carlos Pankratz
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
| | - Miriam Kalbitz
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Konrad Schütze
- Department of Orthopedic Trauma, Hand-, Plastic- and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany
| | - Harald Gündel
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Nele Kaleck
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Gudrun Strauß
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Jean Vacher
- Department of Medicine, Institut de Recherches Cliniques de Montréal, Montréal, QC, Canada
- Institut de Recherche Cliniques de Montréal, Department of Medicine, Université de Montréal, H2W 1R7, Montréal, QC, Canada
| | - Hiroshi Ichinose
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Katja Weimer
- Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Stefan O Reber
- Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, Ulm University Medical Center, Ulm, Germany.
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22
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Zaidi M, Kim SM, Mathew M, Korkmaz F, Sultana F, Miyashita S, Gumerova AA, Frolinger T, Moldavski O, Barak O, Pallapati A, Rojekar S, Caminis J, Ginzburg Y, Ryu V, Davies TF, Lizneva D, Rosen CJ, Yuen T. Bone circuitry and interorgan skeletal crosstalk. eLife 2023; 12:83142. [PMID: 36656634 PMCID: PMC9851618 DOI: 10.7554/elife.83142] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/29/2022] [Indexed: 01/20/2023] Open
Abstract
The past decade has seen significant advances in our understanding of skeletal homeostasis and the mechanisms that mediate the loss of bone integrity in disease. Recent breakthroughs have arisen mainly from identifying disease-causing mutations and modeling human bone disease in rodents, in essence, highlighting the integrative nature of skeletal physiology. It has become increasingly clear that bone cells, osteoblasts, osteoclasts, and osteocytes, communicate and regulate the fate of each other through RANK/RANKL/OPG, liver X receptors (LXRs), EphirinB2-EphB4 signaling, sphingolipids, and other membrane-associated proteins, such as semaphorins. Mounting evidence also showed that critical developmental pathways, namely, bone morphogenetic protein (BMP), NOTCH, and WNT, interact each other and play an important role in postnatal bone remodeling. The skeleton communicates not only with closely situated organs, such as bone marrow, muscle, and fat, but also with remote vital organs, such as the kidney, liver, and brain. The metabolic effect of bone-derived osteocalcin highlights a possible role of skeleton in energy homeostasis. Furthermore, studies using genetically modified rodent models disrupting the reciprocal relationship with tropic pituitary hormone and effector hormone have unraveled an independent role of pituitary hormone in skeletal remodeling beyond the role of regulating target endocrine glands. The cytokine-mediated skeletal actions and the evidence of local production of certain pituitary hormones by bone marrow-derived cells displays a unique endocrine-immune-skeletal connection. Here, we discuss recently elucidated mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, crosstalk between bone and vital organs, as well as opportunities for treating diseases of the skeleton.
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Affiliation(s)
- Mone Zaidi
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Se-Min Kim
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Mehr Mathew
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Funda Korkmaz
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Farhath Sultana
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Sari Miyashita
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Anisa Azatovna Gumerova
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Tal Frolinger
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Ofer Moldavski
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Orly Barak
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Anusha Pallapati
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Satish Rojekar
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - John Caminis
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Yelena Ginzburg
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Vitaly Ryu
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Terry F Davies
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | - Daria Lizneva
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
| | | | - Tony Yuen
- The Mount Sinai Bone Program, Departments of Pharmacological Sciences and of Medicine, and Center of Translational Medicine and Pharmacology, Icahn School of Medicine at Mount SinaiNew YorkUnited States
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23
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Damo E, Agarwal A, Simonetti M. Activation of β2-Adrenergic Receptors in Microglia Alleviates Neuropathic Hypersensitivity in Mice. Cells 2023; 12:cells12020284. [PMID: 36672219 PMCID: PMC9856373 DOI: 10.3390/cells12020284] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/22/2022] [Accepted: 01/08/2023] [Indexed: 01/13/2023] Open
Abstract
Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on α2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of β2-adrenergic receptors (β2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of β2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia as well as the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of β2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to β2-AR signaling in microglia. Our results underline the value of developing microglial β2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings.
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Affiliation(s)
- Elisa Damo
- Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Amit Agarwal
- The Chica and Heinz Schaller Research Group, Institute of Anatomy and Cell Biology, Heidelberg University, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany
- Interdisciplinary Center for Neurosciences, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Manuela Simonetti
- Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
- Correspondence:
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24
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Deng B, Zhang Y, Zhu C, Wang Y, Weatherford E, Xu B, Liu X, Conway SJ, Abel ED, Xiang YK. Divergent Actions of Myofibroblast and Myocyte β 2-Adrenoceptor in Heart Failure and Fibrotic Remodeling. Circ Res 2023; 132:106-108. [PMID: 36458552 PMCID: PMC9985902 DOI: 10.1161/circresaha.122.321816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Affiliation(s)
- Bingqing Deng
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
| | - Yu Zhang
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
| | - Chaoqun Zhu
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
| | - Ying Wang
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
| | - Eric Weatherford
- Fraternal Order of Eagles Diabetes Research Center and Department of Medicine, University of Iowa, Iowa City (E.W., E.D.A.)
| | - Bing Xu
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
- VA Northern California, Mather (B.X., Y.K.X.)
| | - Xianhui Liu
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
| | - Simon J Conway
- Department of Pediatrics, Indiana University School of Medicine (S.J.C.)
| | - E. Dale Abel
- Fraternal Order of Eagles Diabetes Research Center and Department of Medicine, University of Iowa, Iowa City (E.W., E.D.A.)
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA (E.D.A.)
| | - Yang K Xiang
- Department of Pharmacology, University of California at Davis (B.D., Y.Z., C.Z., Y.W., B.X., X.L., Y.K.X.)
- VA Northern California, Mather (B.X., Y.K.X.)
