|
1
|
Shi X, Jiang A, Qiu Z, Lin A, Liu Z, Zhu L, Mou W, Cheng Q, Zhang J, Miao K, Luo P. Novel perspectives on the link between obesity and cancer risk: from mechanisms to clinical implications. Front Med 2024; 18:945-968. [PMID: 39542988 DOI: 10.1007/s11684-024-1094-2] [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: 11/21/2023] [Accepted: 06/07/2024] [Indexed: 11/17/2024]
Abstract
Existing epidemiologic and clinical studies have demonstrated that obesity is associated with the risk of a variety of cancers. In recent years, an increasing number of experimental and clinical studies have unraveled the complex relationship between obesity and cancer risk and the underlying mechanisms. Obesity-induced abnormalities in immunity and biochemical metabolism, including chronic inflammation, hormonal disorders, dysregulation of adipokines, and microbial dysbiosis, may be important contributors to cancer development and progression. These contributors play different roles in cancer development and progression at different sites. Lifestyle changes, weight loss medications, and bariatric surgery are key approaches for weight-centered, obesity-related cancer prevention. Treatment of obesity-related inflammation and hormonal or metabolic dysregulation with medications has also shown promise in preventing obesity-related cancers. In this review, we summarize the mechanisms through which obesity affects the risk of cancer at different sites and explore intervention strategies for the prevention of obesity-associated cancers, concluding with unresolved questions and future directions regarding the link between obesity and cancer. The aim is to provide valuable theoretical foundations and insights for the in-depth exploration of the complex relationship between obesity and cancer risk and its clinical applications.
Collapse
Affiliation(s)
- Xiaoye Shi
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Aimin Jiang
- Department of Urology, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, 200433, China
| | - Zhengang Qiu
- Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Zaoqu Liu
- Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, 100730, China
| | - Lingxuan Zhu
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Weiming Mou
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| | - Kai Miao
- Cancer Centre, Faculty of Health Sciences, University of Macau, Macao SAR, 999078, China.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao SAR, 999078, China.
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| |
Collapse
|
|
2
|
Engin A. Reappraisal of Adipose Tissue Inflammation in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:297-327. [PMID: 39287856 DOI: 10.1007/978-3-031-63657-8_10] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKβ)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
Collapse
Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
| |
Collapse
|
|
3
|
Rogal J, Roosz J, Teufel C, Cipriano M, Xu R, Eisler W, Weiss M, Schenke‐Layland K, Loskill P. Autologous Human Immunocompetent White Adipose Tissue-on-Chip. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2104451. [PMID: 35466539 PMCID: PMC9218765 DOI: 10.1002/advs.202104451] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 03/03/2022] [Indexed: 05/07/2023]
Abstract
Obesity and associated diseases, such as diabetes, have reached epidemic proportions globally. In this era of "diabesity", white adipose tissue (WAT) has become a target of high interest for therapeutic strategies. To gain insights into mechanisms of adipose (patho-)physiology, researchers traditionally relied on animal models. Leveraging Organ-on-Chip technology, a microphysiological in vitro model of human WAT is introduced: a tailored microfluidic platform featuring vasculature-like perfusion that integrates 3D tissues comprising all major WAT-associated cellular components (mature adipocytes, organotypic endothelial barriers, stromovascular cells including adipose tissue macrophages) in an autologous manner and recapitulates pivotal WAT functions, such as energy storage and mobilization as well as endocrine and immunomodulatory activities. A precisely controllable bottom-up approach enables the generation of a multitude of replicates per donor circumventing inter-donor variability issues and paving the way for personalized medicine. Moreover, it allows to adjust the model's degree of complexity via a flexible mix-and-match approach. This WAT-on-Chip system constitutes the first human-based, autologous, and immunocompetent in vitro adipose tissue model that recapitulates almost full tissue heterogeneity and can become a powerful tool for human-relevant research in the field of metabolism and its associated diseases as well as for compound testing and personalized- and precision medicine applications.
Collapse
Affiliation(s)
- Julia Rogal
- Department for Microphysiological Systems, Institute of Biomedical EngineeringEberhard Karls University TübingenÖsterbergstr. 3Tübingen72074Germany
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGBNobelstr. 12Stuttgart70569Germany
| | - Julia Roosz
- NMI Natural and Medical Sciences Institute at the University of TübingenMarkwiesenstr. 55Reutlingen72770Germany
| | - Claudia Teufel
- Department for Microphysiological Systems, Institute of Biomedical EngineeringEberhard Karls University TübingenÖsterbergstr. 3Tübingen72074Germany
| | - Madalena Cipriano
- Department for Microphysiological Systems, Institute of Biomedical EngineeringEberhard Karls University TübingenÖsterbergstr. 3Tübingen72074Germany
- 3R‐Center for In vitro Models and Alternatives to Animal TestingEberhard Karls University TübingenÖsterbergstr. 3Tübingen72074Germany
| | - Raylin Xu
- Fraunhofer Institute for Interfacial Engineering and Biotechnology IGBNobelstr. 12Stuttgart70569Germany
- Harvard Medical School (HMS)25 Shattuck StBostonMA02115USA
| | - Wiebke Eisler
- Clinic for PlasticReconstructiveHand and Burn SurgeryBG Trauma CenterEberhard Karls University TübingenSchnarrenbergstraße 95Tübingen72076Germany
| | - Martin Weiss
- NMI Natural and Medical Sciences Institute at the University of TübingenMarkwiesenstr. 55Reutlingen72770Germany
- Department of Women's HealthEberhard Karls University TübingenCalwerstrasse 7Tübingen72076Germany
| | - Katja Schenke‐Layland
- NMI Natural and Medical Sciences Institute at the University of TübingenMarkwiesenstr. 55Reutlingen72770Germany
- Department of Medicine/CardiologyCardiovascular Research LaboratoriesDavid Geffen School of Medicine at UCLA675 Charles E. Young Drive South, MRL 3645Los AngelesCA90095USA
- Cluster of Excellence iFIT (EXC2180) “Image‐Guided and Functionally Instructed Tumor Therapies”Eberhard Karls University TuebingenRöntgenweg 11Tuebingen72076Germany
- Department for Medical Technologies and Regenerative MedicineInstitute of Biomedical EngineeringEberhard Karls University TübingenSilcherstr. 7/1Tübingen72076Germany
| | - Peter Loskill
- Department for Microphysiological Systems, Institute of Biomedical EngineeringEberhard Karls University TübingenÖsterbergstr. 3Tübingen72074Germany
- NMI Natural and Medical Sciences Institute at the University of TübingenMarkwiesenstr. 55Reutlingen72770Germany
- 3R‐Center for In vitro Models and Alternatives to Animal TestingEberhard Karls University TübingenÖsterbergstr. 3Tübingen72074Germany
| |
Collapse
|
|
4
|
Wang N, Liu BW, Ma CM, Yan Y, Su QW, Yin FZ. Influence of overweight and obesity on the mortality of hospitalized patients with community-acquired pneumonia. World J Clin Cases 2022; 10:104-116. [PMID: 35071510 PMCID: PMC8727241 DOI: 10.12998/wjcc.v10.i1.104] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/28/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity is associated with a better prognosis in patients with community-acquired pneumonia (the so-called obesity survival paradox), but conflicting results have been found.
