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1
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Hunter AL, Bechtold DA. The metabolic significance of peripheral tissue clocks. Commun Biol 2025; 8:497. [PMID: 40140664 PMCID: PMC11947457 DOI: 10.1038/s42003-025-07932-0] [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] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
The circadian clock is a transcriptional-translational feedback loop which oscillates in virtually all nucleated cells of the body. In the decades since its discovery, it has become evident that the molecular clockwork is inextricably linked to energy metabolism. Given the frequency with which metabolic dysfunction and clock disruption co-occur, understanding why and how clock and metabolic processes are reciprocally coupled will have important implications for supporting human health and wellbeing. Here, we discuss the relevance of molecular clock function in metabolic tissues and explore its role not only as a driver of day-night variation in gene expression, but as a key mechanism for maintaining metabolic homeostasis in the face of fluctuating energy supply and demand.
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Affiliation(s)
- A Louise Hunter
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
- Diabetes, Endocrinology & Metabolism Centre, Oxford Road Campus, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK.
| | - David A Bechtold
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
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2
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Chen F, Sarver DC, Saqib M, Velez LM, Aja S, Seldin MM, Wong GW. Loss of CTRP10 results in female obesity with preserved metabolic health. eLife 2025; 13:RP93373. [PMID: 40126547 PMCID: PMC11932693 DOI: 10.7554/elife.93373] [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] [Subscribe] [Scholar Register] [Indexed: 03/25/2025] Open
Abstract
Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologs in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.
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Affiliation(s)
- Fangluo Chen
- Department of Physiology, Johns Hopkins University School of MedicineBaltimoreUnited States
- Center for Metabolism and Obesity Research, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Dylan C Sarver
- Department of Physiology, Johns Hopkins University School of MedicineBaltimoreUnited States
- Center for Metabolism and Obesity Research, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Muzna Saqib
- Department of Physiology, Johns Hopkins University School of MedicineBaltimoreUnited States
- Center for Metabolism and Obesity Research, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Leandro M Velez
- Center for Epigenetics and Metabolism, University of California, IrvineIrvineUnited States
- Department of Biological Chemistry, University of California, IrvineIrvineUnited States
| | - Susan Aja
- Center for Metabolism and Obesity Research, Johns Hopkins University School of MedicineBaltimoreUnited States
- Department of Neuroscience, Johns Hopkins University School of MedicineBaltimoreUnited States
| | - Marcus M Seldin
- Center for Epigenetics and Metabolism, University of California, IrvineIrvineUnited States
- Department of Biological Chemistry, University of California, IrvineIrvineUnited States
| | - G William Wong
- Department of Physiology, Johns Hopkins University School of MedicineBaltimoreUnited States
- Center for Metabolism and Obesity Research, Johns Hopkins University School of MedicineBaltimoreUnited States
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Chen F, Sarver DC, Saqib M, Velez LM, Aja S, Seldin MM, Wong GW. Loss of CTRP10 results in female obesity with preserved metabolic health. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2023.11.01.565163. [PMID: 37961647 PMCID: PMC10635050 DOI: 10.1101/2023.11.01.565163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.
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Affiliation(s)
- Fangluo Chen
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Dylan C. Sarver
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Muzna Saqib
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Leandro M Velez
- Department of Biological Chemistry, University of California, Irvine, Irvine, USA
- Center for Epigenetics and Metabolism, University of California Irvine, Irvine, USA
| | - Susan Aja
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Marcus M. Seldin
- Department of Biological Chemistry, University of California, Irvine, Irvine, USA
- Center for Epigenetics and Metabolism, University of California Irvine, Irvine, USA
| | - G. William Wong
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Engin A. Bariatric Surgery in Obesity: Metabolic Quality Analysis and Comparison of Surgical Options. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:697-726. [PMID: 39287870 DOI: 10.1007/978-3-031-63657-8_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obesity is a constantly growing health problem which reduces quality of life and life expectancy. Bariatric surgery (BS) for obesity is considered when all other conservative treatment modalities have failed. Comparison of the multidisciplinary programs with BS regarding to the weight loss showed that substantial and durable weight reduction have been achieved only with bariatric surgical treatments. Although laparoscopic sleeve gastrectomy is the most popular BS, it has high long-term failure rates, and it is claimed that one of every three patients will undergo another bariatric procedure within a 10-year period. Although BS provides weight loss and improvement of metabolic comorbidities, in long-term follow-up, weight gain is observed in half of the patients, while decrease in bone mass and nutritional deficiencies occur in up to 90%. Moreover, despite significant weight loss, several psychological aspects of patients are worsened in comparison to preoperative levels. Nearly one-fifth of postoperative patients with "Loss-of-eating control" meet food addiction criteria. Therefore, the benefits of weight loss following bariatric procedures alone are still debated in terms of the proinflammatory and metabolic profile of obesity.
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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.
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Barrios-Nolasco A, Domínguez-López A, Miliar-García A, Cornejo-Garrido J, Jaramillo-Flores ME. Anti-Inflammatory Effect of Ethanolic Extract from Tabebuia rosea (Bertol.) DC., Quercetin, and Anti-Obesity Drugs in Adipose Tissue in Wistar Rats with Diet-Induced Obesity. Molecules 2023; 28:molecules28093801. [PMID: 37175211 PMCID: PMC10180162 DOI: 10.3390/molecules28093801] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/18/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is characterized by the excessive accumulation of fat, which triggers a low-grade chronic inflammatory process. Currently, the search for compounds with anti-obesogenic effects that help reduce body weight, as well as associated comorbidities, continues. Among this group of compounds are plant extracts and flavonoids with a great diversity of action mechanisms associated with their beneficial effects, such as anti-inflammatory effects and/or as signaling molecules. In the bark of Tabebuia rosea tree, there are different classes of metabolites with anti-inflammatory properties, such as quercetin. Therefore, the present work studied the effect of the ethanolic extract of T. rosea and quercetin on the mRNA of inflammation markers in obesity compared to the drugs currently used. Total RNA was extracted from epididymal adipose tissue of high-fat diet-induced obese Wistar rats treated with orlistat, phentermine, T. rosea extract, and quercetin. The rats treated with T. rosea and quercetin showed 36 and 31% reductions in body weight compared to the obese control, and they likewise inhibited pro-inflammatory molecules: Il6, Il1b, Il18, Lep, Hif1a, and Nfkb1 without modifying the expression of Socs1 and Socs3. Additionally, only T. rosea overexpressed Lipe. Both T. rosea and quercetin led to a reduction in the expression of pro-inflammatory genes, modifying signaling pathways, which led to the regulation of the obesity-inflammation state.
