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1
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Kargar B, Zamanian Z, Hosseinabadi MB, Gharibi V, Moradi MS, Cousins R. Understanding the role of oxidative stress in the incidence of metabolic syndrome and obstructive sleep apnea. BMC Endocr Disord 2021; 21:77. [PMID: 33882916 PMCID: PMC8059172 DOI: 10.1186/s12902-021-00735-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 04/07/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Understanding the causes and risk factors of metabolic syndrome is important for promoting population health. Oxidative stress has been associated with metabolic syndrome, and also obstructive sleep apnea. These are two diseases which have common prognostic characteristics for heart disease. The aim of this study was to examine the role of oxidative stress in the concurrent presence of metabolic syndrome and obstructive sleep apnea in a working population. METHODS Participants were 163 artisan bakers in Shahroud, Iran, routinely exposed to significant heat stress and other oxidative stress indicators on a daily basis as part of their work. Using a cross-sectional design, data relevant to determining metabolic syndrome status according to International Diabetes Federation criteria, and the presence of obstructive sleep apnea according to the STOP-Bang score, was collected. Analyses included hierarchical binary logistic regression to yield predictors of the two diseases. RESULTS Hierarchical binary logistic regression showed that oxidative stress - alongside obesity, no regular exercise, and smoking - was an independent predictor of metabolic syndrome, but not obstructive sleep apnea. Participants who were obese were 28 times more likely to have metabolic syndrome (OR 28.59, 95% CI 4.91-63.02) and 44 times more likely to have obstructive sleep apnea (OR 44.48, 95% CI 4.91-403.28). Participants meeting metabolic syndrome criteria had significantly higher levels of malondialdehyde (p < 0.05) than those who did not. No difference in oxidative stress index levels were found according to obstructive sleep apnea status. CONCLUSIONS Our findings suggest that oxidative stress contributes to the onset of metabolic syndrome, and that obstructive sleep apnea is involved in oxidative stress. Whilst obesity, exercise, and smoking remain important targets for reducing the incidence of metabolic syndrome and obstructive sleep apnea, policies to control risks of prolonged exposure to oxidative stress are also relevant in occupations where such environmental conditions exist.
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Affiliation(s)
- Behnam Kargar
- Department of Pharmacology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Zamanian
- Department of Occupational Health, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Vahid Gharibi
- Department of Occupational Health, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
- School of Public Health, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohammad Sanyar Moradi
- Department of Occupational Health, School of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Rosanna Cousins
- Department of Psychology, Liverpool Hope University, Liverpool, UK
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2
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Ye JJ, Bian X, Lim J, Medzhitov R. Adiponectin and related C1q/TNF-related proteins bind selectively to anionic phospholipids and sphingolipids. Proc Natl Acad Sci U S A 2020; 117:17381-17388. [PMID: 32632018 PMCID: PMC7382265 DOI: 10.1073/pnas.1922270117] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.
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Affiliation(s)
- Jessica J Ye
- HHMI, Yale University, New Haven, CT 06520
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
| | - Xin Bian
- Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520
- Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520
| | - Jaechul Lim
- HHMI, Yale University, New Haven, CT 06520
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
| | - Ruslan Medzhitov
- HHMI, Yale University, New Haven, CT 06520;
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
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3
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Polito R, Monda V, Nigro E, Messina A, Di Maio G, Giuliano MT, Orrù S, Imperlini E, Calcagno G, Mosca L, Mollica MP, Trinchese G, Scarinci A, Sessa F, Salerno M, Marsala G, Buono P, Mancini A, Monda M, Daniele A, Messina G. The Important Role of Adiponectin and Orexin-A, Two Key Proteins Improving Healthy Status: Focus on Physical Activity. Front Physiol 2020; 11:356. [PMID: 32390865 PMCID: PMC7188914 DOI: 10.3389/fphys.2020.00356] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 03/27/2020] [Indexed: 12/15/2022] Open
Abstract
Exercise represents the most important integrative therapy in metabolic, immunologic and chronic diseases; it represents a valid strategy in the non-pharmacological intervention of lifestyle linked diseases. A large body of evidence indicates physical exercise as an effective measure against chronic non-communicable diseases. The worldwide general evidence for health benefits are both for all ages and skill levels. In a dysregulated lifestyle such as in the obesity, there is an imbalance in the production of different cytokines. In particular, we focused on Adiponectin, an adipokine producted by adipose tissue, and on Orexin-A, a neuropeptide synthesized in the lateral hypothalamus. The production of both Adiponectin and Orexin-A increases following regular and structured physical activity and both these hormones have similar actions. Indeed, they improve energy and glucose metabolism, and also modulate energy expenditure and thermogenesis. In addition, a relevant biological role of Adiponectin and Orexin A has been recently highlighted in the immune system, where they function as immune-suppressor factors. The strong connection between these two cytokines and healthy status is mediated by physical activity and candidates these hormones as potential biomarkers of the beneficial effects induced by physical activity. For these reasons, this review aims to underly the interconnections among Adiponectin, Orexin-A, physical activity and healthy status. Furthermore, it is analyzed the involvement of Adiponectin and Orexin-A in physical activity as physiological factors improving healthy status through physical exercise.
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Affiliation(s)
- Rita Polito
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania "Luigi Vanvitelli", Caserta, Italy.,Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Vincenzo Monda
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Ersilia Nigro
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania "Luigi Vanvitelli", Caserta, Italy.,Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy
| | - Antonietta Messina
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Girolamo Di Maio
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Teresa Giuliano
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Stefania Orrù
- Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Naples, Italy.,IRCCS SDN, Naples, Italy
| | | | - Giuseppe Calcagno
- Dipartimento di Medicina e Scienze della Salute "Vincenzo Tiberio", Università degli Studi del Molise, Campobasso, Italy
| | - Laura Mosca
- Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy
| | - Maria Pina Mollica
- Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy
| | - Giovanna Trinchese
- Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy
| | - Alessia Scarinci
- Dipartimento di Scienze della Formazione, Psicologia, Comunicazione, Università degli Studi di Bari Aldo Moro, Bari, Italy
| | - Francesco Sessa
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Monica Salerno
- Department of Medical, Surgery Sciences and Advanced Technologies "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Gabriella Marsala
- Struttura Complessa di Farmacia, Azienda Ospedaliero Universitaria - Ospedali Riuniti, Foggia, Italy
| | - Pasqualina Buono
- Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy.,Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Naples, Italy.,IRCCS SDN, Naples, Italy
| | - Annamaria Mancini
- Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy.,Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli "Parthenope", Naples, Italy
| | - Marcellino Monda
- Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy
| | - Aurora Daniele
- Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania "Luigi Vanvitelli", Caserta, Italy.,Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy
| | - Giovanni Messina
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
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Lian K, Feng YN, Li R, Liu HL, Han P, Zhou L, Li CX, Wang Q. Middle- and high-molecular weight adiponectin levels in relation to nonalcoholic fatty liver disease. J Clin Lab Anal 2019; 34:e23148. [PMID: 31880002 PMCID: PMC7171302 DOI: 10.1002/jcla.23148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 10/21/2019] [Accepted: 11/15/2019] [Indexed: 12/14/2022] Open
Abstract
Objective Adiponectin (APN) circulates as high‐molecular weight (HMW), medium‐molecular weight (MMW), and low‐molecular weight (LMW) forms. Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. Currently, the role of LMW, MMW, and HMW APN remains largely unclear in NAFLD. Methods We examined the variation of these forms and analyzed the related clinical characteristics in NAFLD. A total of 63 male NAFLD patients (mean age: 43.00 ± 6.10 years) and 70 healthy male subjects (mean age: 42.53 ± 7.98 years) were included in the study. Total APN and other clinical characteristics were measured. The changes in HMW, MMW, and LMW APN were determined in NAFLD patients and NAFLD patients on a high‐fat diet, and the association between the groups was further analyzed. Results Decreased levels of total APN and three APN isoforms were found in NAFLD. Significantly decreased levels of HMW (P < .01) and MMW (P < .001) were observed in NAFLD of high‐fat diet patients. In NAFLD patients, height (R = −.270, P = .032) and N‐epsilon‐(carboxymethyl) lysine (R = −.259, P = .040) significantly correlated with total APN. HMW APN was significantly associated with fasting plasma glucose (R = .350, P = .016), alanine aminotransferase (R = −.321, P = .029), and aspartate aminotransferase (R = −.295, P = .045). Additionally, MMW APN was significantly associated with total cholesterol (R = .357, P = .014) and high‐density lipoprotein (R = .556, P < .0001). Low‐density lipoprotein (R = −.283, P = .054) was also clearly associated with LMW APN in NAFLD patients. Conclusion These results suggest that HMW and MMW APN may be involved in the pathogenesis and progression of NAFLD.