AIM To investigate the relationship between all-cause mortality and body mass index in patients with community-acquired pneumonia.
METHODS This retrospective study included patients with community-acquired pneumonia hospitalized in the First Hospital of Qinhuangdao from June 2013 to November 2018. The patients were grouped as underweight (< 18.5 kg/m2), normal weight (18.5-23.9 kg/m2), and overweight/obesity (≥ 24 kg/m2). The primary outcome was all-cause hospital mortality.
RESULTS Among 2327 patients, 297 (12.8%) were underweight, 1013 (43.5%) normal weight, and 1017 (43.7%) overweight/obesity. The all-cause hospital mortality was 4.6% (106/2327). Mortality was lowest in the overweight/obesity group and highest in the underweight group (2.8%, vs 5.0%, vs 9.1%, P < 0.001). All-cause mortality of overweight/obesity patients was lower than normal-weight patients [odds ratio (OR) = 0.535, 95% confidence interval (CI) = 0.334-0.855, P = 0.009], while the all-cause mortality of underweight patients was higher than that of normal-weight patients (OR = 1.886, 95%CI: 1.161-3.066, P = 0.010). Multivariable analysis showed that abnormal neutrophil counts (OR = 2.38, 95%CI: 1.55-3.65, P < 0.001), abnormal albumin levels (OR = 0.20, 95%CI: 0.06-0.72, P = 0.014), high-risk Confusion-Urea-Respiration-Blood pressure-65 score (OR = 2.89, 95%CI: 1.48-5.64, P = 0.002), and intensive care unit admission (OR = 3.11, 95%CI: 1.77-5.49, P < 0.001) were independently associated with mortality.
CONCLUSION All-cause mortality of normal-weight patients was higher than overweight/ obesity patients, lower than that of underweight patients. Neutrophil counts, albumin levels, Confusion-Urea-Respiration-Blood pressure-65 score, and intensive care unit admission were independently associated with mortality in patients with community-acquired pneumonia.
Collapse
Affiliation(s)
- Ning Wang
- Department of Endocrinology, Hebei Medical University, Shijiazhuang 050017, Hebei Province, China
| | - Bo-Wei Liu
- Department of Endocrinology, First Hospital of Qinhuangdao, Qinhuangdao 066001, Hebei Province, China
| | - Chun-Ming Ma
- Department of Endocrinology, First Hospital of Qinhuangdao, Qinhuangdao 066001, Hebei Province, China
| | - Ying Yan
- Department of Endocrinology, Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Quan-Wei Su
- Department of Endocrinology, Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Fu-Zai Yin
- Department of Endocrinology, First Hospital of Qinhuangdao, Qinhuangdao 066001, Hebei Province, China
| |
Collapse
|
|
5
|
Baldwin A, Hartl M, Tschaikowsky M, Balzer BN, Booth BW. Degradation and release of tannic acid from an injectable tissue regeneration bead matrix in vivo. J Biomed Mater Res B Appl Biomater 2021; 110:1165-1177. [PMID: 34904786 DOI: 10.1002/jbm.b.34990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/03/2021] [Accepted: 11/27/2021] [Indexed: 12/26/2022]
Abstract
The development of multifunctional biomaterials as both tissue regeneration and drug delivery devices is currently a major focus in biomedical research. Tannic Acid (TA), a naturally occurring plant polyphenol, displays unique medicinal abilities as an antioxidant, an antibiotic, and as an anticancer agent. TA has applications in biomaterials acting as a crosslinker in polymer hydrogels improving thermal stability and mechanical properties. We have developed injectable cell seeded collagen beads crosslinked with TA for breast reconstruction and anticancer activity following lumpectomy. This study determined the longevity of the bead implants by establishing a degradation time line and TA release profile in vivo. Beads crosslinked with 0.1% TA and 1% TA were compared to observe the differences in TA concentration on degradation and release. We found collagen/TA beads degrade at similar rates in vivo, yet are resistant to complete degradation after 16 weeks. TA is released over time in vivo through diffusion and cellular activity. Changes in mechanical properties in collagen/TA beads before implantation to after 8 weeks in vivo also indicate loss of TA over a longer period of time. Elastic moduli decreased uniformly in both 0.1% and 1% TA beads. This study establishes that collagen/TA materials can act as a drug delivery system, rapidly releasing TA within the first week following implantation. However, the beads retain TA long term allowing them to resist degradation and remain in situ acting as a cell scaffold and tissue filler. This confirms its potential use as an anticancer and minimally invasive breast reconstructive device following lumpectomy.