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Affiliation(s)
- Alejandro Barrios-Nolasco
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Guillermo Massieu Helguera 239, Col. La Escalera, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07320, Mexico
| | - Aarón Domínguez-López
- Laboratorio de Biología Molecular, Escuela Superior de Medicina (ESM), Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Alcaldía Miguel Hidalgo, Ciudad de Mexico 11340, Mexico
| | - Angel Miliar-García
- Laboratorio de Biología Molecular, Escuela Superior de Medicina (ESM), Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Alcaldía Miguel Hidalgo, Ciudad de Mexico 11340, Mexico
| | - Jorge Cornejo-Garrido
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Guillermo Massieu Helguera 239, Col. La Escalera, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07320, Mexico
| | - María Eugenia Jaramillo-Flores
- Laboratorio de Polímeros, Department de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional, Wilfrido Massieu s/n esq. Manuel I. Stampa. Col. Unidad Profesional Adolfo López Mateos, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07738, Mexico
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Liu Y, Xu K, Yao Y, Liu Z. Current research into A20 mediation of allergic respiratory diseases and its potential usefulness as a therapeutic target. Front Immunol 2023; 14:1166928. [PMID: 37056760 PMCID: PMC10086152 DOI: 10.3389/fimmu.2023.1166928] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Allergic airway diseases are characterized by excessive and prolonged type 2 immune responses to inhaled allergens. Nuclear factor κB (NF-κB) is a master regulator of the immune and inflammatory response, which has been implicated to play a prominent role in the pathogenesis of allergic airway diseases. The potent anti-inflammatory protein A20, termed tumor necrosis factor-α-inducible protein 3 (TNFAIP3), exerts its effects by inhibiting NF-κB signaling. The ubiquitin editing abilities of A20 have attracted much attention, resulting in its identification as a susceptibility gene in various autoimmune and inflammatory disorders. According to the results of genome-wide association studies, several TNFAIP3 gene locus nucleotide polymorphisms have been correlated to allergic airway diseases. In addition, A20 has been found to play a pivotal role in immune regulation in childhood asthma, particularly in the protection against environmentally mediated allergic diseases. The protective effects of A20 against allergy were observed in conditional A20-knockout mice in which A20 was depleted in the lung epithelial cells, dendritic cells, or mast cells. Furthermore, A20 administration significantly decreased inflammatory responses in mouse models of allergic airway diseases. Here, we review emerging findings elucidating the cellular and molecular mechanisms by which A20 regulates inflammatory signaling in allergic airway diseases, as well as discuss its potential as a therapeutic target.
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Affiliation(s)
- Yan Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Xu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Zheng Liu, ; Yin Yao, ; Kai Xu,
| | - Yin Yao
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Zheng Liu, ; Yin Yao, ; Kai Xu,
| | - Zheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China
- Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Zheng Liu, ; Yin Yao, ; Kai Xu,
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Li W, Chen W. Weight cycling based on altered immune microenvironment as a result of metaflammation. Nutr Metab (Lond) 2023; 20:13. [PMID: 36814270 PMCID: PMC9945679 DOI: 10.1186/s12986-023-00731-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
As a result of the obesity epidemic, more people are concerned about losing weight; however, weight regain is common, leading to repeated weight loss and weight cycling. The health benefits of early weight loss are nullified by weight regain after weight cycling, which has much more severe metabolic consequences. Weight cycling alters body composition, resulting in faster fat recovery and slower muscle reconstruction. This evident fat accumulation, muscle loss, and ectopic fat deposition destroy the intestinal barrier, increase the permeability of the small intestinal epithelium, and cause the lipotoxicity of lipid metabolites and toxins to leak into extraintestinal tissues and circulation. It causes oxidative stress and hypoxia in local tissues and immune cell infiltration in various tissues, all contributing to the adaptation to this metabolic change. Immune cells transmit inflammatory responses in adipose and skeletal muscle tissue by secreting cytokines and adipokines, which mediate immune cell pathways and cause metaflammation and inefficient metabolic degradation. In this review, we focus on the regulatory function of the immunological microenvironment in the final metabolic outcome, with a particular emphasis on the cellular and molecular processes of local and systemic metaflammation induced by weight cycling-induced changes in body composition. Metaflammation in adipose and muscle tissues that is difficult to relieve may cause weight cycling. As this chronic low-grade inflammation spreads throughout the body, metabolic complications associated with weight cycling are triggered. Inhibiting the onset and progression of metabolic inflammation and enhancing the immune microenvironment of adipose and muscle tissues may be the first step in addressing weight cycling.
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Affiliation(s)
- Wanyang Li
- grid.413106.10000 0000 9889 6335Department of Clinical Nutrition, Chinese Academy of Medical Sciences - Peking Union Medical College, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730 China
| | - Wei Chen
- Department of Clinical Nutrition, Chinese Academy of Medical Sciences - Peking Union Medical College, Peking Union Medical College Hospital, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
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Raza GS, Sodum N, Kaya Y, Herzig KH. Role of Circadian Transcription Factor Rev-Erb in Metabolism and Tissue Fibrosis. Int J Mol Sci 2022; 23:12954. [PMID: 36361737 PMCID: PMC9655416 DOI: 10.3390/ijms232112954] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 09/12/2023] Open
Abstract
Circadian rhythms significantly affect metabolism, and their disruption leads to cardiometabolic diseases and fibrosis. The clock repressor Rev-Erb is mainly expressed in the liver, heart, lung, adipose tissue, skeletal muscles, and brain, recognized as a master regulator of metabolism, mitochondrial biogenesis, inflammatory response, and fibrosis. Fibrosis is the response of the body to injuries and chronic inflammation with the accumulation of extracellular matrix in tissues. Activation of myofibroblasts is a key factor in the development of organ fibrosis, initiated by hormones, growth factors, inflammatory cytokines, and mechanical stress. This review summarizes the importance of Rev-Erb in ECM remodeling and tissue fibrosis. In the heart, Rev-Erb activation has been shown to alleviate hypertrophy and increase exercise capacity. In the lung, Rev-Erb agonist reduced pulmonary fibrosis by suppressing fibroblast differentiation. In the liver, Rev-Erb inhibited inflammation and fibrosis by diminishing NF-κB activity. In adipose tissue, Rev- Erb agonists reduced fat mass. In summary, the results of multiple studies in preclinical models demonstrate that Rev-Erb is an attractive target for positively influencing dysregulated metabolism, inflammation, and fibrosis, but more specific tools and studies would be needed to increase the information base for the therapeutic potential of these substances interfering with the molecular clock.
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Affiliation(s)
- Ghulam Shere Raza
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Nalini Sodum
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
| | - Yagmur Kaya
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Marmara University, 34854 Istanbul, Turkey
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Medical Research Center, Faculty of Medicine, University of Oulu, 90220 Oulu, Finland
- Oulu University Hospital, University of Oulu, 90220 Oulu, Finland
- Pediatric Gastroenterology and Metabolic Diseases, Pediatric Institute, Poznan University of Medical Sciences, 60-572 Poznań, Poland
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9
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Alimu A, Abudureman H, Wang YZ, Li MY, Wang JS, Liu ZL. Decabromodiphenyl ether causes insulin resistance and glucose and lipid metabolism disorders in mice. World J Diabetes 2021; 12:1267-1281. [PMID: 34512892 PMCID: PMC8394237 DOI: 10.4239/wjd.v12.i8.1267] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 05/15/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Decabromodiphenyl ether (BDE-209) is the most commonly used brominated flame retardant. Recently, BDE-209 has been suspected of being an environmental risk factor for metabolic diseases such as obesity, insulin resistance (IR), type 2 diabetes mellitus, and hypertension.