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Affiliation(s)
- Kun Lian
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yu-Nan Feng
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Rong Li
- Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Hao-Lin Liu
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Peng Han
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lei Zhou
- Department of Clinical Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Cheng-Xiang Li
- Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Qin Wang
- State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, China
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Botta A, Liu Y, Wannaiampikul S, Tungtrongchitr R, Dadson K, Park TS, Sweeney G. An adiponectin-S1P axis protects against lipid induced insulin resistance and cardiomyocyte cell death via reduction of oxidative stress. Nutr Metab (Lond) 2019; 16:14. [PMID: 30828353 PMCID: PMC6385438 DOI: 10.1186/s12986-019-0342-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 02/18/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Adiponectin exerts several beneficial cardiovascular effects, however their specific molecular mechanisms require additional understanding. This study investigated the mechanisms of adiponectin action in the heart during high fat diet (HFD) feeding or in palmitate (PA) treated H9c2 cardiomyoblasts. METHODS 6-week-old male adiponectin knock out (Ad-KO) mice were fed chow or 60% HFD for 6 weeks then received saline or recombinant adiponectin (3μg/g body weight) for an additional 2 weeks. After acute insulin stimulation (4 U/kg), tissue and serum samples were collected for analysis. H9c2 cardiomyocytes were treated ±0.1 mM PA, the adiponectin receptor agonist AdipoRon, or the antioxidant MnTBAP then assays to analyze reactive oxygen species (ROS) production and cell death were conducted. To specifically determine the mechanistic role of S1P, gain and loss of function studies were conducted with adding S1P to cells or the inhibitors THI and SKI-II, respectively. RESULTS HFD feeding induced cardiac insulin resistance in Ad-KO mice, which was reversed following replenishment of normal circulating adiponectin levels. In addition, myocardial total triglyceride was elevated by HFD and lipidomic analysis showed increased levels of ceramides and sphingosine-1-phosphate (S1P), with only the latter being corrected by adiponectin administration. Similarly, treatment of H9C2 cardiomyoblasts with PA led to a significant increase of intracellular S1P but not in conditioned media whereas AdipoRon significantly increased S1P production and secretion from cells. AdipoRon or the antioxidant MnTBAP significantly reduced PA-induced cell death. Gain and loss of function studies suggested S1P secretion and autocrine receptor activation mediated the effect of AdipoRon to attenuate PA-induced ROS production and cell death. CONCLUSION Our data establish adiponectin signaling-mediated increase in S1P secretion as a mechanism via which HFD or PA induced cardiomyocyte lipotoxicity, leading to insulin resistance and cell death, is attenuated.
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Affiliation(s)
- Amy Botta
- Department of Biology, York University, Toronto, ON M3J 1P3 Canada
| | - Ying Liu
- Department of Biology, York University, Toronto, ON M3J 1P3 Canada
| | - Sivaporn Wannaiampikul
- Department of Biology, York University, Toronto, ON M3J 1P3 Canada
- Department of Biochemistry, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Rungsunn Tungtrongchitr
- Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Keith Dadson
- Department of Biology, York University, Toronto, ON M3J 1P3 Canada
| | - Tae-Sik Park
- Department of Life Science, Gachon University, Sungnam, South Korea
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON M3J 1P3 Canada
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6
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Menzies-Gow NJ, Knowles EJ, Rogers I, Rendle DI. Validity and application of immunoturbidimetric and enzyme-linked immunosorbent assays for the measurement of adiponectin concentration in ponies. Equine Vet J 2018; 51:33-37. [DOI: 10.1111/evj.12960] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 03/31/2018] [Indexed: 01/24/2023]
Affiliation(s)
- N. J. Menzies-Gow
- Department of Clinical Sciences and Services; Royal Veterinary College; North Mymms Hertfordshire UK
| | - E. J. Knowles
- Department of Clinical Sciences and Services; Royal Veterinary College; North Mymms Hertfordshire UK
| | - I. Rogers
- Rainbow Equine Lab; Malton North Yorkshire UK
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7
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Kobayashi H, Otsuka H, Yanai M, Haketa A, Hara M, Hishiki M, Abe M, Soma M. Adiponectin is not associated with renal function decline in community-dwelling elderly adults. Medicine (Baltimore) 2018; 97:e10847. [PMID: 29794781 PMCID: PMC6392687 DOI: 10.1097/md.0000000000010847] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Adiponectin secreted by adipocytes plays an important role in the regulation of glucose and fatty acid metabolism. Contrary to findings in patients with chronic kidney disease (CKD), no prospective data about the association of serum adiponectin with renal function decline in the general population have yet appeared. Our objective was to analyze the relationship of total and high molecular weight (HMW) adiponectin with renal function decline as measured by cystatin C in community-dwelling elderly adults without moderate or severe CKD.In a prospective observational analysis, a total of 216 healthy elderly volunteers with eGFRcys ≥60 mL/min/1.73 m underwent anthropometric and laboratory tests at baseline and at follow-up visits. A subgroup with serum samples collected 5 years apart was further analyzed.There were no differences in either total or HMW adiponectin level between subjects subsequently undergoing rapid renal function decline and subjects with normal physiologic renal function decline (P = .71, P = .81). On univariate linear regression, neither total nor HMW adiponectin were associated with annual renal function decline (β = -0.23; P = .71, β = -0.057; P = .90). Multivariate analysis did not show a significant contribution of either total or HMW adiponectin to annual renal function decline (β = -0.50; P = .46, β = 0.01; P = .98). In the logistic regression analysis, we did not observe any statistically significant association of serum adiponectin levels with rapid renal function decline or incidence of CKD.Contrary to findings in populations with CKD, neither total nor HMW adiponectin had a substantial association with renal function decline in an elderly population with eGFRcys ≥60 mL/min/1.73 m. Our results and conclusions should not be extrapolated to subjects with other characteristics.