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25
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Simon T, Kirk J, Dolezalova N, Guyot M, Panzolini C, Bondue A, Lavergne J, Hugues S, Hypolite N, Saeb-Parsy K, Perkins J, Macia E, Sridhar A, Vervoordeldonk MJ, Glaichenhaus N, Donegá M, Blancou P. The cholinergic anti-inflammatory pathway inhibits inflammation without lymphocyte relay. Front Neurosci 2023; 17:1125492. [PMID: 37123375 PMCID: PMC10140439 DOI: 10.3389/fnins.2023.1125492] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/20/2023] [Indexed: 05/02/2023] Open
Abstract
The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) on CD4+ T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF). However, the role of ACh-secreting CD4+ T-cells in the CAP is still controversial and largely based on the absence of this anti-inflammatory pathway in mice lacking T-cells (nude, FoxN1-/-). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting on CD4+ T-cells, NA released by splenic nerve terminals acts directly onto β2-AR on splenic myeloid cells to exert this anti-inflammatory effect. We also show that, while larger doses of LPS are needed to trigger CAP in nude mouse strain compared to other strains, TNF production can be inhibited in these animals lacking CD4+ T-cell by stimulating either the vagus or the splenic nerve. We demonstrate that CD4+ T-cells are dispensable for the CAP after antibody-mediated CD4+ T-cell depletion in wild type mice. Furthermore, we found that NA-mediated inhibition of in vitro LPS-induced TNF secretion by human or porcine splenocytes does not require α7-AChR signaling. Altogether our data demonstrate that activation of the CAP by stimulation of vagus or splenic nerves in mice is mainly mediated by direct binding of NA to β2-AR on splenic macrophages, and suggest that the same mechanism is at play in larger species.
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Affiliation(s)
- Thomas Simon
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | - Joseph Kirk
- The Royal Veterinary College, Hatfield, United Kingdom
| | - Nikola Dolezalova
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Mélanie Guyot
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | | | - Alexandre Bondue
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | - Julien Lavergne
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | | | - Nicolas Hypolite
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Justin Perkins
- Galvani Bioelectronics, Translational Sciences, Stevenage, United Kingdom
| | - Eric Macia
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | - Arun Sridhar
- Galvani Bioelectronics, Translational Sciences, Stevenage, United Kingdom
| | | | - Nicolas Glaichenhaus
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
| | - Matteo Donegá
- Galvani Bioelectronics, Translational Sciences, Stevenage, United Kingdom
| | - Philippe Blancou
- Université Côte d’Azur, CNRS, Molecular and Cellular Pharmacology Institute, Valbonne, France
- *Correspondence: Philippe Blancou,
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26
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You Z, Liu B, Qi H. Neuronal regulation of B-cell immunity: Anticipatory immune posturing? Neuron 2022; 110:3582-3596. [PMID: 36327899 DOI: 10.1016/j.neuron.2022.10.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 12/12/2022]
Abstract
The brain may sense, evaluate, modulate, and intervene in the operation of immune system, which would otherwise function autonomously in defense against pathogens. Antibody-mediated immunity is one arm of adaptive immunity that may achieve sterilizing protection against infection. Lymphoid organs are densely innervated. Immune cells supporting the antigen-specific antibody response express receptors for neurotransmitters and glucocorticoid hormones, and they are subjected to collective regulation by the neuroendocrine and the autonomic nervous system. Emerging evidence reveals a brain-spleen axis that regulates antigen-specific B cell responses and antibody-mediated immunity. In this article, we provide a synthesis of those studies as pertinent to neuronal regulation of B cell responses in secondary lymphoid organs. We propose the concept of defensive immune posturing as a brain-initiated top-down reaction in anticipation of potential tissue injury that requires immune protection.
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Affiliation(s)
- Zhiwei You
- Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing 100084, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Bo Liu
- Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing 100084, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
| | - Hai Qi
- Tsinghua-Peking Center for Life Sciences, Beijing 100084, China; Laboratory of Dynamic Immunobiology, Institute for Immunology, Tsinghua University, Beijing 100084, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
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27
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Ingiosi AM, Frank MG. Noradrenergic Signaling in Astrocytes Influences Mammalian Sleep Homeostasis. Clocks Sleep 2022; 4:332-345. [PMID: 35892990 PMCID: PMC9326550 DOI: 10.3390/clockssleep4030028] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/22/2022] [Accepted: 07/01/2022] [Indexed: 02/01/2023] Open
Abstract
Astrocytes influence sleep expression and regulation, but the cellular signaling pathways involved in these processes are poorly defined. We proposed that astrocytes detect and integrate a neuronal signal that accumulates during wakefulness, thereby leading to increased sleep drive. Noradrenaline (NA) satisfies several criteria for a waking signal integrated by astrocytes. We therefore investigated the role of NA signaling in astrocytes in mammalian sleep. We conditionally knocked out (cKO) β2-adrenergic receptors (β2-AR) selectively in astrocytes in mice and recorded electroencephalographic and electromyographic activity under baseline conditions and in response to sleep deprivation (SDep). cKO of astroglial β2-ARs increased active phase siesta duration under baseline conditions and reduced homeostatic compensatory changes in sleep consolidation and non-rapid eye movement slow-wave activity (SWA) after SDep. Overall, astroglial NA β2-ARs influence mammalian sleep homeostasis in a manner consistent with our proposed model of neuronal-astroglial interactions.
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Affiliation(s)
- Ashley M. Ingiosi
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA;
| | - Marcos G. Frank
- Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA;
- Gleason Institute for Neuroscience, Washington State University, Spokane, WA 99202, USA
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28
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Mele C, Caputo M, Ferrero A, Daffara T, Cavigiolo B, Spadaccini D, Nardone A, Prodam F, Aimaretti G, Marzullo P. Bone Response to Weight Loss Following Bariatric Surgery. Front Endocrinol (Lausanne) 2022; 13:921353. [PMID: 35873004 PMCID: PMC9301317 DOI: 10.3389/fendo.2022.921353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022] Open
Abstract
Obesity is a global health challenge that warrants effective treatments to avoid its multiple comorbidities. Bariatric surgery, a cornerstone treatment to control bodyweight excess and relieve the health-related burdens of obesity, can promote accelerated bone loss and affect skeletal strength, particularly after malabsorptive and mixed surgical procedures, and probably after restrictive surgeries. The increase in bone resorption markers occurs early and persist for up to 12 months or longer after bariatric surgery, while bone formation markers increase but to a lesser extent, suggesting a potential uncoupling process between resorption and formation. The skeletal response to bariatric surgery, as investigated by dual-energy X-ray absorptiometry (DXA), has shown significant loss in bone mineral density (BMD) at the hip with less consistent results for the lumbar spine. Supporting DXA studies, analyses by high-resolution peripheral quantitative computed tomography (HR-pQCT) showed lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number for up to 5 years after bariatric surgery. These alterations translate into an increased risk of fall injury, which contributes to increase the fracture risk in patients who have been subjected to bariatric surgery procedures. As bone deterioration continues for years following bariatric surgery, the fracture risk does not seem to be dependent on acute weight loss but, rather, is a chronic condition with an increasing impact over time. Among the post-bariatric surgery mechanisms that have been claimed to act globally on bone health, there is evidence that micro- and macro-nutrient malabsorptive factors, mechanical unloading and changes in molecules partaking in the crosstalk between adipose tissue, bone and muscle may play a determining role. Given these circumstances, it is conceivable that bone health should be adequately investigated in candidates to bariatric surgery through bone-specific work-up and dedicated postsurgical follow-up. Specific protocols of nutrients supplementation, motor activity, structured rehabilitative programs and, when needed, targeted therapeutic strategies should be deemed as an integral part of post-bariatric surgery clinical support.