Collapse
Affiliation(s)
- Andrew Baldwin
- Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | | | - Mathaeus Tschaikowsky
- Institue of Physical Chemistry, University of Freiburg, Freiburg, Germany.,G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bizan N Balzer
- Institue of Physical Chemistry, University of Freiburg, Freiburg, Germany.,Cluster of Excellence livMatS @ FIT - Freiburg Center for Interactive Materials and Bioinspired Technologies, Freiburg, Germany.,Freiburg Materials Research Center (FMF), Albert Ludwig University of Freiburg, Freiburg, Germany
| | - Brian W Booth
- Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| |
Collapse
|
|
6
|
Remodeling of Macrophages in White Adipose Tissue under the Conditions of Obesity as well as Lipolysis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9980877. [PMID: 34504646 PMCID: PMC8423577 DOI: 10.1155/2021/9980877] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/23/2021] [Accepted: 08/06/2021] [Indexed: 11/20/2022]
Abstract
Adipose tissue macrophages (ATM) are a major source of low-grade inflammation in obesity, and yet reasons driving ATM accumulation in white adipose tissue (WAT) are not fully understood. Emerging evidence suggested that ATM underwent extensive remodeling in obesity. In addition to abundance, ATM in obesity were lipid-laden and metabolically reprogrammed, which in turn was tightly related to their functional alterations and persistence in obesity. Herein, we aimed to discuss that activation of lipid sensing signaling associated with metabolic reprogramming in ATM was indispensible for their migration, retention, or proliferation in obesity. Likewise, lipolysis also induced similar but transient ATM remodeling. Therefore, we assumed that obesity might share overlapping mechanisms with lipolysis in remodeling ATM. Formation of crown-like structures (CLS) in WAT was presumably a common event initiating ATM remodeling, with a spectrum of lipid metabolites released from adipocytes being potential signaling molecules. Moreover, adipose interlerkin-6 (IL-6) exhibited homologous alterations by obesity and lipolysis. Thus, we postulated a positive feedback loop between ATM and adipocytes via IL-6 signaling backing ATM persistence by comparison of ATM remodeling under obesity and lipolysis. An elucidation of ATM persistence could help to provide novel therapeutic targets for obesity-associated inflammation.
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
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: 15] [Impact Index Per Article: 3.8] [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.
Collapse
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
Collapse
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.
| |
Collapse
|
|
9
|
Morigny P, Boucher J, Arner P, Langin D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat Rev Endocrinol 2021; 17:276-295. [PMID: 33627836 DOI: 10.1038/s41574-021-00471-8] [Citation(s) in RCA: 290] [Impact Index Per Article: 72.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2021] [Indexed: 12/14/2022]
Abstract
In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.
Collapse
Affiliation(s)
- Pauline Morigny
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Toulouse, France
- University of Toulouse, Paul Sabatier University, I2MC, UMR1297, Toulouse, France
- Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- The Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Peter Arner
- Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden
| | - Dominique Langin
- Institute of Metabolic and Cardiovascular Diseases (I2MC), Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, Toulouse, France.
- University of Toulouse, Paul Sabatier University, I2MC, UMR1297, Toulouse, France.
- Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France.
- Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France.
| |
Collapse
|
|
10
|
Lou HX, Fu WC, Chen JX, Li TT, Jiang YY, Liu CH, Zhang W. Alisol A 24-acetate stimulates lipolysis in 3 T3-L1 adipocytes. BMC Complement Med Ther 2021; 21:128. [PMID: 33888116 PMCID: PMC8063434 DOI: 10.1186/s12906-021-03296-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 04/02/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Alisol A 24-acetate (AA-24-a), one of the main active triterpenes isolated from the well-known medicinal plant Alisma orientale (Sam.) Juz., exhibits multiple biological activities including hypolipidemic activity. However, its effect on lipid metabolism in adipocytes remains unclear. The present study aimed to clarify the effect of AA-24-a on adipocyte lipolysis and to determine its potential mechanism of action using 3 T3-L1 cells. METHODS We assayed the release of glycerol into culture medium of 3 T3-L1 cells under treatment with AA-24-a. Protein and mRNA expression and phosphorylation levels of the main lipases and kinases involved in lipolysis regulation were determined by quantitative polymerase chain reaction and western blotting. Specific inhibitors of protein kinase A (PKA; H89) and extracellular signal-regulated kinase (ERK; PD98059), which are key enzymes in relevant signaling pathways, were used to examine their roles in AA-24-a-stimulated lipolysis. RESULTS AA-24-a significantly stimulated neutral lipolysis in fully differentiated adipocytes. To determine the underlying mechanism, we assessed the changes in mRNA and protein levels of key lipolysis-related genes in the presence or absence of H89 and PD98059. Both inhibitors reduced AA-24-a-induced lipolysis. Moreover, pretreatment with H89 attenuated AA-24-a-induced phosphorylation of hormone-sensitive lipase at Ser660, while pretreatment with PD98059 attenuated AA-24-a-induced downregulation of peroxisome proliferator-activated receptor-γ and perilipin A. CONCLUSIONS Our results indicate that AA-24-a promoted neutral lipolysis in 3 T3-L1 adipocytes by activating PKA-mediated phosphorylation of hormone-sensitive lipase and ERK- mediated downregulation of expression of perilipin A.
Collapse
Affiliation(s)
- Hai-Xia Lou
- School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
| | - Wen-Cheng Fu
- School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
| | - Jia-Xiang Chen
- School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
| | - Tian-Tian Li
- School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
| | - Ying-Ying Jiang
- School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
| | - Chun-Hui Liu
- China National Institute of Standardization, 4 Zhichun Road, Beijing, 100191, China.
| | - Wen Zhang
- School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
| |
Collapse
|
|
11
|
Henkel J, Klauder J, Statz M, Wohlenberg AS, Kuipers S, Vahrenbrink M, Püschel GP. Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E 2. Biomedicines 2021; 9:biomedicines9050449. [PMID: 33919366 PMCID: PMC8143371 DOI: 10.3390/biomedicines9050449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/10/2021] [Accepted: 04/18/2021] [Indexed: 02/07/2023] Open
Abstract
Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E2 (PGE2) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE2 to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE2 synthesis. PGE2 in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE2 in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.