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Affiliation(s)
| | - Hiromasa Otsuka
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo
| | - Mitsuru Yanai
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo
| | - Akira Haketa
- Division of Nephrology, Hypertension and Endocrinology
| | - Motohiko Hara
- Department of Nursing, School of Health and Social Services, Saitama Prefectural University, Koshigaya-shi, Saitama
| | - Mikano Hishiki
- Department of Diabetes and Endocrinology, Tokyo Metropolitan Hiroo Hospital, Shibuya-ku, Tokyo, Japan
| | - Masanori Abe
- Division of Nephrology, Hypertension and Endocrinology
| | - Masayoshi Soma
- Division of General Medicine, Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo
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8
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Dang TQ, Yoon N, Chasiotis H, Dunford EC, Feng Q, He P, Riddell MC, Kelly SP, Sweeney G. Transendothelial movement of adiponectin is restricted by glucocorticoids. J Endocrinol 2017; 234:101-114. [PMID: 28705835 PMCID: PMC6231241 DOI: 10.1530/joe-16-0363] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 05/10/2017] [Indexed: 12/31/2022]
Abstract
Altered permeability of the endothelial barrier in a variety of tissues has implications both in disease pathogenesis and treatment. Glucocorticoids are potent mediators of endothelial permeability, and this forms the basis for their heavily prescribed use as medications to treat ocular disease. However, the effect of glucocorticoids on endothelial barriers elsewhere in the body is less well studied. Here, we investigated glucocorticoid-mediated changes in endothelial flux of Adiponectin (Ad), a hormone with a critical role in diabetes. First, we used monolayers of endothelial cells in vitro and found that the glucocorticoid dexamethasone increased transendothelial electrical resistance and reduced permeability of polyethylene glycol (PEG, molecular weight 4000 Da). Dexamethasone reduced flux of Ad from the apical to basolateral side, measured both by ELISA and Western blotting. We then examined a diabetic rat model induced by treatment with exogenous corticosterone, which was characterized by glucose intolerance and hyperinsulinemia. There was no change in circulating Ad but less Ad protein in skeletal muscle homogenates, despite slightly higher mRNA levels, in diabetic vs control muscles. Dexamethasone-induced changes in Ad flux across endothelial monolayers were associated with alterations in the abundance of select claudin tight junction (TJ) proteins. shRNA-mediated knockdown of one such gene, claudin-7, in HUVEC resulted in decreased TEER and increased adiponectin flux, confirming the functional significance of Dex-induced changes in its expression. In conclusion, our study identifies glucocorticoid-mediated reductions in flux of Ad across endothelial monolayers in vivo and in vitro This suggests that impaired Ad action in target tissues, as a consequence of reduced transendothelial flux, may contribute to the glucocorticoid-induced diabetic phenotype.
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Affiliation(s)
- Thanh Q Dang
- Department of BiologyFaculty of Science York University, Toronto, Canada
| | - Nanyoung Yoon
- Department of BiologyFaculty of Science York University, Toronto, Canada
| | - Helen Chasiotis
- Department of BiologyFaculty of Science York University, Toronto, Canada
| | - Emily C Dunford
- School of Kinesiology and Health ScienceFaculty of Health and Muscle Health Research Center, York University, Toronto, Canada
| | - Qilong Feng
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Pingnian He
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Michael C Riddell
- School of Kinesiology and Health ScienceFaculty of Health and Muscle Health Research Center, York University, Toronto, Canada
| | - Scott P Kelly
- Department of BiologyFaculty of Science York University, Toronto, Canada
| | - Gary Sweeney
- Department of BiologyFaculty of Science York University, Toronto, Canada
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9
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High-molecular weight adiponectin/HOMA-IR ratio as a biomarker of metabolic syndrome in urban multiethnic Brazilian subjects. PLoS One 2017; 12:e0180947. [PMID: 28746378 PMCID: PMC5528827 DOI: 10.1371/journal.pone.0180947] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 06/12/2017] [Indexed: 12/28/2022] Open
Abstract
Metabolic syndrome (MetS) has an important epidemiological relevance due to its increasing prevalence and association with type 2 diabetes and cardiovascular disease. Insulin resistance is a core feature of the MetS. HOMA-IR is a robust clinical and epidemiological marker of MetS. Adiponectin is an adipokine with insulin-sensitizing and anti-inflammatory functions; its levels decrease as number of components of MetS increases. High-molecular weight adiponectin (HMWA) is the multimer responsible for the relationship of adiponectin with insulin sensitivity. HOMA-IR and HMWA are suitable candidates for MetS biomarkers. The ratio of adiponectin to HOMA-IR has been validated as a powerful index of MetS and considered a better marker of its presence, than either HOMA-IR or adiponectin alone, in selected homogeneous populations. We compared the strength of association between HMWA, HOMA-IR and HMWA/HOMA-IR ratio with MetS and its key components. Our data have shown that the median (25th, 75th percentile) of HMWA/HOMA-IR ratio was lower in subjects with MetS [0.51 (0.33, 1.31)] as compared to those without it [2.19 (1.13, 4.71)]. The correlation coefficient (r) was significantly higher for HMWA/HOMA-IR ratio as compared to HMWA for waist circumference (-0.65; -0.40, respectively); mean blood pressure (-0.27; -0.14, respectively); fasting glucose (-0.38; -0.19, respectively); HDL-cholesterol (0.44; 0.40, respectively); and triglycerides (-0.35; -0.18, respectively). In a multivariable logistic regression analysis, the HMWA/HOMA-IR ratio was a sensitive predictor for MetS, being the only marker that was significantly associated with each and all the individual components of the syndrome. These results expand on previous studies in that we used the active circulating form of adiponectin, i.e. HMWA, and represent a typical Brazilian cohort characterized by intense interethnic admixture. Thus, the HMWA/HOMA-IR ratio is a minimally invasive biomarker for MetS that could be clinically useful in prognosing patient outcome.
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10
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Jo SJ, Kim JW, Choi HO, Kim JH, Kim HJ, Woo SH, Han BH. Capsanthin Inhibits both Adipogenesis in 3T3-L1 Preadipocytes and Weight Gain in High-Fat Diet-Induced Obese Mice. Biomol Ther (Seoul) 2017; 25:329-336. [PMID: 28449555 PMCID: PMC5424644 DOI: 10.4062/biomolther.2017.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 03/18/2017] [Accepted: 03/18/2017] [Indexed: 12/21/2022] Open
Abstract
Adipogenesis in murine preadipocyte 3T3L-1 has been used as a model system to study anti-obese bioactive molecules. During adipogenesis in 3T3-L1 preadipocytes, we found that capsanthin inhibited adipogenesis (IC50; 2.5 μM) and also showed lipolytic activity in differentiated adipocytes from the preadipocytes (ED50; 872 nM). We identified that the pharmacological activity of capsanthin on adipogenesis in 3T3-L1 was mainly due to its adrenoceptor-β2-agonistic activity. In high-fat diet animal model study, capsanthin significantly enhanced spontaneous locomotive activities together with progressive weight-loss. The capsanthin-induced activation of kinetic behavior in mice was associated with the excessive production of ATP initiated by both the enhanced lipolytic activity together with accelerated oxidation of fatty acids due to the adrenoceptor β2-agonistic activity of capsanthin. Capsanthin also dose-dependently increased adiponectin and p-AMPK activity in high fat diet animals, suggesting that capsanthin has both anti-obesity and insulin sensitizing activities.