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Affiliation(s)
- Chiara Mele
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- *Correspondence: Chiara Mele,
| | - Marina Caputo
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Alice Ferrero
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Tommaso Daffara
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Beatrice Cavigiolo
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Daniele Spadaccini
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
| | - Antonio Nardone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
- Istituti Clinici Scientifici Maugeri IRCCS, Neurorehabilitation and Spinal Unit of Pavia Institute, Pavia, and Neurorehabilitation of Montescano Institute, Montescano, PV, Italy
| | - Flavia Prodam
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Gianluca Aimaretti
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Istituto Auxologico Italiano, IRCCS, Laboratory of Metabolic Research, S. Giuseppe Hospital, Piancavallo, Italy
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29
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Freire EBL, d’Alva CB, Madeira MP, Lima GEDCP, Montenegro APDR, Fernandes VO, Montenegro Junior RM, Brazilian Group for the Study of Inherited and Acquired Lipodystrophies (BRAZLIPO). Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:9724. [PMID: 34574647 PMCID: PMC8465110 DOI: 10.3390/ijerph18189724] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/05/2021] [Accepted: 07/16/2021] [Indexed: 12/31/2022]
Abstract
Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.
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Affiliation(s)
| | | | | | | | | | | | - Renan Magalhães Montenegro Junior
- Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará, Fortaleza 60416200, CE, Brazil; (E.B.L.F.); (C.B.d.); (M.P.M.); (G.E.d.C.P.L.); (A.P.D.R.M.); (V.O.F.)
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30
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Cardoso F, Klein Wolterink RGJ, Godinho-Silva C, Domingues RG, Ribeiro H, da Silva JA, Mahú I, Domingos AI, Veiga-Fernandes H. Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit. Nature 2021; 597:410-414. [PMID: 34408322 PMCID: PMC7614847 DOI: 10.1038/s41586-021-03830-7] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 07/16/2021] [Indexed: 12/12/2022]
Abstract
Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1-4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain-body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain-adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the β2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.
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Affiliation(s)
- Filipa Cardoso
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | | | | | - Rita G Domingues
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research (MCCIR), Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Hélder Ribeiro
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - Inês Mahú
- Max Planck Institute for Metabolism Research, Köln, Germany
| | - Ana I Domingos
- Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK
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31
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Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm. Biomedicines 2021; 9:biomedicines9070800. [PMID: 34356863 PMCID: PMC8301386 DOI: 10.3390/biomedicines9070800] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 01/18/2023] Open
Abstract
Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin’s primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.
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32
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Hasegawa S, Inoue T, Nakamura Y, Fukaya D, Uni R, Wu CH, Fujii R, Peerapanyasut W, Taguchi A, Kohro T, Yamada S, Katagiri M, Ko T, Nomura S, Nakanishi Ozeki A, Susaki EA, Ueda HR, Akimitsu N, Wada Y, Komuro I, Nangaku M, Inagi R. Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury. J Am Soc Nephrol 2021; 32:1599-1615. [PMID: 33875568 PMCID: PMC8425643 DOI: 10.1681/asn.2020121723] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 02/15/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI). METHODS We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of β2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling. RESULTS In vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue. CONCLUSIONS The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.
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Affiliation(s)
- Sho Hasegawa
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Tsuyoshi Inoue
- Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yasuna Nakamura
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Daichi Fukaya
- Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Department of Nephrology, Saitama Medical University, Saitama, Japan
| | - Rie Uni
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Chia-Hsien Wu
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Rie Fujii
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Wachirasek Peerapanyasut
- Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Mahidol University, Nakhonsawan Campus, Nakhonsawan, Thailand
| | - Akashi Taguchi
- Isotope Science Center, University of Tokyo, Tokyo, Japan
| | - Takahide Kohro
- Department of Clinical Informatics/Cardiology, Jichi Medical University, Tochigi, Japan
| | - Shintaro Yamada
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Genome Science Division, Research Center for Advanced Science and Technologies, University of Tokyo, Tokyo, Japan
| | - Mikako Katagiri
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Toshiyuki Ko
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Genome Science Division, Research Center for Advanced Science and Technologies, University of Tokyo, Tokyo, Japan
| | - Seitaro Nomura
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan,Genome Science Division, Research Center for Advanced Science and Technologies, University of Tokyo, Tokyo, Japan
| | | | - Etsuo A. Susaki
- Department of Systems Pharmacology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan,Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, Suita, Japan
| | - Hiroki R. Ueda
- Department of Systems Pharmacology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan,Laboratory for Synthetic Biology, RIKEN Center for Biosystems Dynamics Research, Suita, Japan
| | | | - Youichiro Wada
- Isotope Science Center, University of Tokyo, Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Reiko Inagi
- Division of CKD Pathophysiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Petkevicius K, Bidault G, Virtue S, Jenkins B, van Dierendonck XAMH, Dugourd A, Saez-Rodriguez J, Stienstra R, Koulman A, Vidal-Puig A. Norepinephrine promotes triglyceride storage in macrophages via beta2-adrenergic receptor activation. FASEB J 2021; 35:e21266. [PMID: 33484195 PMCID: PMC7898725 DOI: 10.1096/fj.202001101r] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 11/11/2020] [Accepted: 11/30/2020] [Indexed: 01/02/2023]
Abstract
Tissue‐resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti‐inflammatory and tissue‐reparative phenotype in macrophages. As NE has a well‐established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow‐derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2‐adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride‐laden macrophages. We demonstrate that these responses are mediated by a B2AR activation‐dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.