Collapse
Affiliation(s)
- Janin Henkel
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
- Department of Nutritional Biochemistry, Faculty of Life Sciences: Food, Nutrition and Health, University of Bayreuth, D-95326 Kulmbach, Germany
- Correspondence: ; Tel.: +49-33200-885285
| | - Julia Klauder
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
| | - Meike Statz
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
| | - Anne-Sophie Wohlenberg
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
| | - Sonja Kuipers
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
| | - Madita Vahrenbrink
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
| | - Gerhard Paul Püschel
- Department of Nutritional Biochemistry, Institute of Nutritional Science, University of Potsdam, D-14558 Nuthetal, Germany; (J.K.); (M.S.); (A.-S.W.); (S.K.); (M.V.); (G.P.P.)
| |
Collapse
|
|
12
|
Recazens E, Mouisel E, Langin D. Hormone-sensitive lipase: sixty years later. Prog Lipid Res 2020; 82:101084. [PMID: 33387571 DOI: 10.1016/j.plipres.2020.101084] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/12/2020] [Accepted: 12/24/2020] [Indexed: 12/19/2022]
Abstract
Hormone-sensitive lipase (HSL) was initially characterized as the hormonally regulated neutral lipase activity responsible for the breakdown of triacylglycerols into fatty acids in adipose tissue. This review aims at providing up-to-date information on structural properties, regulation of expression, activity and function as well as therapeutic potential. The lipase is expressed as different isoforms produced from tissue-specific alternative promoters. All isoforms are composed of an N-terminal domain and a C-terminal catalytic domain within which a regulatory domain containing the phosphorylation sites is embedded. Some isoforms possess additional N-terminal regions. The catalytic domain shares similarities with bacteria, fungus and vascular plant proteins but not with other mammalian lipases. HSL singularity is provided by regulatory and N-terminal domains sharing no homology with other proteins. HSL has a broad substrate specificity compared to other neutral lipases. It hydrolyzes acylglycerols, cholesteryl and retinyl esters among other substrates. A novel role of HSL, independent of its enzymatic function, has recently been described in adipocytes. Clinical studies revealed dysregulations of HSL expression and activity in disorders, such as lipodystrophy, obesity, type 2 diabetes and cancer-associated cachexia. Development of specific inhibitors positions HSL as a pharmacological target for the treatment of metabolic complications.
Collapse
Affiliation(s)
- Emeline Recazens
- Institute of Metabolic and Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, 31432 Toulouse, France; University of Toulouse, Paul Sabatier University, UMR1297, Toulouse, France
| | - Etienne Mouisel
- Institute of Metabolic and Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, 31432 Toulouse, France; University of Toulouse, Paul Sabatier University, UMR1297, Toulouse, France
| | - Dominique Langin
- Institute of Metabolic and Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1297, 31432 Toulouse, France; University of Toulouse, Paul Sabatier University, UMR1297, Toulouse, France; Franco-Czech Laboratory for Clinical Research on Obesity, Third Faculty of Medicine, Prague and Paul Sabatier University, Toulouse, France; Toulouse University Hospitals, Laboratory of Clinical Biochemistry, Toulouse, France.
| |
Collapse
|
|
13
|
Puchałowicz K, Rać ME. The Multifunctionality of CD36 in Diabetes Mellitus and Its Complications-Update in Pathogenesis, Treatment and Monitoring. Cells 2020; 9:cells9081877. [PMID: 32796572 PMCID: PMC7465275 DOI: 10.3390/cells9081877] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/04/2020] [Accepted: 08/09/2020] [Indexed: 02/08/2023] Open
Abstract
CD36 is a multiligand receptor contributing to glucose and lipid metabolism, immune response, inflammation, thrombosis, and fibrosis. A wide range of tissue expression includes cells sensitive to metabolic abnormalities associated with metabolic syndrome and diabetes mellitus (DM), such as monocytes and macrophages, epithelial cells, adipocytes, hepatocytes, skeletal and cardiac myocytes, pancreatic β-cells, kidney glomeruli and tubules cells, pericytes and pigment epithelium cells of the retina, and Schwann cells. These features make CD36 an important component of the pathogenesis of DM and its complications, but also a promising target in the treatment of these disorders. The detrimental effects of CD36 signaling are mediated by the uptake of fatty acids and modified lipoproteins, deposition of lipids and their lipotoxicity, alterations in insulin response and the utilization of energy substrates, oxidative stress, inflammation, apoptosis, and fibrosis leading to the progressive, often irreversible organ dysfunction. This review summarizes the extensive knowledge of the contribution of CD36 to DM and its complications, including nephropathy, retinopathy, peripheral neuropathy, and cardiomyopathy.
Collapse
|
|
14
|
Evaluation of Fat Accumulation and Adipokine Production during the Long-Term Adipogenic Differentiation of Porcine Intramuscular Preadipocytes and Study of the Influence of Immunobiotics. Cells 2020; 9:cells9071715. [PMID: 32708964 PMCID: PMC7408200 DOI: 10.3390/cells9071715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022] Open
Abstract
The degree of fat accumulation and adipokine production are two major indicators of obesity that are correlated with increased adipose tissue mass and chronic inflammatory responses. Adipocytes have been considered effector cells for the inflammatory responses due to their capacity to express Toll-like receptors (TLRs). In this study, we evaluated the degree of fat accumulation and adipokine production in porcine intramuscular preadipocyte (PIP) cells maintained for in vitro differentiation over a long period without or with stimulation of either TNF-α or TLR2-, TLR3-, or TLR4-ligands. The cytosolic fat accumulation was measured by liquid chromatography and the expression of adipokines (CCL2, IL-6, IL-8 and IL-10) were quantified by RT-qPCR and ELISA at several time points (0 to 20 days) of PIP cells differentiation. Long-term adipogenic differentiation (LTAD) induced a progressive fat accumulation in the adipocytes over time. Activation of TLR3 and TLR4 resulted in an increased rate of fat accumulation into the adipocytes over the LTAD. The production of CCL2, IL-8 and IL-6 were significantly increased in unstimulated adipocytes during the LTAD, while IL-10 expression remained stable over the studied period. An increasing trend of adiponectin and leptin production was also observed during the LTAD. On the other hand, the stimulation of adipocytes with TLRs agonists or TNF-α resulted in an increasing trend of CCL2, IL-6 and IL-8 production while IL-10 remained stable in all four treatments during the LTAD. We also examined the influences of several immunoregulatory probiotic strains (immunobiotics) on the modulation of the fat accumulation and adipokine production using supernatants of immunobiotic-treated intestinal immune cells and the LTAD of PIP cells. Immunobiotics have shown a strain-specific ability to modulate the fat accumulation and adipokine production, and differentiation of adipocytes. Here, we expanded the utility and potential application of our in vitro PIP cells model by evaluating an LTAD period (20 days) in order to elucidate further insights of chronic inflammatory pathobiology of adipocytes associated with obesity as well as to explore the prospects of immunomodulatory intervention for obesity such as immunobiotics.