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Affiliation(s)
- Sung Jun Jo
- Life Science Research Institute, E.S. Biotech. Co. Ltd., Cheonan 31257, Republic of Korea
| | - Jeung Won Kim
- Life Science Research Institute, E.S. Biotech. Co. Ltd., Cheonan 31257, Republic of Korea
| | - Hye Ok Choi
- Life Science Research Institute, E.S. Biotech. Co. Ltd., Cheonan 31257, Republic of Korea
| | - Jung Hwan Kim
- Life Science Research Institute, E.S. Biotech. Co. Ltd., Cheonan 31257, Republic of Korea
| | - Hyung Joong Kim
- Life Science Research Institute, E.S. Biotech. Co. Ltd., Cheonan 31257, Republic of Korea
| | - Sun Hee Woo
- Department of Agronomia, Chungbuk National University, Cheongju 28644, Republic of Korea
| | - Byung Hoon Han
- Life Science Research Institute, E.S. Biotech. Co. Ltd., Cheonan 31257, Republic of Korea
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11
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Lopategi A, López-Vicario C, Alcaraz-Quiles J, García-Alonso V, Rius B, Titos E, Clària J. Role of bioactive lipid mediators in obese adipose tissue inflammation and endocrine dysfunction. Mol Cell Endocrinol 2016; 419:44-59. [PMID: 26433072 DOI: 10.1016/j.mce.2015.09.033] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 09/18/2015] [Accepted: 09/28/2015] [Indexed: 12/14/2022]
Abstract
White adipose tissue is recognized as an active endocrine organ implicated in the maintenance of metabolic homeostasis. However, adipose tissue function, which has a crucial role in the development of obesity-related comorbidities including insulin resistance and non-alcoholic fatty liver disease, is dysregulated in obese individuals. This review explores the physiological functions and molecular actions of bioactive lipids biosynthesized in adipose tissue including sphingolipids and phospholipids, and in particular fatty acids derived from phospholipids of the cell membrane. Special emphasis is given to polyunsaturated fatty acids of the omega-6 and omega-3 families and their conversion to bioactive lipid mediators through the cyclooxygenase and lipoxygenase pathways. The participation of omega-3-derived lipid autacoids in the resolution of adipose tissue inflammation and in the prevention of obesity-associated hepatic complications is also thoroughly discussed.
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Affiliation(s)
- Aritz Lopategi
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain.
| | - Cristina López-Vicario
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain
| | - José Alcaraz-Quiles
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain
| | - Verónica García-Alonso
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain
| | - Bibiana Rius
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain
| | - Esther Titos
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain; CIBERehd, University of Barcelona, Barcelona 08036, Spain
| | - Joan Clària
- Department of Biochemistry and Molecular Genetics, Hospital Clínic, IDIBAPS, Barcelona 08036, Spain; CIBERehd, University of Barcelona, Barcelona 08036, Spain; Department of Physiological Sciences I, University of Barcelona, Barcelona 08036, Spain.
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12
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Dostal AM, Samavat H, Espejo L, Arikawa AY, Stendell-Hollis NR, Kurzer MS. Green Tea Extract and Catechol-O-Methyltransferase Genotype Modify Fasting Serum Insulin and Plasma Adiponectin Concentrations in a Randomized Controlled Trial of Overweight and Obese Postmenopausal Women. J Nutr 2016; 146:38-45. [PMID: 26581683 PMCID: PMC4700981 DOI: 10.3945/jn.115.222414] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 10/16/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Green tea consumption has been associated with favorable changes in body weight and obesity-related hormones, although it is not known whether these changes result from green tea polyphenols or caffeine. OBJECTIVE We examined the impact of decaffeinated green tea extract (GTE) containing 843 mg of (-)-epigallocatechin-3-gallate on anthropometric variables, obesity-associated hormones, and glucose homeostasis. METHODS The Minnesota Green Tea Trial was a 12-mo randomized, double-blind, placebo-controlled clinical trial of 937 healthy postmenopausal women assigned to either decaffeinated GTE (1315 mg total catechins/d) or a placebo, stratified by catechol-O-methyltransferase (COMT) genotype. This study was conducted in a subset of 237 overweight and obese participants [body mass index (BMI) ≥25 kg/m(2)]. RESULTS No changes in energy intake, body weight, BMI, or waist circumference (WC) were observed over 12 mo in women taking GTE (n = 117) or placebo (n = 120). No differences were seen in circulating leptin, ghrelin, adiponectin, or glucose concentrations at month 12. Participants randomly assigned to GTE with baseline insulin ≥10 μIU/mL (n = 23) had a decrease in fasting serum insulin from baseline to month 12 (-1.43 ± 0.59 μIU/mL), whereas those randomly assigned to placebo with baseline insulin ≥10 μIU/mL (n = 19) had an increase in insulin over 12 mo (0.55 ± 0.64 μIU/mL, P < 0.01). Participants with the homozygous high-activity (G/G) form of COMT had significantly lower adiponectin (5.97 ± 0.50 compared with 7.58 ± 0.53 μg/mL, P = 0.03) and greater insulin concentrations (7.63 ± 0.53 compared with 6.18 ± 0.36 μIU/mL, P = 0.02) at month 12 compared with those with the low-activity (A/A) genotype, regardless of treatment group. CONCLUSIONS Decaffeinated GTE was not associated with reductions in body weight, BMI, or WC and did not alter energy intake or mean hormone concentrations in healthy postmenopausal women over 12 mo. GTE decreased fasting insulin concentrations in those with elevated baseline fasting concentrations. The high-activity form of the COMT enzyme may be associated with elevations in insulin and a reduction in adiponectin concentrations over time. This trial was registered at http://www.clinicaltrials.gov as NCT00917735.
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Affiliation(s)
- Allison M Dostal
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Hamed Samavat
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Luis Espejo
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN
| | - Andrea Y Arikawa
- Department of Nutrition and Dietetics, University of North Florida, Jacksonville, FL; and
| | - Nicole R Stendell-Hollis
- Department of Nutrition, Exercise, and Health Sciences, Central Washington University, Ellensburg, WA
| | - Mindy S Kurzer
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN;
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13
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Wasinski F, Bacurau RFP, Estrela GR, Klempin F, Arakaki AM, Batista RO, Mafra FFP, do Nascimento LFR, Hiyane MI, Velloso LA, Câmara NOS, Araujo RC. Exercise during pregnancy protects adult mouse offspring from diet-induced obesity. Nutr Metab (Lond) 2015; 12:56. [PMID: 26690877 PMCID: PMC4683957 DOI: 10.1186/s12986-015-0052-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 12/09/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Physical exercise induces positive alterations in gene expression involved in the metabolism of obesity. Maternal exercise provokes adaptations soon after birth in the offspring. Here, we investigated whether adult mouse offspring of swim-trained mothers is protected against the development of the deleterious effects of high fat diet (HFD). METHODS Our study comprises two parts. First, female C57BL/6 mice were divided into one sedentary and one swim-trained group (before and during pregnancy, n = 18). In the second part, adult offspring (n = 12) of trained and sedentary mothers was challenged to HFD for 16 weeks. Notably, most of the analysis was done in male offspring. RESULTS Our results demonstrate that maternal exercise has several beneficial effects on the mouse offspring and protects them from the deleterious effects of HFD in the adult. Specifically, swimming during pregnancy leads to lower birth weight in offspring through 2 months of age. When subjected to HFD for 4 month in the adulthood, our study presents novel data on the male offspring's metabolism of trained mothers. The offspring gained less weight, which was accompanied by less body fat, and they used more calories during daytime compared with offspring of sedentary mothers. Furthermore, we observed increased adiponectin expression in skeletal muscle, which was accompanied by decreased leptin levels and increased insulin sensitivity. Decreased interleukin-6 expression and increased peptide PYY levels were observed in sera of adult offspring of mothers that swam during pregnancy. CONCLUSIONS Our results point to the conclusion that maternal exercise is beneficial to protect the offspring from developing obesity, which could be important for succeeding generations as well.