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Affiliation(s)
- Kasparas Petkevicius
- Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
| | - Guillaume Bidault
- Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
| | - Sam Virtue
- Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
| | - Benjamin Jenkins
- Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
| | - Xanthe A M H van Dierendonck
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Aurelien Dugourd
- Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.,Institute for Computational Biomedicine, Faculty of Medicine & Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Julio Saez-Rodriguez
- Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.,Institute for Computational Biomedicine, Faculty of Medicine & Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Rinke Stienstra
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.,Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Albert Koulman
- Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom
| | - Antonio Vidal-Puig
- Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom.,Wellcome Trust Sanger Institute, Hinxton, United Kingdom
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34
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Petkevicius K, Bidault G, Virtue S, Newland SA, Dale M, Dugourd A, Saez-Rodriguez J, Mallat Z, Vidal-Puig A. Macrophage beta2-adrenergic receptor is dispensable for the adipose tissue inflammation and function. Mol Metab 2021; 48:101220. [PMID: 33774223 PMCID: PMC8086137 DOI: 10.1016/j.molmet.2021.101220] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Neuroimmune interactions between the sympathetic nervous system (SNS) and macrophages are required for the homeostasis of multiple tissues, including the adipose tissue. It has been proposed that the SNS maintains adipose tissue macrophages (ATMs) in an anti-inflammatory state via direct norepinephrine (NE) signaling to macrophages. This study aimed to investigate the physiological importance of this paradigm by utilizing a mouse model in which the adrenergic signaling from the SNS to macrophages, but not to other adipose tissue cells, was disrupted. METHODS We generated a macrophage-specific B2AR knockout mouse (Adrb2ΔLyz2) by crossing Adrb2fl/fl and Lyz2Cre/+ mice. We have previously shown that macrophages isolated from Adrb2ΔLyz2 animals do not respond to NE stimulation in vitro. Herein we performed a metabolic phenotyping of Adrb2ΔLyz2 mice on either chow or high-fat diet (HFD). We also assessed the adipose tissue function of Adrb2ΔLyz2 animals during fasting and cold exposure. Finally, we transplanted Adrb2ΔLyz2 bone marrow to low-density lipoprotein receptor (LDLR) knockout mice and investigated the development of atherosclerosis during Western diet feeding. RESULTS We demonstrated that SNS-associated ATMs have a transcriptional profile indicative of activated beta-2 adrenergic receptor (B2AR), the main adrenergic receptor isoform in myeloid cells. However, Adrb2ΔLyz2 mice have unaltered energy balance on a chow or HFD. Furthermore, Adrb2ΔLyz2 mice show similar levels of adipose tissue inflammation and function during feeding, fasting, or cold exposure, and develop insulin resistance during HFD at the same rate as controls. Finally, macrophage-specific B2AR deletion does not affect the development of atherosclerosis on an LDL receptor-null genetic background. CONCLUSIONS Overall, our data suggest that the SNS does not directly modulate the phenotype of adipose tissue macrophages in either lean mice or mouse models of cardiometabolic disease. Instead, sympathetic nerve activity exerts an indirect effect on adipose tissue macrophages through the modulation of adipocyte function.
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MESH Headings
- Adipocytes/metabolism
- Adipose Tissue, White/metabolism
- Animals
- Atherosclerosis/complications
- Atherosclerosis/genetics
- Atherosclerosis/metabolism
- Bone Marrow Transplantation/methods
- Cells, Cultured
- Diet, High-Fat/adverse effects
- Diet, Western/adverse effects
- Disease Models, Animal
- Female
- Insulin Resistance/genetics
- Macrophages/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Obesity/complications
- Obesity/genetics
- Obesity/metabolism
- Panniculitis/genetics
- Panniculitis/metabolism
- Phenotype
- Receptors, Adrenergic, beta-2/genetics
- Receptors, Adrenergic, beta-2/metabolism
- Signal Transduction/genetics
- Sympathetic Nervous System/metabolism
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Affiliation(s)
- Kasparas Petkevicius
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom.
| | - Guillaume Bidault
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom
| | - Sam Virtue
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom
| | - Stephen A Newland
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Martin Dale
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom
| | - Aurelien Dugourd
- Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine & Heidelberg University Hospital, Heidelberg, Germany
| | - Julio Saez-Rodriguez
- Joint Research Centre for Computational Biomedicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Institute for Computational Biomedicine, Heidelberg University, Faculty of Medicine & Heidelberg University Hospital, Heidelberg, Germany
| | - Ziad Mallat
- Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Antonio Vidal-Puig
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, MDU MRC, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
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35
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Kuramoto N, Nomura K, Kohno D, Kitamura T, Karsenty G, Hosooka T, Ogawa W. Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load. Sci Rep 2021; 11:3447. [PMID: 33568757 PMCID: PMC7876046 DOI: 10.1038/s41598-021-83098-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/22/2021] [Indexed: 02/07/2023] Open
Abstract
Phosphatidylinositol 3-kinase (PI3K) plays an important role in protein metabolism and cell growth. We here show that mice (M-PDK1KO mice) with skeletal muscle-specific deficiency of 3'-phosphoinositide-dependent kinase 1 (PDK1), a key component of PI3K signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of mechanical load-induced muscle hypertrophy. Whereas mechanical load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by mechanical load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of kinase cascades such as the S6K-S6 axis, which plays a key role in protein synthesis. Administration of the β2-adrenergic receptor (AR) agonist clenbuterol activated the S6K-S6 axis in skeletal muscle and induced muscle hypertrophy in mice. These effects of clenbuterol were attenuated in M-PDK1KO mice, and mechanical load-induced activation of the S6K-S6 axis and muscle hypertrophy were inhibited in mice with skeletal muscle-specific deficiency of β2-AR. Our results suggest that PDK1 regulates skeletal muscle mass under the static condition and that it contributes to mechanical load-induced muscle hypertrophy, at least in part by mediating signaling from β2-AR.
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Affiliation(s)
- Naoki Kuramoto
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kazuhiro Nomura
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Daisuke Kohno
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Gerard Karsenty
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Tetsuya Hosooka
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
- Division of Development of Advanced Therapy for Metabolic Diseases, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
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36
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Garbe A, Graef F, Appelt J, Schmidt-Bleek K, Jahn D, Lünnemann T, Tsitsilonis S, Seemann R. Leptin Mediated Pathways Stabilize Posttraumatic Insulin and Osteocalcin Patterns after Long Bone Fracture and Concomitant Traumatic Brain Injury and Thus Influence Fracture Healing in a Combined Murine Trauma Model. Int J Mol Sci 2020; 21:E9144. [PMID: 33266324 PMCID: PMC7729898 DOI: 10.3390/ijms21239144] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 11/19/2020] [Accepted: 11/28/2020] [Indexed: 12/23/2022] Open
Abstract
Recent studies on insulin, leptin, osteocalcin (OCN), and bone remodeling have evoked interest in the interdependence of bone formation and energy household. Accordingly, this study attempts to investigate trauma specific hormone changes in a murine trauma model and its influence on fracture healing. Thereunto 120 female wild type (WT) and leptin-deficient mice underwent either long bone fracture (Fx), traumatic brain injury (TBI), combined trauma (Combined), or neither of it and therefore served as controls (C). Blood samples were taken weekly after trauma and analyzed for insulin and OCN concentrations. Here, WT-mice with Fx and, moreover, with combined trauma showed a greater change in posttraumatic insulin and OCN levels than mice with TBI alone. In the case of leptin-deficiency, insulin changes were still increased after bony lesion, but the posttraumatic OCN was no longer trauma specific. Four weeks after trauma, hormone levels recovered to normal/basal line level in both mouse strains. Thus, WT- and leptin-deficient mice show a trauma specific hyperinsulinaemic stress reaction leading to a reduction in OCN synthesis and release. In WT-mice, this causes a disinhibition and acceleration of fracture healing after combined trauma. In leptin-deficiency, posttraumatic OCN changes are no longer specific and fracture healing is impaired regardless of the preceding trauma.