Collapse
|
|
15
|
Kane H, Lynch L. Innate Immune Control of Adipose Tissue Homeostasis. Trends Immunol 2019; 40:857-872. [DOI: 10.1016/j.it.2019.07.006] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 12/19/2022]
|
|
16
|
Liu B, Hutchison AT, Thompson CH, Lange K, Heilbronn LK. Markers of adipose tissue inflammation are transiently elevated during intermittent fasting in women who are overweight or obese. Obes Res Clin Pract 2019; 13:408-415. [PMID: 31302012 DOI: 10.1016/j.orcp.2019.07.001] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 06/24/2019] [Accepted: 07/01/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE This study compared the effects of daily calorie restriction (DR) versus intermittent fasting (IF) on markers of inflammation and extracellular matrix deposition in adipose tissue and skeletal muscle in a controlled feeding trial in women with overweight or obesity. METHODS Women (N = 76) were randomised to one of three diets and provided with all foods at 100% (IF100) or 70% (IF70 and DR70) of calculated energy requirements for 8 weeks. IF groups ate breakfast prior to fasting for 24-h on 3 non-consecutive days/week. Weight, body composition, serum non-esterified fatty acids (NEFA), tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), M1- and M2-macrophage markers by qPCR and immunohistochemistry in adipose tissue and skeletal muscle were measured following a 12-h overnight fast (fed day, all groups) and a 24-h fast (IF groups only). RESULTS IF70 resulted in greater weight and fat losses and reductions in serum NEFA versus DR70 and IF100 (P < 0.05) after fed days. Markers of inflammation in serum (TNFα, IL6 and IL10), subcutaneous adipose tissue and skeletal muscle (CD68, CD40 and CD163) were unchanged by DR or IF after fed days. After fasting, NEFA, M1-macrophages (CD40+) in adipose tissue, and M2-macrophages (CD163+) in muscle were increased in IF70 and IF100 (all P < 0.05) and the changes in NEFA and mRNA of pan-macrophage marker CD68 in adipose tissue were positively correlated (r = 0.56, P = 0.002). CONCLUSIONS Unlike caloric restriction, IF transiently elevated markers of macrophage infiltration in adipose tissue and skeletal muscle, possibly in response to marked increases in adipose tissue lipolysis.
Collapse
Affiliation(s)
- Bo Liu
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia; Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia
| | - Amy T Hutchison
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia; Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia
| | - Campbell H Thompson
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia
| | - Kylie Lange
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia
| | - Leonie K Heilbronn
- Adelaide Medical School, University of Adelaide, Adelaide, South Australia 5000, Australia; Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.
| |
Collapse
|
|
17
|
Liu B, Page AJ, Hatzinikolas G, Chen M, Wittert GA, Heilbronn LK. Intermittent Fasting Improves Glucose Tolerance and Promotes Adipose Tissue Remodeling in Male Mice Fed a High-Fat Diet. Endocrinology 2019; 160:169-180. [PMID: 30476012 DOI: 10.1210/en.2018-00701] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023]
Abstract
Obesity is associated with increased macrophage and extracellular matrix accumulation in adipose tissue, which can be partially reversed following weight loss by daily caloric restriction. This study examined the effects of 8 weeks of intermittent fasting (IF; 24-hour fast on 3 nonconsecutive days per week) in mice fed a chow or high-fat diet (HFD; 43% fat) on markers of adipose tissue inflammation and fibrosis. We found that IF decreased energy intake, body weight, and fat cell size in HFD-fed mice and decreased fat mass and improved glucose tolerance in chow- and HFD-fed mice. IF decreased mRNA levels of macrophage markers (Lgals3, Itgax, Ccl2, and Ccl3) in inguinal and gonadal fat, as well as adipose tissue macrophage numbers in HFD-fed mice only, and altered genes involved in NLRP3 inflammasome pathway in both diet groups. IF increased mRNA levels of matrix metallopeptidase 9, which is involved in extracellular matrix degradation, and reduced mRNA levels of collagen 6 α-1 and tissue inhibitor of matrix metallopeptidase 1, as well as fibrosis in gonadal fat in HFD-fed mice. In summary, our results show that intermittent fasting improved glucose tolerance in chow- and HFD-fed mice and ameliorated adipose tissue inflammation and fibrosis in HFD-fed mice.
Collapse
Affiliation(s)
- Bo Liu
- Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Amanda J Page
- Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - George Hatzinikolas
- Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Miaoxin Chen
- Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- Centre for Reproductive Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gary A Wittert
- Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Leonie K Heilbronn
- Centre for Nutrition and Gastrointestinal Disease, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| |
Collapse
|
|
18
|
Gancheva S, Jelenik T, Álvarez-Hernández E, Roden M. Interorgan Metabolic Crosstalk in Human Insulin Resistance. Physiol Rev 2018; 98:1371-1415. [PMID: 29767564 DOI: 10.1152/physrev.00015.2017] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.