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Affiliation(s)
- Frederick Wasinski
- />Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 andar, 04039-032 São Paulo, SP Brazil
- />Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900 São Paulo, SP Brazil
| | | | - Gabriel Rufino Estrela
- />Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 andar, 04039-032 São Paulo, SP Brazil
- />Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900 São Paulo, SP Brazil
| | | | - Aline Midori Arakaki
- />Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 andar, 04039-032 São Paulo, SP Brazil
- />Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900 São Paulo, SP Brazil
| | - Rogerio Oliveira Batista
- />Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 andar, 04039-032 São Paulo, SP Brazil
- />Department of Medicine, Division of Nephrology, Federal University of São Paulo, 04023-900 São Paulo, SP Brazil
| | | | | | - Meire Ioshie Hiyane
- />Department of Immunology, Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP Brazil
| | - Lício Augusto Velloso
- />Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas, Campinas, SP Brazil
| | - Niels Olsen Saraiva Câmara
- />Department of Immunology, Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, SP Brazil
| | - Ronaldo Carvalho Araujo
- />Department of Biophysics, Federal University of São Paulo, Rua Pedro de Toledo, 669 9 andar, 04039-032 São Paulo, SP Brazil
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14
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Jahng JWS, Turdi S, Kovacevic V, Dadson K, Li RK, Sweeney G. Pressure Overload-Induced Cardiac Dysfunction in Aged Male Adiponectin Knockout Mice Is Associated With Autophagy Deficiency. Endocrinology 2015; 156:2667-77. [PMID: 25961840 DOI: 10.1210/en.2015-1162] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Heart failure is a leading cause of death, especially in the elderly or obese and diabetic populations. Various remodeling events have been characterized, which collectively contribute to the progression of heart failure. Of particular interest, autophagy has recently emerged as an important determinant of cardiac remodeling and function. Here, we used aged, 13-month-old, male adiponectin knockout (Ad-KO) or wild-type (wt) mice subjected to aortic banding to induce pressure overload (PO). Cardiac strain analysis using speckle tracking echocardiography indicated significant dysfunction at an earlier stage in Ad-KO than wt. Analysis of autophagy by Western blotting for Light Chain 3 or microtubule-associated proteins 1B and Sequestosome 1 together with transmission electron microscopy of left ventricular tissue indicated a lack of PO-induced cardiac autophagy in Ad-KO compared with wt mice. Associated with this was mitochondrial degeneration and evidence of enhanced endoplasmic reticulum stress. Western blotting for Light Chain 3 or microtubule-associated proteins 1B, examination of flux using tandem fluoresent tagged-Light Chain 3, and analysis of lysosomal activity in H9c2 cardiac myoblasts treated with adiponectin indicated that adiponectin enhanced autophagy flux. In conclusion, adiponectin directly stimulates autophagic flux and the lack of autophagy in response to PO in aged mice lacking adiponectin may contribute to cellular events which exacerbate the development of cardiac dysfunction.
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Affiliation(s)
- James Won Suk Jahng
- Department of Biology (J.W.S.J., S.T., V.K., K.D., G.S.), York University, Toronto M3J 1P3, Canada; and Division of Cardiovascular Surgery and Toronto General Research Institute (R.-K.L.), University Health Network, Toronto M3J 1P3, Canada
| | - Subat Turdi
- Department of Biology (J.W.S.J., S.T., V.K., K.D., G.S.), York University, Toronto M3J 1P3, Canada; and Division of Cardiovascular Surgery and Toronto General Research Institute (R.-K.L.), University Health Network, Toronto M3J 1P3, Canada
| | - Vera Kovacevic
- Department of Biology (J.W.S.J., S.T., V.K., K.D., G.S.), York University, Toronto M3J 1P3, Canada; and Division of Cardiovascular Surgery and Toronto General Research Institute (R.-K.L.), University Health Network, Toronto M3J 1P3, Canada
| | - Keith Dadson
- Department of Biology (J.W.S.J., S.T., V.K., K.D., G.S.), York University, Toronto M3J 1P3, Canada; and Division of Cardiovascular Surgery and Toronto General Research Institute (R.-K.L.), University Health Network, Toronto M3J 1P3, Canada
| | - Ren-Ke Li
- Department of Biology (J.W.S.J., S.T., V.K., K.D., G.S.), York University, Toronto M3J 1P3, Canada; and Division of Cardiovascular Surgery and Toronto General Research Institute (R.-K.L.), University Health Network, Toronto M3J 1P3, Canada
| | - Gary Sweeney
- Department of Biology (J.W.S.J., S.T., V.K., K.D., G.S.), York University, Toronto M3J 1P3, Canada; and Division of Cardiovascular Surgery and Toronto General Research Institute (R.-K.L.), University Health Network, Toronto M3J 1P3, Canada
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15
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Park SE, Park CY, Sweeney G. Biomarkers of insulin sensitivity and insulin resistance: Past, present and future. Crit Rev Clin Lab Sci 2015; 52:180-90. [PMID: 26042993 DOI: 10.3109/10408363.2015.1023429] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Insulin resistance in insulin target tissues including liver, skeletal muscle and adipose tissue is an early step in the progression towards type 2 diabetes. Accurate diagnostic parameters reflective of insulin resistance are essential. Longstanding tests for fasting blood glucose and HbA1c are useful and although the hyperinsulinemic euglycemic clamp remains a "gold standard" for accurately determining insulin resistance, it cannot be implemented on a routine basis. The study of adipokines, and more recently myokines and hepatokines, as potential biomarkers for insulin sensitivity is now an attractive and relatively straightforward approach. This review discusses potential biomarkers including adiponectin, RBP4, chemerin, A-FABP, FGF21, fetuin-A, myostatin, IL-6, and irisin, all of which may play significant roles in determining insulin sensitivity. We also review potential future directions of new biological markers for measuring insulin resistance, including metabolomics and gut microbiome. Collectively, these approaches will provide clinicians with the tools for more accurate, and perhaps personalized, diagnosis of insulin resistance.