AIM To investigate the effects of BDE-209 on IR and glucose and lipid metabolism in C57BL/6 mice.
METHODS Adult male C57BL/6 mice were randomly divided into high, medium-high, medium, medium-low, and low dose BDE-209 groups, and a control group (n = 6 per group), which received 1000, 800, 600, 450, 300, and 0 mg/kg BDE-209, respectively. After BDE-209 exposure for 60 d, the mice were fasted overnight, and then sacrificed to obtain tissues. An automatic biochemical analyzer was used to detect serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C); enzyme-linked immunosorbent assay kits were used to detect fasting serum insulin (FINS), leptin (LEP), and adiponectin (Adp) levels; a blood glucose meter was used to detect fasting blood glucose (FBG). Morphological changes of the liver were observed by hematoxylin and eosin staining. Real-time quantitative polymerase chain reaction and Western blot were used to determine the messenger ribonucleic acid (mRNA) and protein levels, respectively, of LEP, Adp, and peroxisome proliferators activated receptor-γ (PPARγ) in mouse liver and adipose tissues.
RESULTS There was a statistically significant difference in the weight of mice in each group after 45 and 60 d of exposure (P < 0.05). After 60 d of exposure, the weight of liver and adipose tissues in the exposure groups were greater than that of the control group (P < 0.05). The liver tissue structure was disordered and the liver tissues were accompanied by local inflammatory cell infiltration in the high, medium-high, and medium dose BDE-209 groups. The levels of FINS, insulin sensitivity index, Adp, and HDL-C were decreased in the BDE-209 group compared with the control group, as were the mRNA and protein levels of Adp in liver and adipose tissues (P < 0.05). Serum level of FBG and LEP were higher in the BDE-209 group than in controls. TC, TG, and LDL-C levels as well as the mRNA and protein expression of LEP and PPARγ in liver and adipose tissues were higher than those in the control group (P < 0.05). Homeostatic assessment model of IR was higher in the medium and medium-low dose BDE-209 groups (P < 0.05).
CONCLUSION BDE-209 increases the body weight, fat and liver tissue weight, TC, TG, and LDL-C, reduces HDL-C, and causes IR in mice, which may be related to activating the PPARγ receptor.
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Affiliation(s)
- Ayiguli Alimu
- Department of Epidemiology and Health Statistics, School of Public Health, Xinjiang Medical University, Urumqi 0991, Xinjiang Uygur Autonomous Region, China
| | - Haiqiemuhan Abudureman
- Department of Epidemiology and Health Statistics, School of Public Health, Xinjiang Medical University, Urumqi 0991, Xinjiang Uygur Autonomous Region, China
| | - Yong-Zhi Wang
- Department of Public Health, Xinjiang Second Medical College, Cremayi 834000, Xinjiang Uygur Autonomous Region, China
| | - Mei-Yan Li
- Department of Epidemiology and Health Statistics, School of Public Health, Xinjiang Medical University, Urumqi 0991, Xinjiang Uygur Autonomous Region, China
| | - Jia-Sui Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Xinjiang Medical University, Urumqi 0991, Xinjiang Uygur Autonomous Region, China
| | - Zao-Ling Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Xinjiang Medical University, Urumqi 0991, Xinjiang Uygur Autonomous Region, China
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10
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Hunter AL, Pelekanou CE, Barron NJ, Northeast RC, Grudzien M, Adamson AD, Downton P, Cornfield T, Cunningham PS, Billaud JN, Hodson L, Loudon ASI, Unwin RD, Iqbal M, Ray DW, Bechtold DA. Adipocyte NR1D1 dictates adipose tissue expansion during obesity. eLife 2021; 10:e63324. [PMID: 34350828 PMCID: PMC8360653 DOI: 10.7554/elife.63324] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 07/30/2021] [Indexed: 12/13/2022] Open
Abstract
The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.
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Affiliation(s)
- Ann Louise Hunter
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Charlotte E Pelekanou
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Nichola J Barron
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Rebecca C Northeast
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Magdalena Grudzien
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Antony D Adamson
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Polly Downton
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Thomas Cornfield
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, and NIHR Oxford Biomedical Research Centre, John Radcliffe HospitalOxfordUnited Kingdom
| | - Peter S Cunningham
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | | | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, and NIHR Oxford Biomedical Research Centre, John Radcliffe HospitalOxfordUnited Kingdom
| | - Andrew SI Loudon
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Richard D Unwin
- Stoller Biomarker Discovery Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - Mudassar Iqbal
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
| | - David W Ray
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, and NIHR Oxford Biomedical Research Centre, John Radcliffe HospitalOxfordUnited Kingdom
| | - David A Bechtold
- Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of ManchesterManchesterUnited Kingdom
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Winn NC, Cottam MA, Wasserman DH, Hasty AH. Exercise and Adipose Tissue Immunity: Outrunning Inflammation. Obesity (Silver Spring) 2021; 29:790-801. [PMID: 33899336 DOI: 10.1002/oby.23147] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/02/2021] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Chronic inflammation is considered a precipitating factor and possibly an underlying cause of many noncommunicable diseases, including cardiovascular disease, metabolic diseases, and some cancers. Obesity, which manifests in more than 650 million people worldwide, is the most common chronic inflammatory condition, with visceral adiposity thought to be the major inflammatory hub that links obesity and chronic disease. Adipose tissue (AT) inflammation is triggered or heightened in large part by (1) accelerated immune cell recruitment, (2) reshaping of the AT stromal-immuno landscape (e.g., immune cells, endothelial cells, fibroblasts, adipocyte progenitors), and (3) perturbed AT immune cell function. Exercise, along with diet management, is a cornerstone in promoting weight loss and preventing weight regain. This review focuses on evidence that increased physical activity reduces AT inflammation caused by hypercaloric diets or genetic obesity. The precise cell types and mechanisms responsible for the therapeutic effects of exercise on AT inflammation remain poorly understood. This review summarizes what is known about obesity-induced AT inflammation and immunomodulation and highlights mechanisms by which aerobic exercise combats inflammation by remodeling the AT immune landscape. Furthermore, key areas are highlighted that require future exploration and novel discoveries into the burgeoning field of how the biology of exercise affects AT immunity.