Collapse
Affiliation(s)
- Sofiya Gancheva
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Tomas Jelenik
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Elisa Álvarez-Hernández
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Michael Roden
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| |
Collapse
|
|
19
|
Verboven K, Wouters K, Gaens K, Hansen D, Bijnen M, Wetzels S, Stehouwer CD, Goossens GH, Schalkwijk CG, Blaak EE, Jocken JW. Abdominal subcutaneous and visceral adipocyte size, lipolysis and inflammation relate to insulin resistance in male obese humans. Sci Rep 2018; 8:4677. [PMID: 29549282 PMCID: PMC5856747 DOI: 10.1038/s41598-018-22962-x] [Citation(s) in RCA: 162] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 03/05/2018] [Indexed: 12/16/2022] Open
Abstract
Obesity is associated with a disturbed adipose tissue (AT) function characterized by adipocyte hypertrophy, an impaired lipolysis and pro-inflammatory phenotype, which contributes to insulin resistance (IR). We investigated whether AT phenotype in different AT depots of obese individuals with and without type 2 diabetes mellitus (T2DM) is associated with whole-body IR. Subcutaneous (SC) and visceral (V) AT biopsies from 18 lean, 17 obese and 8 obese T2DM men were collected. AT phenotype was characterized by ex vivo measurement of basal and stimulated lipolysis (mature adipocytes), adipocyte size distribution (AT tissue sections) and AT immune cells (flow cytometry). In VAT, mean adipocyte size, CD45+ leukocytes and M1 macrophages were significantly increased in both obese groups compared to lean individuals. In SCAT, despite adipocyte hypertrophy, no significant differences in immune cell populations between groups were found. In SCAT, multiple linear regression analysis showed that none of the AT phenotype markers independently contributed to HOMA-IR while in VAT, mean adipocyte size was significantly related to HOMA-IR. In conclusion, beside adipocyte hypertrophy in VAT, M1 macrophage- or B-cell-mediated inflammation, may contribute to IR, while inflammation in hypertrophic SCAT does not seem to play a major role in IR.
Collapse
Affiliation(s)
- K Verboven
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands. .,Rehabilitation Research Center, BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.
| | - K Wouters
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - K Gaens
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - D Hansen
- Rehabilitation Research Center, BIOMED Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.,Heart Centre Hasselt, Jessa Hospital, Hasselt, Belgium
| | - M Bijnen
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - S Wetzels
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - C D Stehouwer
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - G H Goossens
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - C G Schalkwijk
- Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - E E Blaak
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - J W Jocken
- Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
| |
Collapse
|
|
20
|
Olszowski T, Gutowska I, Baranowska-Bosiacka I, Łukomska A, Drozd A, Chlubek D. Cadmium Alters the Concentration of Fatty Acids in THP-1 Macrophages. Biol Trace Elem Res 2018; 182:29-36. [PMID: 28600650 PMCID: PMC5808062 DOI: 10.1007/s12011-017-1071-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022]
Abstract
Fatty acid composition of human immune cells influences their function. The aim of this study was to evaluate the effects of known toxicant and immunomodulator, cadmium, at low concentrations on levels of selected fatty acids (FAs) in THP-1 macrophages. The differentiation of THP-1 monocytes into macrophages was achieved by administration of phorbol myristate acetate. Macrophages were incubated with various cadmium chloride (CdCl2) solutions for 48 h at final concentrations of 5 nM, 20 nM, 200 nM, and 2 μM CdCl2. Fatty acids were extracted from samples according to the Folch method. The fatty acid levels were determined using gas chromatography. The following fatty acids were analyzed: long-chain saturated fatty acids (SFAs) palmitic acid and stearic acid, very long-chain saturated fatty acid (VLSFA) arachidic acid, monounsaturated fatty acids (MUFAs) palmitoleic acid, oleic acid and vaccenic acid, and n-6 polyunsaturated fatty acids (PUFAs) linoleic acid and arachidonic acid. Treatment of macrophages with very low concentrations of cadmium (5-200 nM) resulted in significant reduction in the levels of arachidic, palmitoleic, oleic, vaccenic, and linoleic acids and significant increase in arachidonic acid levels (following exposure to 5 nM Cd), without significant reduction of palmitic and stearic acid levels. Treatment of macrophages with the highest tested cadmium concentration (2 μM) produced significant reduction in the levels of all examined FAs: SFAs, VLSFA, MUFAs, and PUFAs. In conclusion, cadmium at tested concentrations caused significant alterations in THP-1 macrophage fatty acid levels, disrupting their composition, which might dysregulate fatty acid/lipid metabolism thus affecting macrophage behavior and inflammatory state.
Collapse
Affiliation(s)
- Tomasz Olszowski
- Department of Hygiene and Epidemiology, Pomeranian Medical University, Powstańców Wlkp. 72 Str, 70-111, Szczecin, Poland
| | - Izabela Gutowska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str, 71-460, Szczecin, Poland
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72 Str, 70-111, Szczecin, Poland.
| | - Agnieszka Łukomska
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str, 71-460, Szczecin, Poland
| | - Arleta Drozd
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24 Str, 71-460, Szczecin, Poland
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72 Str, 70-111, Szczecin, Poland
| |
Collapse
|
|
21
|
Chan KL, Tam TH, Boroumand P, Prescott D, Costford SR, Escalante NK, Fine N, Tu Y, Robertson SJ, Prabaharan D, Liu Z, Bilan PJ, Salter MW, Glogauer M, Girardin SE, Philpott DJ, Klip A. Circulating NOD1 Activators and Hematopoietic NOD1 Contribute to Metabolic Inflammation and Insulin Resistance. Cell Rep 2017; 18:2415-2426. [PMID: 28273456 DOI: 10.1016/j.celrep.2017.02.027] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 12/09/2016] [Accepted: 02/07/2017] [Indexed: 12/19/2022] Open
Abstract
Insulin resistance is a chronic inflammatory condition accompanying obesity or high fat diets that leads to type 2 diabetes. It is hypothesized that lipids and gut bacterial compounds in particular contribute to metabolic inflammation by activating the immune system; however, the receptors detecting these "instigators" of inflammation remain largely undefined. Here, we show that circulating activators of NOD1, a receptor for bacterial peptidoglycan, increase with high fat feeding in mice, suggesting that NOD1 could be a critical sensor leading to metabolic inflammation. Hematopoietic depletion of NOD1 did not prevent weight gain but protected chimeric mice against diet-induced glucose and insulin intolerance. Mechanistically, while macrophage infiltration of adipose tissue persisted, notably these cells were less pro-inflammatory, had lower CXCL1 production, and consequently, lower neutrophil chemoattraction into the tissue. These findings reveal macrophage NOD1 as a cell-specific target to combat diet-induced inflammation past the step of macrophage infiltration, leading to insulin resistance.