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Affiliation(s)
- Se Eun Park
- a Division of Endocrinology and Metabolism, Department of Internal Medicine , Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine , Seoul , South Korea and
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16
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Metabolomic profiling in liver of adiponectin-knockout mice uncovers lysophospholipid metabolism as an important target of adiponectin action. Biochem J 2015; 469:71-82. [PMID: 25915851 DOI: 10.1042/bj20141455] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 04/27/2015] [Indexed: 12/21/2022]
Abstract
Adiponectin mediates anti-diabetic effects via increasing hepatic insulin sensitivity and direct metabolic effects. In the present study, we conducted a comprehensive and unbiased metabolomic profiling of liver tissue from AdKO (adiponectin-knockout) mice, with and without adiponectin supplementation, fed on an HFD (high-fat diet) to derive insight into the mechanisms and consequences of insulin resistance. Hepatic lipid accumulation and insulin resistance induced by the HFD were reduced by adiponectin. The HFD significantly altered levels of 147 metabolites, and bioinformatic analysis indicated that one of the most striking changes was the profile of increased lysophospholipids. These changes were largely corrected by adiponectin, at least in part via direct regulation of PLA2 (phospholipase A2) as palmitate-induced PLA2 activation was attenuated by adiponectin in primary hepatocytes. Notable decreases in several glycerolipids after the HFD were reversed by adiponectin, which also corrected elevations in several diacyglycerol and ceramide species. Our data also indicate that stimulation of ω-oxidation of fatty acids by the HFD is enhanced by adiponectin. In conclusion, this metabolomic profiling approach in AdKO mice identified important targets of adiponectin action, including PLA2, to regulate lysophospholipid metabolism and ω-oxidation of fatty acids.
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17
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Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice. PLoS One 2015; 10:e0121049. [PMID: 25910275 PMCID: PMC4409146 DOI: 10.1371/journal.pone.0121049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 02/05/2015] [Indexed: 12/16/2022] Open
Abstract
Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM) remodeling in response to pressure overload (PO). Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO) and wild-type (WT) mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson’s trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects.
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18
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Hata A, Yonemoto K, Shikama Y, Aki N, Kosugi C, Tamura A, Ichihara T, Minagawa T, Kuwamura Y, Miyoshi M, Nakao T, Funaki M. Cut-off value of total adiponectin for managing risk of developing metabolic syndrome in male Japanese workers. PLoS One 2015; 10:e0118373. [PMID: 25705909 PMCID: PMC4337907 DOI: 10.1371/journal.pone.0118373] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 01/11/2015] [Indexed: 11/26/2022] Open
Abstract
Aim To determine the optimal cut-off value of serum total adiponectin for managing the risk of developing metabolic syndrome (MetS) in male Japanese workers. Methods A total of 365 subjects without MetS aged 20–60 years were followed up prospectively for a mean of 3.1 years. The accelerated failure-time model was used to estimate time ratio (TR) and cut-off value for developing MetS. Results During follow-up, 45 subjects developed MetS. Age-adjusted TR significantly declined with decreasing total adiponectin level (≤ 4.9, 5.0–6.6, 6.7–8.8 and ≥ 8.9 μg/ml, P for trend = 0.003). In multivariate analyses, TR of MetS was 0.12 (95% CI 0.02–0.78; P = 0.03) in subjects with total adiponectin level of 5.0–6.6 μg/ml, and 0.15 (95% CI 0.02–0.97; P = 0.047) in subjects with total adiponectin level ≤ 4.9 μg/ml compared with those with total adiponectin level ≥ 8.9 μg/ml. The accelerated failure-time model showed that the optimal cut-off value of total adiponectin for managing the risk of developing MetS was 6.2 μg/ml. In the multivariate-adjusted model, the mean time to the development of MetS was 78% shorter for total adiponectin level ≤ 6.2 μg/ml compared with > 6.2 μg/ml (TR 0.22, 95% CI: 0.08–0.64, P = 0.005). Conclusion Our findings suggest that the cut-off value for managing the risk of developing MetS is 6.2 μg/ml in male Japanese workers. Subjects with total adiponectin level ≤ 6.2 μg/ml developed MetS more rapidly than did those with total adiponectin level > 6.2 μg/ml.
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Affiliation(s)
- Akiko Hata
- Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan
- * E-mail:
| | - Koji Yonemoto
- Biostatistics Center, Kurume University, Fukuoka, Japan
| | - Yosuke Shikama
- Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan
| | - Nanako Aki
- Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan
- Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Medical Sciences, Tokushima, Japan
| | - Chisato Kosugi
- Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan
| | - Ayako Tamura
- Department of Nursing Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Takako Ichihara
- Department of Nursing Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Takako Minagawa
- Department of Nursing Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Yumi Kuwamura
- Department of Nursing Science, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Masashi Miyoshi
- Clinical laboratory, Tokushima University Hospital, Tokushima, Japan
| | - Takayuki Nakao
- Clinical laboratory, Tokushima University Hospital, Tokushima, Japan
| | - Makoto Funaki
- Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan
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Liu Y, Palanivel R, Rai E, Park M, Gabor TV, Scheid MP, Xu A, Sweeney G. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes 2015; 64:36-48. [PMID: 25071026 DOI: 10.2337/db14-0267] [Citation(s) in RCA: 170] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Numerous studies have characterized the antidiabetic effects of adiponectin, yet the precise cellular mechanisms in skeletal muscle, in particular, changes in autophagy, require further clarification. In the current study, we used a high-fat diet (HFD) to induce obesity and insulin resistance in wild-type (WT) or adiponectin knockout (Ad-KO) mice with and without adiponectin replenishment. Temporal analysis of glucose tolerance and insulin sensitivity using hyperinsulinemic-euglycemic clamp and muscle insulin receptor substrate and Akt phosphorylation demonstrated exaggerated and more rapid HFD-induced insulin resistance in skeletal muscle of Ad-KO mice. Superoxide dismutase activity, the reduced glutathione-to-glutathione disulfide ratio, and lipid peroxidation indicated that HFD-induced oxidative stress was corrected by adiponectin. Gene array analysis implicated several antioxidant enzymes, including Gpxs, Prdx, Sod, and Nox4, in mediating this effect. Adiponectin also attenuated palmitate-induced reactive oxygen species production in cultured myotubes and improved insulin-stimulated glucose uptake in primary muscle cells. Increased LC3-II and decreased p62 expression suggested that HFD induced autophagy in muscle of WT mice; however, these changes were not observed in Ad-KO mice. Replenishing adiponectin in Ad-KO mice increased LC3-II and Beclin1 and decreased p62 protein levels, induced fibroblast growth factor-21 expression, and corrected HFD-induced decreases in LC3, Beclin1, and ULK1 gene expression. In vitro studies examining changes in phospho-ULK1 (Ser555), LC3-II, and lysosomal enzyme activity confirmed that adiponectin directly induced autophagic flux in cultured muscle cells in an AMPK-dependent manner. We overexpressed an inactive mutant of Atg5 to create an autophagy-deficient cell model, and together with pharmacological inhibition of autophagy, demonstrated reduced insulin sensitivity under these conditions. In summary, adiponectin stimulated skeletal muscle autophagy and antioxidant potential to reduce insulin resistance caused by HFD.