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Affiliation(s)
- Anja Garbe
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
| | - Frank Graef
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
| | - Jessika Appelt
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany;
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany;
| | - Denise Jahn
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
- Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany;
| | - Tim Lünnemann
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
| | - Serafeim Tsitsilonis
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
| | - Ricarda Seemann
- Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany; (F.G.); (J.A.); (D.J.); (T.L.); (S.T.); (R.S.)
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37
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Diaz-Salazar C, Bou-Puerto R, Mujal AM, Lau CM, von Hoesslin M, Zehn D, Sun JC. Cell-intrinsic adrenergic signaling controls the adaptive NK cell response to viral infection. J Exp Med 2020; 217:133715. [PMID: 32045471 PMCID: PMC7144534 DOI: 10.1084/jem.20190549] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 10/23/2019] [Accepted: 01/13/2020] [Indexed: 12/26/2022] Open
Abstract
Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here, we describe one such signal that is provided by the adrenergic nervous system, and demonstrate that cell-intrinsic adrenergic signaling is required for optimal adaptive NK cell responses. Early during mouse cytomegalovirus (MCMV) infection, NK cells up-regulated Adrb2 (which encodes the β2-adrenergic receptor), a process dependent on IL-12 and STAT4 signaling. NK cell-specific deletion of Adrb2 resulted in impaired NK cell expansion and memory during MCMV challenge, in part due to a diminished proliferative capacity. As a result, NK cell-intrinsic adrenergic signaling was required for protection against MCMV. Taken together, we propose a novel role for the adrenergic nervous system in regulating circulating lymphocyte responses to viral infection.
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Affiliation(s)
- Carlos Diaz-Salazar
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.,Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY
| | - Regina Bou-Puerto
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.,Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY
| | - Adriana M Mujal
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Colleen M Lau
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Madlaina von Hoesslin
- Division of Animal Physiology and Immunology, Technical University of Munich, Freising, Germany
| | - Dietmar Zehn
- Division of Animal Physiology and Immunology, Technical University of Munich, Freising, Germany
| | - Joseph C Sun
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.,Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY.,Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY
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38
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Wieduwild E, Girard-Madoux MJ, Quatrini L, Laprie C, Chasson L, Rossignol R, Bernat C, Guia S, Ugolini S. β2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection. J Exp Med 2020; 217:133716. [PMID: 32045472 PMCID: PMC7144531 DOI: 10.1084/jem.20190554] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 10/28/2019] [Accepted: 01/13/2020] [Indexed: 12/16/2022] Open
Abstract
In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the β2-adrenergic receptor (β2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection. Mice treated with a β2-AR agonist were more susceptible to MCMV infection. By contrast, β2-AR deficiency resulted in a better clearance of the virus, less tissue damage, and greater resistance to MCMV. Mechanistically, we found a correlation between higher levels of IFN-γ production by liver natural killer (NK) cells and stronger resistance to MCMV. However, the control of NK cell IFN-γ production was not cell intrinsic, revealing a cell-extrinsic downregulation of the antiviral NK cell response by adrenergic neuroendocrine signals. This pathway reduces host immune defense, suggesting that the blockade of the β2-AR signaling could be used to increase resistance to infectious diseases.
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Affiliation(s)
- Elisabeth Wieduwild
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Mathilde J Girard-Madoux
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Linda Quatrini
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France.,Department of Immunology, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, Rome, Italy
| | - Caroline Laprie
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Lionel Chasson
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Rafaëlle Rossignol
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Claire Bernat
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Sophie Guia
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Sophie Ugolini
- Aix Marseille University, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre d'Immunologie de Marseille-Luminy, Marseille, France
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39
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Ordaz G, Juárez A, Pérez RE, Martínez HE, Ortiz R. Effects of Opuntia ficus-indica in the diet of primiparous sows on the metabolic profile during late gestation and lactation and feed intake during lactation. J Anim Physiol Anim Nutr (Berl) 2020; 104:1884-1895. [PMID: 32683754 DOI: 10.1111/jpn.13413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 04/16/2020] [Accepted: 06/09/2020] [Indexed: 12/22/2022]
Abstract
The goal of this study was to evaluate the effects of dietary Opuntia ficus-indica L. (OFI) on the metabolic profile of primiparous sows during late gestation and lactation, and its impact on voluntary feed intake (VFI) during lactation. From day 85 of gestation to weaning, 32 sows were divided into four feeding schemes (n = 8 sows/scheme): Basal diet (BD) without OFI supplementation; Test scheme I, BD during gestation and BD + OFI during lactation; Test scheme II, BD + OFI during both gestation and lactation, and Test scheme III, BD + OFI during gestation and BD during lactation. Blood samples were obtained during gestation (day 85 and 100) and lactation (day 0, 3, 7, 14 and 21) to determine plasma glucose, insulin, triglycerides, leptin, osteocalcin, ghrelin and agouti-related protein (AgRP). VFI was higher (20% higher than that of controls) in sows that received dietary OFI during lactation (p < .05). The concentration of plasma glucose was lower in sows that consumed OFI than sows fed the conventional diet (p < .05). Plasma insulin concentrations were higher in sows that consumed OFI, than in sows that did not (p < .05). Triglyceride concentrations during gestation, farrowing and lactation were also lower in sows that consumed OFI (p < .05). OFI intake caused lower plasma concentrations of leptin during lactation (p < .05). Osteocalcin was higher in sows that consumed OFI versus controls (p < .05): 8.6% and 13.4% during gestation and lactation respectively. From day 3 of lactation, sows that consumed OFI had higher concentrations of ghrelin (p < .05). The concentration of plasma AgRP was higher (p < .05) in sows that consumed OFI versus controls: 3.1% and 14.2% in gestation and lactation respectively. We concluded that OFI intake by primiparous sows during late gestation and lactation favourably modulated the factors that caused insulin resistance and increased sow performance.