Collapse
Affiliation(s)
- Kenny L Chan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Theresa H Tam
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Parastoo Boroumand
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - David Prescott
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Sheila R Costford
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Nichole K Escalante
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Noah Fine
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada
| | - YuShan Tu
- Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Susan J Robertson
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Dilshaayee Prabaharan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Zhi Liu
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Philip J Bilan
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Michael W Salter
- Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Neurosciences and Mental Health Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Michael Glogauer
- Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5S 3E2, Canada
| | - Stephen E Girardin
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Amira Klip
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada; Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
| |
Collapse
|
|
22
|
Cucchi F, Rossmeislova L, Simonsen L, Jensen MR, Bülow J. A vicious circle in chronic lymphoedema pathophysiology? An adipocentric view. Obes Rev 2017; 18:1159-1169. [PMID: 28660651 DOI: 10.1111/obr.12565] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/07/2017] [Accepted: 04/25/2017] [Indexed: 12/11/2022]
Abstract
Chronic lymphoedema is a disease caused by a congenital or acquired damage to the lymphatic system and characterized by complex chains of pathophysiologic events such as lymphatic fluid stasis, chronic inflammation, lymphatic vessels impairment, adipose tissue deposition and fibrosis. These events seem to maintain and reinforce themselves through a positive feedback loop: regardless of the initial cause of lymphatic stasis, the dysfunctional adipose tissue and its secretion products can worsen lymphatic vessels' function, aggravating lymph leakage and stagnation, which can promote further adipose tissue deposition and fibrosis, similar to what may happen in obesity. In addition to the current knowledge about the tight and ancestral interrelation between immunity system and metabolism, there is evidence for similarities between obesity-related and lymphatic damage-induced lymphoedema. Together, these observations indicate strong reciprocal relationship between lymphatics and adipose tissue and suggest a possible key role of the adipocyte in the pathophysiology of chronic lymphoedema's vicious circle.
Collapse
Affiliation(s)
- F Cucchi
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - L Rossmeislova
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - L Simonsen
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - M R Jensen
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - J Bülow
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark.,Department of Biomedical Sciences, Copenhagen University, Denmark
| |
Collapse
|
|
23
|
Pereira JX, Cavalcante Y, Wanzeler de Oliveira R. The role of inflammation in adipocytolytic nonsurgical esthetic procedures for body contouring. Clin Cosmet Investig Dermatol 2017; 10:57-66. [PMID: 28260937 PMCID: PMC5327851 DOI: 10.2147/ccid.s125580] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background The adipocytolytic non-surgical esthetic procedures are indicated for the reduction of localized fat and are effective in reducing local adiposity through the ablation of adipocytes with fast and lasting results, besides causing local inflammation. Objective This study aimed to characterize the adipocytolytic procedures and correlate the phases of the inflammatory process with the results obtained from such procedures, in order to clarify the role of inflammation triggered by the adipocytolytic procedures and its relation with the lipolytic process, with a focus on body shaping. Methods This work is an integrative literature review that presents a total of 72 articles published between 1998 and 2015, derived from the PubMed database, in order to establish a relationship between clinical and basic science research, assuming an important role in medical practice based on evidence. Results The results show that the adipocytolytic procedures are characterized by triggering inflammation arising from the disruption of adipocytes by interfering with the lipolytic signaling pathways in both acute and chronic phases of inflammation through the direct action of proinflammatory cytokines or catecholamines. Therefore, inflammation plays an important role in modulating the lipolytic process, influencing body shaping. Conclusion The inflammatory process assists the adipolytic process in all stages of inflammation, contributing to the reduction of body contouring.
Collapse
|
|
24
|
The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 960:221-245. [PMID: 28585201 DOI: 10.1007/978-3-319-48382-5_9] [Citation(s) in RCA: 190] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
25
|
Montagner A, Polizzi A, Fouché E, Ducheix S, Lippi Y, Lasserre F, Barquissau V, Régnier M, Lukowicz C, Benhamed F, Iroz A, Bertrand-Michel J, Al Saati T, Cano P, Mselli-Lakhal L, Mithieux G, Rajas F, Lagarrigue S, Pineau T, Loiseau N, Postic C, Langin D, Wahli W, Guillou H. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 2016; 65:1202-14. [PMID: 26838599 PMCID: PMC4941147 DOI: 10.1136/gutjnl-2015-310798] [Citation(s) in RCA: 550] [Impact Index Per Article: 61.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 01/04/2016] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD). DESIGN We constructed a novel hepatocyte-specific PPARα knockout (Pparα(hep-/-)) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing. RESULTS Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparα(hep-/-) mice when compared with Pparα(-/-) mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα(-/-) mice became overweight during ageing while Pparα(hep-/-) remained lean. However, like Pparα(-/-) mice, Pparα(hep-/-) fed a standard diet developed hepatic steatosis in ageing. CONCLUSIONS Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD.