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Affiliation(s)
- Nathan C Winn
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Matthew A Cottam
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- Vanderbilt Mouse Metabolic Phenotyping Center, Nashville, Tennessee, USA
| | - Alyssa H Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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12
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Qu P, Li Y, Hu X, Guo Y, Zhu Y, Li X, Zhao J. THE EFFECT OF ADIPONECTIN VIA REGULATING THE BONE MICROENVIRONMENT OXIDATIVE STRESS ON OSTEOGENESIS IN TYPE 2 DIABETIC RATS. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2021; 17:168-176. [PMID: 34925564 PMCID: PMC8665241 DOI: 10.4183/aeb.2021.168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
OBJECTIVE To observe the effect of adiponectin on osteogenesis in type 2 diabetic rats. METHODS The 4th-week-old male SD rats were divided into normal control group (n=18) and diabetic model group (n = 42). Type 2 diabetes was induced by high-fat and high-sugar diet and intraperitoneal injection of a low dose of streptozotocin (STZ). The successfully-induced diabetic rats were divided into diabetic group (DM=18) and adiponectin intervention group (APN=18). APN group was injected with APN 10 μg/kg*d. The rats were separately sacrificed at the 4th, 8th and 12th week after the intervention. Bone microstructure and adipose tissue were observed via HE staining. Bone marrow was extracted from one side of the femur, and the supernatant was achieved by centrifugation. After BMD assessed by DXA, the other side of the femur was for further HE staining. Runx-2 expression in the bone marrow cells was detected by RT-PCR. BALP and AOPPs in bone marrow supernatant were assayed by ELISA. AGEs were detected by immunohistochemical staining. RESULTS With the feeding time over, blood glucose, AOPP, and AGEs were increased, and Runx-2 mRNA, BALP, BMD were decreased in diabetic rat group(P<0.05). Oxidative stress (OS) maker (AOPP) was decreased and osteogenesis makers (Runx2 mRNA, BALP) were increased after intervention with exogenous adiponectin (P<0.05). At the 8th and 12th week, the trabecular bone became thinner and broken, and the fat cell number increased in all 3 groups, especially in the DM group. The adiponectin intervention group showed that the trabecular bone structure was moderately restored. CONCLUSIONS OS is obvious in bone micro-environment in diabetic rats. OS may have an inhibitory effect on regulation of osteogenic differentiation factor Runx2, causing down regulation of osteoblast differentiation and bone formation. Adiponectin may improve OS response and protect the bone structure.
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Affiliation(s)
- P. Qu
- Taiyuan Central Hospital, Department of Endocrinology, Shanxi Medical University, Shanxi, China
| | - Y. Li
- Taiyuan Central Hospital, Department of Endocrinology, Shanxi Medical University, Shanxi, China
| | - X. Hu
- Shanxi Medical University Second Affiliated Hospital, Department of Osteology, Shanxi, China
| | - Y. Guo
- Taiyun Central Hospital, Shanxi Medical University, Department of Pneumology, Shanxi, China
| | - Y. Zhu
- Shanxi Medical University Second Affiliated Hospital, Department of Endocrinology, Taiyuan, Shanxi, China
| | - X. Li
- Shanxi Medical University Second Affiliated Hospital, Department of Endocrinology, Taiyuan, Shanxi, China
| | - J. Zhao
- Shandong Provincial Qianfoshan Hospital, Shandong University, Department of Endocrinology, Jinan, Shandong, PR China
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13
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Bale S, Varga J, Bhattacharyya S. Role of RP105 and A20 in negative regulation of toll-like receptor activity in fibrosis: potential targets for therapeutic intervention. AIMS ALLERGY AND IMMUNOLOGY 2021. [DOI: 10.3934/allergy.2021009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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14
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Abstract
Inflammation is triggered by stimulation of innate sensors that recognize pathogens, chemical and physical irritants, and damaged cells subsequently initiating a well-orchestrated adaptive immune response. Immune cell activation is a strictly regulated and self-resolving process supported by an array of negative feedback mechanisms to sustain tissue homeostasis. The disruption of these regulatory pathways forms the basis of chronic inflammatory diseases, including periodontitis. Ubiquitination, a covalent posttranslational modification of target proteins with ubiquitin, has a profound effect on the stability and activity of its substrates, thereby regulating the immune system at molecular and cellular levels. Through the cooperative actions of E3 ubiquitin ligases and deubiquitinases, ubiquitin modifications are implicated in several biological processes, including proteasomal degradation, transcriptional regulation, regulation of protein-protein interactions, endocytosis, autophagy, DNA repair, and cell cycle regulation. A20 (tumor necrosis factor α-induced protein 3 or TNFAIP3) is a ubiquitin-editing enzyme that mainly functions as an endogenous regulator of inflammation through termination of nuclear factor (NF)-κB activation as part of a negative feedback loop. A20 interacts with substrates that reside downstream of immune sensors, including Toll-like receptors, nucleotide-binding oligomerization domain-containing receptors, lymphocyte receptors, and cytokine receptors. Due to its pleiotropic functions as a ubiquitin binding protein, deubiquitinase and ubiquitin ligase, and its versatile role in various signaling pathways, aberrant A20 levels are associated with numerous conditions such as rheumatoid arthritis, diabetes, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, Sjögren syndrome, coronary artery disease, multiple sclerosis, cystic fibrosis, asthma, cancer, neurological disorders, and aging-related sequelae. Similarly, A20 has recently been implicated as an essential regulator of inflammation in the oral cavity. This review presents information on the ubiquitin system and regulation of NF-κB by ubiquitination using A20 as a representative molecule and highlights how the dysregulation of this system can lead to several immune pathologies, including oral cavity-related disorders mainly focusing on periodontitis.
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Affiliation(s)
- E.C. Mooney
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Philips Institute for Oral Health Research, Virginia Commonwealth University, School of Dentistry, Richmond, VA, USA
| | - S.E. Sahingur
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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15
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Abstract
The circadian clock protein REVERBα is proposed to be a key regulator of liver metabolism. We now show that REVERBα action is critically dependent on metabolic state. Using transgenic mouse models, we show that the true role of REVERBα is to buffer against aberrant responses to metabolic perturbation, rather than confer rhythmic regulation to programs of lipid synthesis and storage, as has been thought previously. Thus, in the case of liver metabolism, the clock does not so much drive rhythmic processes, as provide protection against mistimed feeding cues. Understanding how the clock is coupled to metabolism is critical for understanding metabolic disease and the impacts of circadian disruptors such as shift work and 24-h lifestyles. The nuclear receptor REVERBα is a core component of the circadian clock and proposed to be a dominant regulator of hepatic lipid metabolism. Using antibody-independent ChIP-sequencing of REVERBα in mouse liver, we reveal a high-confidence cistrome and define direct target genes. REVERBα-binding sites are highly enriched for consensus RORE or RevDR2 motifs and overlap with corepressor complex binding. We find no evidence for transcription factor tethering and DNA-binding domain-independent action. Moreover, hepatocyte-specific deletion of Reverbα drives only modest physiological and transcriptional dysregulation, with derepressed target gene enrichment limited to circadian processes. Thus, contrary to previous reports, hepatic REVERBα does not repress lipogenesis under basal conditions. REVERBα control of a more extensive transcriptional program is only revealed under conditions of metabolic perturbation (including mistimed feeding, which is a feature of the global Reverbα−/− mouse). Repressive action of REVERBα in the liver therefore serves to buffer against metabolic challenge, rather than drive basal rhythmicity in metabolic activity.