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Affiliation(s)
- Gerardo Ordaz
- Centro Nacional de Investigación Disciplinaria en Fisiología y Mejoramiento Animal, Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias, Querétaro, Mexico
| | - Aureliano Juárez
- Instituto de Investigaciones Agropecuarias y Forestales, Universidad Michoacana de San Nicolás de Hidalgo, Michoacán, Mexico
| | - Rosa E Pérez
- Facultad de Químico Farmacobiología, Universidad Michoacana de San Nicolás de Hidalgo, Michoacán, Mexico
| | - Héctor E Martínez
- Facultad de Químico Farmacobiología, Universidad Michoacana de San Nicolás de Hidalgo, Michoacán, Mexico
| | - Ruy Ortiz
- Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Michoacán, México
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40
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Ducy P. Bone Regulation of Insulin Secretion and Glucose Homeostasis. Endocrinology 2020; 161:5895464. [PMID: 32822470 DOI: 10.1210/endocr/bqaa149] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 08/18/2020] [Indexed: 12/31/2022]
Abstract
For centuries our image of the skeleton has been one of an inert structure playing a supporting role for muscles and a protective role for inner organs like the brain. Cell biology and physiology modified this view in the 20st century by defining the constant interplay between bone-forming and bone resorbing cells that take place during bone growth and remodeling, therefore demonstrating that bone is as alive as any other tissues in the body. During the past 40 years human and, most important, mouse genetics, have allowed not only the refinement of this notion by identifying the many genes and regulatory networks responsible for the crosstalk existing between bone cells, but have redefined the role of bone by showing that its influence goes way beyond its own physiology. Among its newly identified functions is the regulation of energy metabolism by 2 bone-derived hormones, osteocalcin and lipocalin-2. Their biology and respective roles in this process are the topic of this review.
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Affiliation(s)
- Patricia Ducy
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York
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41
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Matheis F, Muller PA, Graves CL, Gabanyi I, Kerner ZJ, Costa-Borges D, Ahrends T, Rosenstiel P, Mucida D. Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss. Cell 2020; 180:64-78.e16. [PMID: 31923400 DOI: 10.1016/j.cell.2019.12.002] [Citation(s) in RCA: 202] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 09/25/2019] [Accepted: 12/03/2019] [Indexed: 12/18/2022]
Abstract
Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via β2-adrenergic receptor (β2-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.
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Affiliation(s)
- Fanny Matheis
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Paul A Muller
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
| | - Christina L Graves
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Ilana Gabanyi
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Zachary J Kerner
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Diego Costa-Borges
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Tomasz Ahrends
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
| | - Daniel Mucida
- Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
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42
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Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SMY, Shamsi F, Assaad S, Lin ETY, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell 2020; 182:578-593.e19. [PMID: 32679029 DOI: 10.1016/j.cell.2020.06.031] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 04/06/2020] [Accepted: 06/18/2020] [Indexed: 02/08/2023]
Abstract
Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.
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Affiliation(s)
- Yulia Shwartz
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Meryem Gonzalez-Celeiro
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland
| | - Chih-Lung Chen
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 100, Taiwan
| | - H Amalia Pasolli
- Electron Microscopy Resource Center, The Rockefeller University, New York, NY 10065, USA
| | - Shu-Hsien Sheu
- Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
| | - Sabrina Mai-Yi Fan
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 100, Taiwan
| | - Farnaz Shamsi
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Steven Assaad
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Edrick Tai-Yu Lin
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 100, Taiwan
| | - Bing Zhang
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Pai-Chi Tsai
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Megan He
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
| | - Yu-Hua Tseng
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
| | - Sung-Jan Lin
- Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 100, Taiwan; Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
| | - Ya-Chieh Hsu
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
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43
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Zhang B, Ma S, Rachmin I, He M, Baral P, Choi S, Gonçalves WA, Shwartz Y, Fast EM, Su Y, Zon LI, Regev A, Buenrostro JD, Cunha TM, Chiu IM, Fisher DE, Hsu YC. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature 2020; 577:676-681. [PMID: 31969699 PMCID: PMC7184936 DOI: 10.1038/s41586-020-1935-3] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 12/13/2019] [Indexed: 01/24/2023]
Abstract
Empirical and anecdotal evidence have associated stress with accelerated hair greying (formation of unpigmented hairs)1,2, but the scientific evidence linking the two is scant. Here, we report that acute stress leads to hair greying through fast depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics3,4, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of immune attack or adrenal stress hormones. Rather, hair greying results from activation of the sympathetic nerves that innervate the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which drives quiescent MeSCs into rapid proliferation, followed by differentiation, migration, and permanent depletion from the niche. Transient suppression of MeSC proliferation prevents stress-induced hair greying. Our studies demonstrate that acute stress-induced neuronal activity can drive rapid and permanent loss of somatic stem cells, and illustrate an example in which somatic stem cell maintenance is directly influenced by the overall physiological state of the organism.
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Affiliation(s)
- Bing Zhang
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Sai Ma
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA.,Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Inbal Rachmin
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | - Megan He
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA.,Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA
| | - Pankaj Baral
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - Sekyu Choi
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA
| | - William A Gonçalves
- Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Yulia Shwartz
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Eva M Fast
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA.,Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Yiqun Su
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | - Leonard I Zon
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA.,Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Biology and Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.,Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Jason D Buenrostro
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Thiago M Cunha
- Department of Immunology, Harvard Medical School, Boston, MA, USA.,Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA, USA
| | - David E Fisher
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | - Ya-Chieh Hsu
- Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Stem Cell Institute, Cambridge, MA, USA.
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44
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Stowell RD, Sipe GO, Dawes RP, Batchelor HN, Lordy KA, Whitelaw BS, Stoessel MB, Bidlack JM, Brown E, Sur M, Majewska AK. Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex. Nat Neurosci 2019; 22:1782-1792. [PMID: 31636451 PMCID: PMC6875777 DOI: 10.1038/s41593-019-0514-0] [Citation(s) in RCA: 213] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 09/12/2019] [Indexed: 12/28/2022]
Abstract
Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of β2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of β2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.
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Affiliation(s)
- Rianne D Stowell
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
- Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Grayson O Sipe
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ryan P Dawes
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
- Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Hanna N Batchelor
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
| | - Katheryn A Lordy
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
| | - Brendan S Whitelaw
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
- Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Mark B Stoessel
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
- Neuroscience Graduate Program, University of Rochester Medical Center, Rochester, NY, USA
| | - Jean M Bidlack
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, USA
| | - Edward Brown
- Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA
| | - Mriganka Sur
- Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ania K Majewska
- Department of Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.
- Center for Visual Science, University of Rochester Medical Center, Rochester, NY, USA.