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Affiliation(s)
- Ying Liu
- Department of Biology, York University, Toronto, ON, Canada
| | | | - Esther Rai
- Department of Biology, York University, Toronto, ON, Canada
| | - Min Park
- Department of Biology, York University, Toronto, ON, Canada
| | - Tim V Gabor
- Department of Biology, York University, Toronto, ON, Canada
| | | | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology and Department of Medicine, the University of Hong Kong, Hong Kong
| | - Gary Sweeney
- Department of Biology, York University, Toronto, ON, Canada
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Marette A, Liu Y, Sweeney G. Skeletal muscle glucose metabolism and inflammation in the development of the metabolic syndrome. Rev Endocr Metab Disord 2014; 15:299-305. [PMID: 25326656 DOI: 10.1007/s11154-014-9296-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Insulin resistance and metabolic dysfunction in skeletal muscle play a major role in the development of the metabolic syndrome and type 2 diabetes. Numerous mechanisms have been proposed to explain the pathophysiology of obesity-linked metabolic dysfunction and this review will focus on the contributing role of adiponectin and inflammation. The beneficial effects of adiponectin on both insulin action and inflammation are now well documented and will be reviewed. More recent work provided new insights into adiponectin signaling mechanisms. The development of strategies to mimic adiponectin action holds promise that adiponectin-based compounds may translate into effective therapeutic applications. We will also discussed the novel role of long chain ω-3 PUFA-derived resolution mediators, which in addition to resolving inflammation, can also exert glucoregulatory effects in models of obesity and insulin resistance. We will focus on one resolution mediator, protectin DX (PDX), which was recently shown to act as a muscle interleukin-6 secretagogue. PDX and its isomer PD1 also enhance adiponectin expression and action. Ultimately, it is via a better understanding the molecular mechanisms of action via which inflammation, insulin resistance and metabolic dysfunction occur in skeletal muscle, and also how they crosstalk with each other, that we can generate new and improved therapies for obesity-linked metabolic complications.
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Affiliation(s)
- André Marette
- Department of Medicine, Faculty of Medicine and Heart and Lung Institute, Laval University, Québec, QC, Canada,
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21
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Palanivel R, Ganguly R, Turdi S, Xu A, Sweeney G. Adiponectin stimulates Rho-mediated actin cytoskeleton remodeling and glucose uptake via APPL1 in primary cardiomyocytes. Metabolism 2014; 63:1363-73. [PMID: 25108566 DOI: 10.1016/j.metabol.2014.07.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 05/14/2014] [Accepted: 07/05/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Adiponectin is known to confer its cardioprotective effects in obesity and type 2 diabetes, mainly by regulating glucose and fatty acid metabolism in cardiomyocytes. Dynamic actin cytoskeleton remodeling is involved in regulation of multiple biological functions, including glucose uptake. Here we investigated in neonatal cardiomyocytes whether adiponectin induced actin cytoskeleton remodeling and if this played a role in adiponectin-stimulated glucose uptake. MATERIALS/METHODS Primary cardiomyocytes were treated with full-length and globular adiponectin (fAd and gAd, respectively). RESULTS Both fAd and gAd increased RhoA activity, phosphorylation of the Rho/ROCK signaling target cofilin and actin polymerization to form filamentous actin as determined by rhodamine-phallodin immunofluorescence and quantitative analysis of filamentous to globular actin ratio. Scanning electron microscopy also demonstrated structural remodeling. Adiponectin stimulated glucose uptake, was significantly abrogated in the presence of inhibitors of actin cytoskeleton remodeling (cytochalasin D) and Rho/ROCK signaling (C3 transferase, Y27632). We showed that adiponectin increased colocalization of actin and APPL1 and that actin remodeling, phosphorylation of AMPK, p38MAPK and cofilin, glucose uptake and oxidation were all attenuated after siRNA-mediated knockdown of APPL1. CONCLUSION We show that adiponectin mediates Rho/ROCK-dependent actin cytoskeleton remodeling to increase glucose uptake and metabolism via APPL1 signaling.
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Affiliation(s)
| | - Riya Ganguly
- Department of Biology, York University, Toronto, Canada
| | - Subat Turdi
- Department of Biology, York University, Toronto, Canada
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, the University of Hong Kong
| | - Gary Sweeney
- Department of Biology, York University, Toronto, Canada.
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22
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Adiponectin and markers of metabolic syndrome in obese children and adolescents: impact of 8-mo regular physical exercise program. Pediatr Res 2014; 76:159-65. [PMID: 24819375 DOI: 10.1038/pr.2014.73] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2013] [Accepted: 02/20/2014] [Indexed: 11/08/2022]
Abstract
BACKGROUND Adiponectin circulates as low-, medium-, and high-molecular-weight multimers (LMW, MMW, and HMW) and influences lipid profile and insulin resistance (IR), HMW being considered as the most biologically active form. We aimed to study the relation between adiponectin and markers of metabolic syndrome (MS) in pediatric obesity, and the impact of physical exercise. METHODS The study consisted of a cross-sectional part and an 8-mo physical exercise program. Lipid profile, insulin, glucose, C-reactive protein (CRP), total adiponectin (TA), and homeostasis model assessment IR (HOMA-IR) were measured. Adiponectin multimers were studied in a prepubertal group. RESULTS Obesity is associated with increased dyslipidemia, IR, and inflammation. TA is correlated inversely with adiposity, triglycerides, HOMA-IR, and CRP, and positively with high-density lipoprotein cholesterol (HDLc)/total cholesterol (TC) ratio. HMW mimicked TA associations. The intervention program led to a reduction of TC, low-density lipoprotein cholesterol (LDLc), insulin, HOMA-IR, and trunk percentage of fat, and an increase of HDLc/TC ratio, in the obese group. BMI improvements prevented adiponectin reduction and correlated with increments in HMW and MMW. CONCLUSION Obesity-related increase in MS features might be linked to lower adiponectin. HMW and MMW were the multimers that most explained the MS features. The intervention program improved the lipid profile and IR, and prevented the reduction of adiponectin.
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Zheng F, Zhang S, Lu W, Wu F, Yin X, Yu D, Pan Q, Li H. Regulation of insulin resistance and adiponectin signaling in adipose tissue by liver X receptor activation highlights a cross-talk with PPARγ. PLoS One 2014; 9:e101269. [PMID: 24972069 PMCID: PMC4074121 DOI: 10.1371/journal.pone.0101269] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 06/05/2014] [Indexed: 01/15/2023] Open
Abstract
Liver X receptors (LXRs) have been recognized as a promising therapeutic target for atherosclerosis; however, their role in insulin sensitivity is controversial. Adiponectin plays a unique role in maintaining insulin sensitivity. Currently, no systematic experiments elucidating the role of LXR activation in insulin function based on adiponectin signaling have been reported. Here, we investigated the role of LXR activation in insulin resistance based on adiponectin signaling, and possible mechanisms. C57BL/6 mice maintained on a regular chow received the LXR agonist, T0901317 (30 mg/kg.d) for 3 weeks by intraperitoneal injection, and differentiated 3T3-L1 adipocytes were treated with T0901317 or GW3965. T0901317 treatment induced significant insulin resistance in C57BL/6 mice. It decreased adiponectin gene transcription in epididymal fat, as well as serum adiponectin levels. Activity of AMPK, a key mediator of adiponectin signaling, was also decreased, resulting in decreased Glut-4 membrane translocation in epididymal fat. In contrast, adiponectin activity was not changed in the liver of T0901317 treated mice. In vitro, both T0901317 and GW3965 decreased adiponectin expression in adipocytes in a dose-dependent manner, an effect which was diminished by LXRα silencing. ChIP-qPCR studies demonstrated that T0901317 decreased the binding of PPARγ to the PPAR-responsive element (PPRE) of the adiponectin promoter in a dose-dependent manner. Furthermore, T0901317 exerted an antagonistic effect on the expression of adiponectin in adipocytes co-treated with 3 µM Pioglitazone. In luciferase reporter gene assays, T0901317 dose-dependently inhibited PPRE-Luc activity in HEK293 cells co-transfected with LXRα and PPARγ. These results suggest that LXR activation induces insulin resistance with decreased adiponectin signaling in epididymal fat, probably due to negative regulation of PPARγ signaling. These findings indicate that the potential of LXR activation as a therapeutic target for atherosclerosis may be limited by the possibility of exacerbating insulin resistance-related disease.