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16
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Wu Y, He X, Huang N, Yu J, Shao B. A20: a master regulator of arthritis. Arthritis Res Ther 2020; 22:220. [PMID: 32958016 PMCID: PMC7504854 DOI: 10.1186/s13075-020-02281-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023] Open
Abstract
A20, also known as TNF-α-induced protein 3 (TNFAIP3), is an anti-inflammatory protein that plays an important part in both immune responses and cell death. Impaired A20 function is associated with several human inflammatory and autoimmune diseases. Although the role of A20 in mediating inflammation has been frequently discussed, its intrinsic link to arthritis awaits further explanation. Here, we review new findings that further demonstrate the molecular mechanisms through which A20 regulates inflammatory arthritis, and we discuss the regulation of A20 by many factors. We conclude by reviewing the latest A20-associated mouse models that have been applied in related research because they reflect the characteristics of arthritis, the study of which will hopefully cast new light on anti-arthritis treatments.
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Affiliation(s)
- Yongyao Wu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Xiaomin He
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Ning Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
| | - Jiayun Yu
- State Key Laboratory of Biotherapy anf Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bin Shao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China. .,State Key Laboratory of Biotherapy anf Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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17
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Soltani N, Marandi SM, Kazemi M, Esmaeil N. Combined All-Extremity High-Intensity Interval Training Regulates Immunometabolic Responses through Toll-Like Receptor 4 Adaptors and A20 Downregulation in Obese Young Females. Obes Facts 2020; 13:415-431. [PMID: 32615574 PMCID: PMC7445579 DOI: 10.1159/000509132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 06/02/2020] [Indexed: 12/17/2022] Open
Abstract
Metainflammation and malfunctions of toll-like receptor 4 (TLR4) are related to obesity-induced immunometabolic morbidities. There are almost no studies relating exercise training to the TLR4 pathway and its adaptors and negative regulators. Thirty young women with obesity (exercise group and control group) were included in a 10-week all-extremity combined high-intensity interval training program. The immunomodulatory impacts of exercise on TLR4, its related adaptors (TIR domain-containing adaptor-inducing IFN-β[TRIF], myeloid differentiation factor 88 [MyD88],and tumor receptor-associated factor 6 [TRAF6]), transcriptional factors (nuclear factor [NF]-κB and interferon regulatory factor 3 [IRF3]), and negative regulator (A20) mRNA levels were assessed by real-time PCR. Also, the serum concentration of TLR4 final products (tumor necrosis factor α [TNFα] and interferon γ [IFNγ]) was measured by ELISA. Cardiorespiratory and body composition parameters were tested, as well. There was a significant improvement in body composition and cardiorespiratory fitness. This intervention downregulated TLR4 (from 2.25 ± 1.07 to 0.84 ± 1.01), MyD88 (from 4.53 ± 5.15 to 1.27 ± 0.88), NF-κB (from 1.61 ± 2.03 to 0.23 ± 0.39), IRF3 (from 1.22 ± 0.77 to 0.25 ± 0.36), and A20 (from 0.88 ± 0.59 to 0.22 ± 0.33) levels and reduced the TNFα concentrations (from 22.39 ± 11.43 to 6.26 ± 5.31) significantly in the exercise group, while no statistically significant change was found in TRIF and TRAF6 expression and IFNγ circulating levels. It is concluded that long-term exercise modifies the inflammatory pathways and modulates the immune function at the early stages of inflammation initiation in circulating immune cells. Accordingly, we suggest time-efficient exercise protocols as a possible therapy approach for the prevention of M1 polarization.
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Affiliation(s)
- Nakisa Soltani
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
| | - Sayed Mohammad Marandi
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Isfahan, Iran
- **Sayed Mohammad Marandi, Department of Exercise Physiology, Faculty of Sport Sciences, University of Isfahan, Azadi Sq., Isfahan 81746-73441 (Iran),
| | - Mohammad Kazemi
- Department of Genetics and Molecular Biology, University of Medical Sciences, Isfahan, Iran
| | - Nafiseh Esmaeil
- Department of Immunology, School of Medicine, University of Medical Sciences, Isfahan, Iran
- *Nafiseh Esmaeil, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 81746-73461 (Iran),
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18
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More than an Anti-diabetic Bariatric Surgery, Metabolic Surgery Alleviates Systemic and Local Inflammation in Obesity. Obes Surg 2019; 28:3658-3668. [PMID: 30187424 DOI: 10.1007/s11695-018-3400-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Obesity, associated with increased risk of type 2 diabetes (T2D), cardiovascular disease, and hepatic steatosis et al., has become a major global health problem. Recently, obesity has been proven to be under a status of low-grade, chronic inflammation, which contributes to insulin resistance and T2D. Bariatric surgery is currently an effective treatment for the control of morbid obesity and T2D, which impels ongoing efforts to clarify physiological and molecular mechanisms mediating these benefits. The correlation between obesity, inflammation, and T2D has been revealed to a certain extent, and studies have shed light on the effect of bariatric surgery on inflammatory status of subjects with obesity. Based on recent findings, this review focuses on the relationship between inflammation, obesity, and bariatric surgery.
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19
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Momtazi G, Lambrecht BN, Naranjo JR, Schock BC. Regulators of A20 (TNFAIP3): new drug-able targets in inflammation. Am J Physiol Lung Cell Mol Physiol 2018; 316:L456-L469. [PMID: 30543305 DOI: 10.1152/ajplung.00335.2018] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Persistent activation of the transcription factor Nuclear factor-κB (NF-κB) is central to the pathogenesis of many inflammatory disorders, including those of the lung such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, management of the inflammatory component of these diseases still remains suboptimal. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in several autoimmune and inflammatory disorders and more recently in terms of chronic lung disorders. However, the underlying mechanism for the apparent lack of A20 in CF, COPD, and asthma has not been investigated. Transcriptional regulation of A20 is complex and requires coordination of different transcription factors. In this review we examine the existing body of research evidence on the regulation of A20, concentrating on pulmonary inflammation. Special focus is given to the repressor downstream regulatory element antagonist modulator (DREAM) and its nuclear and cytosolic action to regulate inflammation. We provide evidence that would suggest the A20-DREAM axis to be an important player in (airway) inflammatory responses and point to DREAM as a potential future therapeutic target for the modification of phenotypic changes in airway inflammatory disorders. A schematic summary describing the role of DREAM in inflammation with a focus on chronic lung diseases as well as the possible consequences of altered DREAM expression on immune responses is provided.