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45
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Godinho-Silva C, Domingues RG, Rendas M, Raposo B, Ribeiro H, da Silva JA, Vieira A, Costa RM, Barbosa-Morais NL, Carvalho T, Veiga-Fernandes H. Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis. Nature 2019; 574:254-258. [PMID: 31534216 PMCID: PMC6788927 DOI: 10.1038/s41586-019-1579-3] [Citation(s) in RCA: 149] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 08/13/2019] [Indexed: 12/25/2022]
Abstract
Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence2,3. Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut 'postcode receptors' of ILC3s. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis.
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Affiliation(s)
| | - Rita G Domingues
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Miguel Rendas
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Bruno Raposo
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Hélder Ribeiro
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Joaquim Alves da Silva
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Champalimaud Clinical Centre, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Ana Vieira
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | - Rui M Costa
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA
| | - Nuno L Barbosa-Morais
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Tânia Carvalho
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
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Seidu S, Kunutsor SK, Khunti K. Association of circulating osteocalcin with cardiovascular disease and intermediate cardiovascular phenotypes: systematic review and meta-analysis. SCAND CARDIOVASC J 2019; 53:286-295. [DOI: 10.1080/14017431.2019.1655166] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Samuel Seidu
- Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
| | - Setor K Kunutsor
- National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK
- Translational Health Sciences, Bristol Medical School, Musculoskeletal Research Unit, University of Bristol, Learning & Research Building (Level 1), Southmead Hospital, Bristol, UK
| | - Kamlesh Khunti
- Leicester Diabetes Centre, Leicester General Hospital, Leicester, UK
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Leicester, UK
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Cameron RB, Gibbs WS, Miller SR, Dupre TV, Megyesi J, Beeson CC, Schnellmann RG. Proximal Tubule β 2-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury. J Pharmacol Exp Ther 2019; 369:173-180. [PMID: 30709866 PMCID: PMC11046739 DOI: 10.1124/jpet.118.252833] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 01/04/2019] [Indexed: 04/28/2024] Open
Abstract
Acute kidney injury (AKI) is the rapid loss of renal function after an insult, and renal proximal tubule cells (RPTCs) are central to the pathogenesis of AKI. The β 2-adrenergic receptor (β 2AR) agonist formoterol accelerates the recovery of renal function in mice after ischemia-reperfusion injury (IRI) with associated rescue of mitochondrial proteins; however, the cell type responsible for this recovery remains unknown. The role of RPTCs in formoterol-induced recovery of renal function was assessed in a proximal tubule-specific knockout of the β 2AR (γGT-Cre:ADRB2Flox/Flox). These mice and wild-type controls (ADRB2Flox/Flox) were subjected to renal IRI, followed by once-daily dosing of formoterol beginning 24 hours post-IRI and euthanized at 144 hours. Compared with ADRB2Flox/Flox mice, γGT-Cre:ADRB2Flox/Flox mice had decreased renal cortical mRNA expression of the β 2AR. After IRI, formoterol treatment restored renal function in ADRB2Flox/Flox but not γGT-Cre:ADRB2Flox/Flox mice as measured by serum creatinine, histopathology, and expression of kidney injury marker-1 (KIM-1). Formoterol-treated ADRB2Flox/Flox mice exhibited recovery of mitochondrial proteins and DNA copy number, whereas γGT-Cre:ADRB2Flox/Flox mice treated with formoterol did not. Analysis of mitochondrial morphology by transmission electron microscopy demonstrated that formoterol increased mitochondrial number and density in ADRB2Flox/Flox mice but not in γGT-Cre:ADRB2Flox/Flox mice. These data demonstrate that proximal tubule β 2AR regulates renal mitochondrial homeostasis. Formoterol accelerates the recovery of renal function after AKI by activating proximal tubule β 2AR to induce mitochondrial biogenesis and demonstrates the overall requirement of RPTCs in renal recovery.
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Affiliation(s)
- Robert B Cameron
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
| | - Whitney S Gibbs
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
| | - Siennah R Miller
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
| | - Tess V Dupre
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
| | - Judit Megyesi
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
| | - Craig C Beeson
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
| | - Rick G Schnellmann
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (R.B.C., W.S.G., C.C.B.); College of Pharmacy, University of Arizona (R.B.C., W.S.G., S.R.M., T.V.D., R.G.S.), and Southern Arizona VA Healthcare System (R.G.S.), Tuscon, Arizona; and Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.M.)
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Liu Y, Liu X, R Lewis J, Brock K, C Brennan-Speranza T, Teixeira-Pinto A. Relationship between serum osteocalcin/undercarboxylated osteocalcin and type 2 diabetes: a systematic review/meta-analysis study protocol. BMJ Open 2019; 9:e023918. [PMID: 30862632 PMCID: PMC6429918 DOI: 10.1136/bmjopen-2018-023918] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION The global burden of type 2 diabetes (T2DM) is steadily increasing. Experimental studies have demonstrated that a novel hormone secreted by bone cells, osteocalcin (OC), can stimulate beta-cell proliferation and improve insulin sensitivity in mice. Observational studies in humans have investigated the relationship between OC and metabolic parameters, and T2DM. Importantly, few studies have reported on the undercarboxylated form of OC (ucOC), which is the putative active form of OC suggested to affect glucose metabolism. OBJECTIVES We will conduct a systematic review and meta-analysis to: (1) compare the levels of serum OC and ucOC between T2DM and normal glucose-tolerant controls (NGC); (2) investigate the risk ratios between serum OC and ucOC, and T2DM; (3) determine the correlation coefficient between OC and ucOC and fasting insulin levels, homeostatic model assessment-insulin resistance, haemoglobin A1c and fasting glucose levels and (4) explore potential sources of between-study heterogeneity. The secondary objective is to compare the serum OC and ucOC between pre-diabetes (PD) and NGC and between T2DM and PD. HODS AND ANALYSIS This study will report items in line with the guidelines outlined in preferred reporting items for systematic reviews and meta-analysis of observational studies in epidemiology. We will include observational studies (cohort, case-control and cross-sectional studies) and intervention studies with baseline data. Three databases (MEDLINE, EMBASE and SCOPUS) will be searched from inception until July 2018 without language restrictions. Two reviewers will independently screen the titles and abstracts and conduct a full-text assessment to identify eligible studies. Discrepancies will be resolved by consensus with a third reviewer. The risk of bias assessment will be conducted by two reviewers independently based on the Newcastle-Ottawa Scale. Potential sources of between-study heterogeneity will be tested using meta-regression/subgroup analyses. Contour-enhanced funnel plots and Egger's test will be used to identify potential publication bias. ETHICS AND DISSEMINATION Formal ethical approval is not required. We will disseminate the results to a peer-reviewed publication and conference presentation. PROSPERO REGISTRATION NUMBER CRD42017073127.