Collapse
Affiliation(s)
| | - Arnaud Polizzi
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Edwin Fouché
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Simon Ducheix
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Yannick Lippi
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | | | - Valentin Barquissau
- INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
- University of Toulouse, UMR1048, Paul Sabatier University, France
| | - Marion Régnier
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Céline Lukowicz
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Fadila Benhamed
- INSERM U1016, Cochin Institute, Paris, France
- CNRS UMR 8104, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Alison Iroz
- INSERM U1016, Cochin Institute, Paris, France
- CNRS UMR 8104, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Justine Bertrand-Michel
- INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
- University of Toulouse, UMR1048, Paul Sabatier University, France
| | - Talal Al Saati
- INSERM/UPS-US006/CREFRE, Service d'Histopathologie, CHU Purpan, Toulouse, France
| | - Patricia Cano
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | | | | | | | - Sandrine Lagarrigue
- INRA UMR1348 Pegase, Saint-Gilles, France
- Agrocampus Ouest, UMR1348 Pegase, Rennes, France
- Université Européenne de Bretagne, France
| | - Thierry Pineau
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Nicolas Loiseau
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| | - Catherine Postic
- INSERM U1016, Cochin Institute, Paris, France
- CNRS UMR 8104, Paris, France
- University of Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Dominique Langin
- INSERM UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
- University of Toulouse, UMR1048, Paul Sabatier University, France
- Laboratory of Clinical Biochemistry, Toulouse University Hospitals, Toulouse, France
| | - Walter Wahli
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Center for Integrative Genomics, University of Lausanne, Genopode Building, Lausanne, Switzerland
| | - Hervé Guillou
- INRA UMR1331, ToxAlim, University of Toulouse, Toulouse, France
| |
Collapse
|
|
26
|
Abstract
Inflammation originating from the adipose tissue is considered to be one of the main driving forces for the development of insulin resistance and type 2 diabetes in obese individuals. Although a plethora of different immune cells shapes adipose tissue inflammation, this review is specifically focused on the contribution of macrophages that reside in adipose tissue in lean and obese conditions. Both conventional and tissue-specific functions of adipose tissue macrophages (ATMs) in lean and obese adipose tissue are discussed and linked with metabolic and inflammatory changes that occur during the development of obesity. Furthermore, we will address various circulating and adipose tissue-derived triggers that may be involved in shaping the ATM phenotype and underlie ATM function in lean and obese conditions. Finally, we will highlight how these changes affect adipose tissue inflammation and may be targeted for therapeutic interventions to improve insulin sensitivity in obese individuals.
Collapse
Affiliation(s)
- Lily Boutens
- Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Nutrition, Metabolism and Genomics Group, Wageningen University, Bomenweg 2, 6703 HD, Wageningen, the Netherlands
| | - Rinke Stienstra
- Department of Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
- Nutrition, Metabolism and Genomics Group, Wageningen University, Bomenweg 2, 6703 HD, Wageningen, the Netherlands.
| |
Collapse
|
|
27
|
Hersoug LG, Møller P, Loft S. Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obes Rev 2016; 17:297-312. [PMID: 26712364 DOI: 10.1111/obr.12370] [Citation(s) in RCA: 206] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 11/18/2015] [Accepted: 11/19/2015] [Indexed: 12/12/2022]
Abstract
The composition of the gut microbiota and excessive ingestion of high-fat diets (HFD) are considered to be important factors for development of obesity. In this review we describe a coherent mechanism of action for the development of obesity, which involves the composition of gut microbiota, HFD, low-grade inflammation, expression of fat translocase and scavenger receptor CD36, and the scavenger receptor class B type 1 (SR-BI). SR-BI binds to both lipids and lipopolysaccharide (LPS) from Gram-negative bacteria, which may promote incorporation of LPS in chylomicrons (CMs). These CMs are transported via lymph to the circulation, where LPS is transferred to other lipoproteins by translocases, preferentially to HDL. LPS increases the SR-BI binding, transcytosis of lipoproteins over the endothelial barrier,and endocytosis in adipocytes. Especially large size adipocytes with high metabolic activity absorb LPS-rich lipoproteins. In addition, macrophages in adipose tissue internalize LPS-lipoproteins. This may contribute to the polarization from M2 to M1 phenotype, which is a consequence of increased LPS delivery into the tissue during hypertrophy. In conclusion, evidence suggests that LPS is involved in the development of obesity as a direct targeting molecule for lipid delivery and storage in adipose tissue.
Collapse
Affiliation(s)
- L-G Hersoug
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - P Møller
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - S Loft
- Section of Environmental Health, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
28
|
Morigny P, Houssier M, Mouisel E, Langin D. Adipocyte lipolysis and insulin resistance. Biochimie 2015; 125:259-66. [PMID: 26542285 DOI: 10.1016/j.biochi.2015.10.024] [Citation(s) in RCA: 318] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 10/30/2015] [Indexed: 12/15/2022]
Abstract
Obesity-induced insulin resistance is a major risk factor for the development of type 2 diabetes. Basal fat cell lipolysis (i.e., fat cell triacylglycerol breakdown into fatty acids and glycerol in the absence of stimulatory factors) is elevated during obesity and is closely associated with insulin resistance. Inhibition of adipocyte lipolysis may therefore be a promising therapeutic strategy for treating insulin resistance and preventing obesity-associated type 2 diabetes. In this review, we explore the relationship between adipose lipolysis and insulin sensitivity. After providing an overview of the components of fat cell lipolytic machinery, we describe the hypotheses that may support the causality between lipolysis and insulin resistance. Excessive circulating fatty acids may ectopically accumulate in insulin-sensitive tissues and impair insulin action. Increased basal lipolysis may also modify the secretory profile of adipose tissue, influencing whole body insulin sensitivity. Finally, excessive fatty acid release may also worsen adipose tissue inflammation, a well-known parameter contributing to insulin resistance. Partial genetic or pharmacologic inhibition of fat cell lipases in mice as well as short term clinical trials using antilipolytic drugs in humans support the benefit of fat cell lipolysis inhibition on systemic insulin sensitivity and glucose metabolism, which occurs without an increase of fat mass. Modulation of fatty acid fluxes and, putatively, of fat cell secretory pattern may explain the amelioration of insulin sensitivity whereas changes in adipose tissue immune response do not seem involved.
Collapse
Affiliation(s)
- Pauline Morigny
- INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; University of Toulouse, UMR1048, Paul Sabatier University, France
| | - Marianne Houssier
- INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; University of Toulouse, UMR1048, Paul Sabatier University, France
| | - Etienne Mouisel
- INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; University of Toulouse, UMR1048, Paul Sabatier University, France
| | - Dominique Langin
- INSERM, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; University of Toulouse, UMR1048, Paul Sabatier University, France; Toulouse University Hospitals, Department of Clinical Biochemistry, Toulouse, France.
| |
Collapse
|