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Affiliation(s)
- G Momtazi
- Centre for Experimental Medicine, Queen's University of Belfast , Belfast , United Kingdom
| | - B N Lambrecht
- VIB Center for Inflammation Research, Ghent, Belgium.,Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - J R Naranjo
- Spanish Network for Biomedical Research in Neurodegenerative Diseases (Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas), Instituto de Salud Carlos III, Madrid, Spain.,National Biotechnology Center, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
| | - B C Schock
- Centre for Experimental Medicine, Queen's University of Belfast , Belfast , United Kingdom
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20
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Ripley EM, Clarke GD, Hamidi V, Martinez RA, Settles FD, Solis C, Deng S, Abdul-Ghani M, Tripathy D, DeFronzo RA. Reduced skeletal muscle phosphocreatine concentration in type 2 diabetic patients: a quantitative image-based phosphorus-31 MR spectroscopy study. Am J Physiol Endocrinol Metab 2018; 315:E229-E239. [PMID: 29509433 PMCID: PMC6139498 DOI: 10.1152/ajpendo.00426.2017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mitochondrial function has been examined in insulin-resistant (IR) states including type 2 diabetes mellitus (T2DM). Previous studies using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) in T2DM reported results as relative concentrations of metabolite ratios, which could obscure differences in phosphocreatine ([PCr]) and adenosine triphosphate concentrations ([ATP]) between T2DM and normal glucose tolerance (NGT) individuals. We used an image-guided 31P-MRS method to quantitate [PCr], inorganic phosphate [Pi], phosphodiester [PDE], and [ATP] in vastus lateralis (VL) muscle in 11 T2DM and 14 NGT subjects. Subjects also received oral glucose tolerance test, euglycemic insulin clamp, 1H-MRS to measure intramyocellular lipids [IMCL], and VL muscle biopsy to evaluate mitochondrial density. T2DM subjects had lower absolute [PCr] and [ATP] than NGT subjects (PCr 28.6 ± 3.2 vs. 24.6 ± 2.4, P < 0.002, and ATP 7.18 ± 0.6 vs. 6.37 ± 1.1, P < 0.02) while [PDE] was higher, but not significantly. [PCr], obtained using the traditional ratio method, showed no significant difference between groups. [PCr] was negatively correlated with HbA1c ( r = -0.63, P < 0.01) and fasting plasma glucose ( r = -0.51, P = 0.01). [PDE] was negatively correlated with Matsuda index ( r = -0.43, P = 0.03) and M/I ( r = -0.46, P = 0.04), but was positively correlated with [IMCL] ( r = 0.64, P < 0.005), HbA1c, and FPG ( r = 0.60, P = 0.001). To summarize, using a modified, in vivo quantitative 31P-MRS method, skeletal muscle [PCr] and [ATP] are reduced in T2DM, while this difference was not observed with the traditional ratio method. The strong inverse correlation between [PCr] vs. HbA1c, FPG, and insulin sensitivity supports the concept that lower baseline skeletal muscle [PCr] is related to key determinants of glucose homeostasis.
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Affiliation(s)
- Erika M Ripley
- Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Geoffrey D Clarke
- Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
- Research Imaging Institute, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Vala Hamidi
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Robert A Martinez
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Floyd D Settles
- Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Carolina Solis
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Shengwen Deng
- Research Imaging Institute, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Muhammad Abdul-Ghani
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Devjit Tripathy
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
| | - Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center at San Antonio , San Antonio, Texas
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Abstract
PURPOSE OF REVIEW Obesity rates in the USA have reached pandemic levels with one third of the population with obesity in 2015-2016 (39.8% of adults and 18.5% of youth). It is a major public health concern, and it is prudent to understand the factors which contribute. Racial and ethnic disparities are pronounced in both the prevalence and treatment of obesity and must be addressed in the efforts to combat obesity. RECENT FINDINGS Disparities in prevalence of obesity in racial/ethnic minorities are apparent as early as the preschool years and factors including genetics, diet, physical activity, psychological factors, stress, income, and discrimination, among others, must be taken into consideration. A multidisciplinary team optimizes lifestyle and behavioral interventions, pharmacologic therapy, and access to bariatric surgery to develop the most beneficial and equitable treatment plans. The reviewed studies outline disparities that exist and the impact that race/ethnicity have on disease prevalence and treatment response. Higher prevalence and reduced treatment response to lifestyle, behavior, pharmacotherapy, and surgery, are observed in racial and ethnic minorities. Increased research, diagnosis, and access to treatment in the pediatric and adult populations of racial and ethnic minorities are proposed to combat the burgeoning obesity epidemic and to prevent increasing disparity.
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Affiliation(s)
- Angel S Byrd
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexander T Toth
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Fatima Cody Stanford
- Harvard Medical School, Boston, MA, USA.
- MGH Weight Center, Gastrointestinal Unit-Department of Medicine, Massachusetts General Hospital, 50 Staniford Street, Suite 430, Boston, MA, 02114, USA.
- Department of Pediatrics-Endocrinology, Massachusetts General Hospital, Boston, MA, USA.
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22
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Labrecque J, Laforest S, Michaud A, Biertho L, Tchernof A. Impact of Bariatric Surgery on White Adipose Tissue Inflammation. Can J Diabetes 2017; 41:407-417. [PMID: 28365202 DOI: 10.1016/j.jcjd.2016.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 09/23/2016] [Accepted: 12/05/2016] [Indexed: 12/14/2022]
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23
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Does Bariatric Surgery Improve Obesity Associated Comorbid Conditions. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 960:545-570. [PMID: 28585216 DOI: 10.1007/978-3-319-48382-5_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Obesity is a constantly growing health problem which reduces quality of life and life expectancy. Bariatric surgery for obesity is taken into account when all other conservative treatment modalities have failed. Comparison of the multidisciplinary programs with bariatric surgery regarding to weight loss showed that substantial and durable weight reduction have been achieved only with bariatric surgical treatments. However, the benefits of weight loss following bariatric procedures are still debated regarding the pro-inflammatory and metabolic profile of obesity.
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24
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Zhang Y, Zhang XJ, Wang PX, Zhang P, Li H. Reprogramming Innate Immune Signaling in Cardiometabolic Disease. Hypertension 2017; 69:747-760. [PMID: 28320852 DOI: 10.1161/hypertensionaha.116.08192] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Yaxing Zhang
- From the Department of Cardiology, Renmin Hospital (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), School of Basic Medical Sciences (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Institute of Model Animal (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), and Medical Research Institute, School of Medicine (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Wuhan University, P.R. China
| | - Xiao-Jing Zhang
- From the Department of Cardiology, Renmin Hospital (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), School of Basic Medical Sciences (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Institute of Model Animal (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), and Medical Research Institute, School of Medicine (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Wuhan University, P.R. China
| | - Pi-Xiao Wang
- From the Department of Cardiology, Renmin Hospital (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), School of Basic Medical Sciences (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Institute of Model Animal (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), and Medical Research Institute, School of Medicine (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Wuhan University, P.R. China
| | - Peng Zhang
- From the Department of Cardiology, Renmin Hospital (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), School of Basic Medical Sciences (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Institute of Model Animal (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), and Medical Research Institute, School of Medicine (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Wuhan University, P.R. China
| | - Hongliang Li
- From the Department of Cardiology, Renmin Hospital (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), School of Basic Medical Sciences (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Institute of Model Animal (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), and Medical Research Institute, School of Medicine (Y.Z., X.-J.Z., P.-X.W., P.Z., H.L.), Wuhan University, P.R. China.