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Affiliation(s)
- Yihui Liu
- Centre for Kidney Research, Children's Hospital, Westmead, New South Wales, Australia
- School Public Health, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Xiaoying Liu
- School Public Health, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Joshua R Lewis
- Centre for Kidney Research, Children's Hospital, Westmead, New South Wales, Australia
- School of Medicine, Faculty of Medicine and Health, The University of Western Australia, Perth, Western Australia, Australia
| | - Kaye Brock
- School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia
| | | | - Armando Teixeira-Pinto
- Centre for Kidney Research, Children's Hospital, Westmead, New South Wales, Australia
- School Public Health, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
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49
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Wędrychowicz A, Sztefko K, Starzyk JB. Sclerostin and its association with insulin resistance in children and adolescents. Bone 2019; 120:232-238. [PMID: 30055341 DOI: 10.1016/j.bone.2018.07.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 07/06/2018] [Accepted: 07/24/2018] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Recent studies have shown that sclerostin, which is mainly known as a negative regulator of bone formation, could play an important role in the crosstalk between bone and glucose metabolism. The aim of this study was to investigate the relationship between sclerostin, other bone and fat related factors as osteocalcin (OC), Receptor Activator of Nuclear Factor NF-қB ligand (RANKL), leptin and adiponectin with glucose metabolism and insulin action in children and adolescents with obesity compared with healthy children and adolescents. METHODS Fifty-five obese children and adolescents, a mean age of 13.2 ± 3.4 yrs., BMI 28.89 ± 5.5 kg/m2, and 26 healthy controls (mean age 13.0 ± 4.3 yrs., BMI 19.96 ± 3.1 kg/m2), sex-, and Tanner stage-matched were included into the study. Fasting blood samples for measurement of sclerostin, glucose, lipid profile, HbA1c, C-peptide, OC, RANKL, leptin and adiponectin, and vitamin D were taken at 8.00 AM. RESULTS Sclerostin, osteocalcin, RANKL, and adiponectin levels did not differ between obese patients and the control group. Leptin and fasting insulin levels were significantly higher in obese subjects compared with controls (p < 0.01, p = 0.01, respectively). A positive correlation between sclerostin and OC (r = 0.417, p = 0.027) and negative correlations between sclerostin and HOMA-IR and between sclerostin and age (r = -0.24, p = 0.045, r = -0.23, p = 0.037, respectively) were found in all of the subjects. Sclerostin did not correlate with HbA1c, lipids, RANKL and fat-derived leptin and adiponectin. Partial correlation analysis adjusted for age, SDS-BMI and Tanner staging only revealed a negative correlation between sclerostin and HOMA-IR (r = -0.3, p = 0.01). In obese patients this correlation was stronger than in the whole group (r = -0.39, p = 0.005). Moreover, a negative correlation between sclerostin and insulin was found in obese patients (r = -0.39, p = 0.006). In the healthy cohort, sclerostin had a negative correlation only with C-peptide (r = -0.79, p = 0.02). CONCLUSIONS Sclerostin could play an important role in the regulation of glucose metabolism in children and adolescents, regardless of other fat and bone-derived factors. In obese young patients it's action could be associated with decreasing insulin resistance.
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Affiliation(s)
- Anna Wędrychowicz
- Department of Pediatric and Adolescent Endocrinology, Pediatric Institute, Medical College, Jagiellonian University in Krakow, Poland.
| | - Krystyna Sztefko
- Department of Clinical Biochemistry, Pediatric Institute, Medical College, Jagiellonian University in Krakow, Poland
| | - Jerzy B Starzyk
- Department of Pediatric and Adolescent Endocrinology, Pediatric Institute, Medical College, Jagiellonian University in Krakow, Poland
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50
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Hoffman BU, Baba Y, Griffith TN, Mosharov EV, Woo SH, Roybal DD, Karsenty G, Patapoutian A, Sulzer D, Lumpkin EA. Merkel Cells Activate Sensory Neural Pathways through Adrenergic Synapses. Neuron 2018; 100:1401-1413.e6. [PMID: 30415995 DOI: 10.1016/j.neuron.2018.10.034] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 09/21/2018] [Accepted: 10/22/2018] [Indexed: 01/06/2023]
Abstract
Epithelial-neuronal signaling is essential for sensory encoding in touch, itch, and nociception; however, little is known about the release mechanisms and neurotransmitter receptors through which skin cells govern neuronal excitability. Merkel cells are mechanosensory epidermal cells that have long been proposed to activate neuronal afferents through chemical synaptic transmission. We employed a set of classical criteria for chemical neurotransmission as a framework to test this hypothesis. RNA sequencing of adult mouse Merkel cells demonstrated that they express presynaptic molecules and biosynthetic machinery for adrenergic transmission. Moreover, live-cell imaging directly demonstrated that Merkel cells mediate activity- and VMAT-dependent release of fluorescent catecholamine neurotransmitter analogs. Touch-evoked firing in Merkel-cell afferents was inhibited either by pre-synaptic silencing of SNARE-mediated vesicle release from Merkel cells or by neuronal deletion of β2-adrenergic receptors. Together, these results identify both pre- and postsynaptic mechanisms through which Merkel cells excite mechanosensory afferents to encode gentle touch. VIDEO ABSTRACT.
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Affiliation(s)
- Benjamin U Hoffman
- Department of Physiology & Cellular Biophysics, Columbia University, New York, NY, USA; Program in Neurobiology & Behavior, Columbia University, New York, NY, USA
| | - Yoshichika Baba
- Department of Physiology & Cellular Biophysics, Columbia University, New York, NY, USA
| | - Theanne N Griffith
- Department of Physiology & Cellular Biophysics, Columbia University, New York, NY, USA
| | - Eugene V Mosharov
- Departments of Psychiatry, Neurology, and Pharmacology, Columbia University: Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Seung-Hyun Woo
- The Scripps Research Institute & Howard Hughes Medical Institute, La Jolla, CA, USA
| | - Daniel D Roybal
- Pharmacology Graduate Program, Columbia University, New York, NY, USA
| | - Gerard Karsenty
- Department of Genetics and Development, Columbia University, New York, NY, USA
| | - Ardem Patapoutian
- The Scripps Research Institute & Howard Hughes Medical Institute, La Jolla, CA, USA
| | - David Sulzer
- Departments of Psychiatry, Neurology, and Pharmacology, Columbia University: Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Ellen A Lumpkin
- Department of Physiology & Cellular Biophysics, Columbia University, New York, NY, USA; Program in Neurobiology & Behavior, Columbia University, New York, NY, USA; Department of Dermatology, Columbia University, New York, NY, USA.
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