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25
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Paltoglou G, Schoina M, Valsamakis G, Salakos N, Avloniti A, Chatzinikolaou A, Margeli A, Skevaki C, Papagianni M, Kanaka-Gantenbein C, Papassotiriou I, Chrousos GP, Fatouros IG, Mastorakos G. Interrelations among the adipocytokines leptin and adiponectin, oxidative stress and aseptic inflammation markers in pre- and early-pubertal normal-weight and obese boys. Endocrine 2017; 55:925-933. [PMID: 28092067 DOI: 10.1007/s12020-017-1227-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 01/04/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE Presumed interrelationships among deleterious aspects of adipose tissue metabolism, inflammation, and cellular oxidative stress could be influenced by pubertal hormonal changes. They were investigated in pre- and early pubertal normal-weight and obese boys before and after an exercise bout employed as an energy demanding stimulator. METHODS Cross-sectional study. Seventy-six healthy pre- (mean ± SD, 10.6 ± 0.2 years old, 28 normal-weight, and 11 obese) and early-(11.4 ± 0.2 years old, 25 normal-weight, and 12 obese) pubertal boys, were blood-sampled before and after a bout of exercise at 70% VO2 max. Leptin, adiponectin, markers of inflammation (high-sensitivity C-reactive protein, high sensitivity IL-6), pro- (thiobarbitouric acid reactive substances, protein carbonyls) and anti- (glutathione, oxidized glutathione, glutathione peroxidase, catalase, total antioxidant capacity) oxidation were measured. RESULTS Baseline and post-exercise adiponectin was greater and leptin and high-sensitivity C-reactive protein were lower in normal-weight than in obese pre- and early pubertal boys, while high sensitivity IL-6 was greater in obese than in normal-weight pre-pubertal boys. In pre-pubertal obese boys: at baseline, high-sensitivity C-reactive protein correlated negatively with catalase; high sensitivity IL-6 correlated positively with protein carbonyls; Δ (difference during exercise) adiponectin correlated positively with Δcatalase. In all boys: at baseline, high sensitivity IL-6 correlated positively with leptin and was the best negative and the second best positive predictor for post-exercise glutathione/oxidized glutathione and protein carbonyls, respectively; leptin was the best negative predictor for post-exercise glutathione; waist to height ratio was the best positive predictor for post-exercise thiobarbitouric acid reactive substances; body mass index z-score and adiponectin were, respectively, the best positive predictor for post-exercise protein carbonyls and catalase. CONCLUSIONS In all subjects, leptin and adiponectin predict negatively and positively anti-oxidation, respectively, while high sensitivity IL-6 predicts positively and negatively pro- and anti-oxidation, respectively. High-sensitivity C-reactive protein is increased and negatively associated with anti-oxidation in pre-pubertal obese boys, suggesting that childhood obesity is associated with aseptic inflammation and oxidative stress.
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Affiliation(s)
- George Paltoglou
- Endocrine Unit, "Aretaieion" Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece
- First Department of Pediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece
| | - Maria Schoina
- Department of Physical Education and Sports Sciences, Democritus University of Thrace, Komotini, Greece
| | - George Valsamakis
- Endocrine Unit, "Aretaieion" Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece
| | - Nicolaos Salakos
- Second Department of Obstetrics and Gynecology, "Aretaieion" Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece
| | - Alexandra Avloniti
- Department of Physical Education and Sports Sciences, Democritus University of Thrace, Komotini, Greece
| | - Athanasios Chatzinikolaou
- Department of Physical Education and Sports Sciences, Democritus University of Thrace, Komotini, Greece
| | - Alexandra Margeli
- Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Chrysanthi Skevaki
- Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Maria Papagianni
- Pediatric Endocrinology Unit, Third Department of Pediatrics, "Hippokrateion" General Hospital of Thessaloniki, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - Christina Kanaka-Gantenbein
- First Department of Pediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece
| | - Ioannis Papassotiriou
- Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - George P Chrousos
- First Department of Pediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece
| | - Ioannis G Fatouros
- Department of Physical Education and Sports Sciences, University of Thessaly, Trikala, Greece
| | - George Mastorakos
- Endocrine Unit, "Aretaieion" Hospital, National and Kapodistrian University of Athens - Faculty of Medicine, Athens, Greece.
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Targeting of the circadian clock via CK1δ/ε to improve glucose homeostasis in obesity. Sci Rep 2016; 6:29983. [PMID: 27439882 PMCID: PMC4954991 DOI: 10.1038/srep29983] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 06/24/2016] [Indexed: 12/21/2022] Open
Abstract
Growing evidence indicates that disruption of our internal timing system contributes to the incidence and severity of metabolic diseases, including obesity and type 2 diabetes. This is perhaps not surprising since components of the circadian clockwork are tightly coupled to metabolic processes across the body. In the current study, we assessed the impact of obesity on the circadian system in mice at a behavioural and molecular level, and determined whether pharmacological targeting of casein kinase 1δ and ε (CK1δ/ε), key regulators of the circadian clock, can confer metabolic benefit. We demonstrate that although behavioural rhythmicity was maintained in diet-induced obesity (DIO), gene expression profiling revealed tissue-specific alteration to the phase and amplitude of the molecular clockwork. Clock function was most significantly attenuated in visceral white adipose tissue (WAT) of DIO mice, and was coincident with elevated tissue inflammation, and dysregulation of clock-coupled metabolic regulators PPARα/γ. Further, we show that daily administration of a CK1δ/ε inhibitor (PF-5006739) improved glucose tolerance in both DIO and genetic (ob/ob) models of obesity. These data further implicate circadian clock disruption in obesity and associated metabolic disturbance, and suggest that targeting of the clock represents a therapeutic avenue for the treatment of metabolic disorders.
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Kuschnerus K, Landmesser U, Kränkel N. Vascular repair strategies in type 2 diabetes: novel insights. Cardiovasc Diagn Ther 2015; 5:374-86. [PMID: 26543824 DOI: 10.3978/j.issn.2223-3652.2015.05.11] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Impaired functions of vascular cells are responsible for the majority of complications in patients with type 2 diabetes (T2D). Recently a better understanding of mechanisms contributing to development of vascular dysfunction and the role of systemic inflammatory activation and functional alterations of several secretory organs, of which adipose tissue has more recently been investigated, has been achieved. Notably, the progression of vascular disease within the context of T2D appears to be driven by a multitude of incremental signaling shifts. Hence, successful therapies need to target several mechanisms in parallel, and over a long time period. This review will summarize the latest molecular strategies and translational developments of cardiovascular therapy in patients with T2D.
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Affiliation(s)
- Kira Kuschnerus
- Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik für Kardiologie, Berlin, Germany
| | - Ulf Landmesser
- Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik für Kardiologie, Berlin, Germany
| | - Nicolle Kränkel
- Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Medizinische Klinik für Kardiologie, Berlin, Germany
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28
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Tureck LV, Leite N, Souza RLR, da Silva Timossi L, Osiecki ACV, Osiecki R, Alle LF. ADIPOQ single nucleotide polymorphism: Association with adiponectin and lipoproteins levels restricted to men. Meta Gene 2015; 5:98-104. [PMID: 26137445 PMCID: PMC4484719 DOI: 10.1016/j.mgene.2015.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 05/22/2015] [Accepted: 06/08/2015] [Indexed: 12/12/2022] Open
Abstract
Adiponectin is an adipokine inversely correlated with obesity, which has beneficial effect on insulin resistance and lipid metabolism. Considering its potential as a therapeutic target in the metabolic disorder contexts, and in order to add knowledge in the area, our study evaluated the ADIPOQ 276G > T polymorphism effect on adiponectin levels, and on lipoproteins of clinical interest in a population sample composed of 211 healthy individuals. Significant effects were observed only among men: the carriers of heterozygous genotype (GT) showed high levels of adiponectin (p = 0.018), while the rare homozygous genotype (TT) gave its carriers a negative phenotype, represented by higher levels of low density lipoprotein cholesterol (LDL-C) (p = 0.004 and p = 0.005) and total cholesterol (TC) (p = 0.010 and p = 0.005) compared to carriers of other genotypes (GG and GT respectively), the independent effect of SNP on LDL-C and TC levels was confirmed by multiple regression analysis (p = 0.008 and p = 0.044). We found no evidence of correlation between circulating adiponectin levels and biochemical markers, which suggests, therefore, an SNP 276G > T independent effect on adiponectin levels and on lipoprotein metabolism in men enrolled in this study.
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Key Words
- 276G > T SNP
- ADIPOQ gene
- AMPK, adenosine monophosphate-activated protein kinase
- Adiponectin
- BMI, body mass index
- ELISA, enzyme-Linked Immunosorbent assay
- GWA study, genome-wide association study
- Gender effect
- HDL-C, high density lipoprotein cholesterol
- HL, hepatic lipase
- IDL, intermediate density lipoproteins
- LDL-C, low density lipoprotein cholesterol
- LDLR, LDL-C receptor
- LPL, lipoprotein lipase
- Lipid metabolism
- SNP, single-nucleotide polymorphism
- TC, total cholesterol
- TG, triglycerides
- VLDL, very low density lipoproteins
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Affiliation(s)
- Luciane Viater Tureck
- Polymorphism and Linkage Laboratory, Department of Genetics, Federal University of Paraná, Brazil
| | - Neiva Leite
- Department of Physical Education, Federal University of Paraná, Brazil
| | | | | | | | - Raul Osiecki
- Department of Physical Education, Federal University of Paraná, Brazil
| | - Lupe Furtado Alle
- Polymorphism and Linkage Laboratory, Department of Genetics, Federal University of Paraná, Brazil
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Liu W, Wang H, Wang Y, Li H, Ji L. Metabolic factors-triggered inflammatory response drives antidepressant effects of exercise in CUMS rats. Psychiatry Res 2015; 228:257-264. [PMID: 26144579 DOI: 10.1016/j.psychres.2015.05.102] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 05/15/2015] [Accepted: 05/25/2015] [Indexed: 12/22/2022]
Abstract
Chronic stress is a potential contributing factor for depression, accompanying with metabolic and inflammatory response. Exercise is considered as a treatment for depression, but mechanisms underlying its beneficial effects still remain unknown. The objectives of present study were to confirm that metabolic factors-triggered inflammatory response mediates the antidepressant actions of exercise in chronic unpredictable mild stress (CUMS) rats. It has been found that CUMS stimulated expression of ghrelin and its receptor Ghsr, but inhibited expression of leptin and its receptor LepRb. Ghrelin, via binding to Ghsr, induced phosphorylation of GSK-3β on Tyr216 and decreased phosphorylation on Ser9, thus increasing GSK-3β activity. Conversely, ghrelin binding to Ghsr decreased STAT3 activity, through decreasing phosphorylation of STAT3 on Tyr705 and increasing Ser727 phosphorylation. Negatively correlated with ghrelin, leptin binding to LepRb had opposite effects on the activity of GSK-3β and STAT3 via phosphorylation. In addition, decreased leptin level initiated NLRP3 activity via LepRb. Furthermore, GSK-3β inhibited STAT3 activation, thus promoting the expression of NLRP3. Meanwhile, swim improved metabolic and inflammatory response both in CUMS and control rats. Our findings suggest that exercise not only ameliorates metabolic disturbance and inflammatory response in depression, but also contributes to metabolic and inflammatory function in normal conditions.
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Affiliation(s)
- Weina Liu
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China.
| | - Hongmei Wang
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China
| | - Yangkai Wang
- Department of Physiology, Second Military Medical University, Shanghai 200433, China
| | - Haipeng Li
- School of Physical Education & Health Care, Hangzhou Normal University, Hangzhou 311121, China
| | - Liu Ji
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China.
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30
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Zhang XJ, Zhang P, Li H. Interferon regulatory factor signalings in cardiometabolic diseases. Hypertension 2015; 66:222-47. [PMID: 26077571 DOI: 10.1161/hypertensionaha.115.04898] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2015] [Accepted: 05/14/2015] [Indexed: 12/24/2022]
Affiliation(s)
- Xiao-Jing Zhang
- From the Department of Cardiology, Renmin Hospital (X.-J.Z., P.Z., H.L.) and Cardiovascular Research Institute (X.-J.Z., P.Z., H.L.), Wuhan University, Wuhan, China; and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, PR China (X.-J.Z.)
| | - Peng Zhang
- From the Department of Cardiology, Renmin Hospital (X.-J.Z., P.Z., H.L.) and Cardiovascular Research Institute (X.-J.Z., P.Z., H.L.), Wuhan University, Wuhan, China; and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, PR China (X.-J.Z.)
| | - Hongliang Li
- From the Department of Cardiology, Renmin Hospital (X.-J.Z., P.Z., H.L.) and Cardiovascular Research Institute (X.-J.Z., P.Z., H.L.), Wuhan University, Wuhan, China; and State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, PR China (X.-J.Z.).
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Abstract
Coordinated daily rhythms are evident in most aspects of our physiology, driven by internal timing systems known as circadian clocks. Our understanding of how biological clocks are built and function has grown exponentially over the past 20 years. With this has come an appreciation that disruption of the clock contributes to the pathophysiology of numerous diseases, from metabolic disease to neurological disorders to cancer. However, it remains to be determined whether it is the disruption of our rhythmic physiology per se (loss of timing itself), or altered functioning of individual clock components that drive pathology. Here, we review the importance of circadian rhythms in terms of how we (and other organisms) relate to the external environment, but also in relation to how internal physiological processes are coordinated and synchronized. These issues are of increasing importance as many aspects of modern life put us in conflict with our internal clockwork.
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Affiliation(s)
- Alexander C West
- Faculty of Life Sciences, University of Manchester, Manchester, UK
| | - David A Bechtold
- Faculty of Life Sciences, University of Manchester, Manchester, UK
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