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Affiliation(s)
- Fenping Zheng
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Saifei Zhang
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Weina Lu
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Fang Wu
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Xueyao Yin
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Dan Yu
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
| | - Qianqian Pan
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P.R. China
| | - Hong Li
- Department of Endocrinology, Sir Run Run Shaw Hospital Affiliated with School of Zhejiang University, Hangzhou, Zhejiang, P. R. China
- * E-mail:
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Abstract
Adiponectin is among the most studied adipokines, the collection of molecules secreted from adipose tissue. It is also one of the most architecturally complex adipokines with its various oligomeric states that include trimers, hexamers, nonamers (9mers), dodecamers (12mers), and octadecamers (18mers). The importance of adiponectin in metabolic regulation is underscored by its strong positive associations with improvement in insulin action and also decreased risks for developing type 2 diabetes. Understanding the mechanisms involved in maintaining the steady-state concentrations of adiponectin oligomers in circulation is therefore likely to provide important insight into the development of insulin resistance. This review will discuss the current state of knowledge regarding the biochemical composition of adiponectin oligomers, the commonly used techniques to analyze them, and the known post-translational modifications that affect their assembly. Evidence based on in vitro oligomer assembly reactions in support of a "cystine ratchet" model of adiponectin oligomer formation will be considered along with limitations of the evidence. Secretory pathway proteins that have been shown to affect the distribution of adiponectin oligomers will also be discussed along with hypotheses regarding their potential involvement in the cystine ratchet model of adiponectin oligomerization.
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Affiliation(s)
- Tsu-Shuen Tsao
- Department of Chemistry and Biochemistry, University of Arizona, MRB Diabetes Research, P.O. Box 245218, Tucson, AZ, 85724, USA,
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25
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Abstract
Cardiovascular disease, including heart failure, is a principal cause of death in individuals with obesity and diabetes. However, the mechanisms of obesity- and diabetes-induced heart disease are multifaceted and remain to be clearly defined. Of relevance to this review, there is currently great research and clinical interest in the endocrine effects of adipokines on the myocardium and their role in heart failure. We will discuss the potential significance of adipokines in the pathogenesis of heart failure via their ability to regulate remodeling events including metabolism, hypertrophy, fibrosis, and cell death. As an excellent example, we will first focus on adiponectin which is best known to confer numerous cardioprotective effects. However, we comprehensively discuss the existing literature that highlights it would be naive to assume that this was always the case. We also focus on lipocalin-2 which mediates pro-inflammatory and pro-apoptotic effects. It is important when studying actions of adipokines to integrate cellular and mechanistic analyses and translate these to physiologically relevant in vivo models and clinical studies. However, assimilating studies on numerous cardiac remodeling events which ultimately dictate cardiac dysfunction into a unifying conclusion is challenging. Nevertheless, there is undoubted potential for the use of adipokines as robust biomarkers and appropriate therapeutic targets in heart failure.
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Affiliation(s)
- Min Park
- Department of Biology, York University, Toronto, ON, M3J 1P3, Canada
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26
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Lim S, Quon MJ, Koh KK. Modulation of adiponectin as a potential therapeutic strategy. Atherosclerosis 2014; 233:721-728. [PMID: 24603219 DOI: 10.1016/j.atherosclerosis.2014.01.051] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 01/26/2014] [Accepted: 01/27/2014] [Indexed: 12/22/2022]
Abstract
Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.
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Affiliation(s)
- Soo Lim
- Division of Endocrinology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Michael J Quon
- Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Kwang Kon Koh
- Cardiology, Gachon University Gil Medical Center, Incheon, Republic of Korea; Gachon Cardiovascular Research Institute, Incheon, Republic of Korea.
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27
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Miyazaki T, Hiki M, Shimada K, Kume A, Kiyanagi T, Sumiyoshi K, Ohmura H, Daida H. The High Molecular Weight Adiponectin Level is Associated with the Atherogenic Lipoprotein Profiles in Healthy Japanese Males. J Atheroscler Thromb 2014; 21:672-9. [DOI: 10.5551/jat.22152] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Malloy VL, Perrone CE, Mattocks DAL, Ables GP, Caliendo NS, Orentreich DS, Orentreich N. Methionine restriction prevents the progression of hepatic steatosis in leptin-deficient obese mice. Metabolism 2013; 62:1651-61. [PMID: 23928105 DOI: 10.1016/j.metabol.2013.06.012] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 05/30/2013] [Accepted: 06/27/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVE This study investigated the effects of dietary methionine restriction (MR) on the progression of established hepatic steatosis in the leptin-deficient ob/ob mouse. MATERIAL/METHODS Ten-week-old ob/ob mice were fed diets containing 0.86% (control-fed; CF) or 0.12% methionine (MR) for 14 weeks. At 14 weeks, liver and fat were excised and blood was collected for analysis. In another study, blood was collected to determine in vivo triglyceride (TG) and very-low-density lipoprotein (VLDL) secretion rates. Liver histology was conducted to determine the severity of steatosis. Hepatic TG, free fatty acid levels, and fatty acid oxidation (FAO) were also measured. Gene expression was analyzed by quantitative PCR. RESULTS MR reversed the severity of steatosis in the ob/ob mouse. This was accompanied by reduced body weight despite similar weight-specific food intake. Compared with the CF group, hepatic TG levels were significantly reduced in response to MR, but adipose tissue weight was not decreased. MR reduced insulin and HOMA ratios but increased total and high-molecular-weight adiponectin levels. Scd1 gene expression was significantly downregulated, while Acadvl, Hadha, and Hadhb were upregulated in MR, corresponding with increased β-hydroxybutyrate levels and a trend toward increased FAO. The VLDL secretion rate was also significantly increased in the MR mice, as were the mRNA levels of ApoB and Mttp. The expression of inflammatory markers, such as Tnf-α and Ccr2, was also downregulated by MR. CONCLUSIONS Our data indicate that MR reverses steatosis in the ob/ob mouse liver by promoting FAO, increasing the export of lipids, and reducing obesity-related inflammatory responses.
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Affiliation(s)
- Virginia L Malloy
- Orentreich Foundation for the Advancement of Science, Inc., 855 Route 301, Cold Spring-on-Hudson, NY 10516, USA.
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29
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Eglit T, Ringmets I, Lember M. Obesity, high-molecular-weight (HMW) adiponectin, and metabolic risk factors: prevalence and gender-specific associations in Estonia. PLoS One 2013; 8:e73273. [PMID: 24039900 PMCID: PMC3767784 DOI: 10.1371/journal.pone.0073273] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
Background The metabolic consequences of obesity are associated with an imbalance of adipocytokines, e.g. adiponectin. However, some obese subjects remain metabolically healthy and have adiponectin levels similar to normal body weight subjects. Current estimates of the prevalence of obesity in Estonia have relied only on self-report data. Objectives To estimate the prevalence of obesity in Estonia, to test for associations between HMW adiponectin and metabolic risk factors and to test if HMW adiponectin levels differentiate metabolically healthy and metabolically unhealthy subjects. Methods We conducted a population-based cross-sectional multicentre study to gather history, examination and blood test results for 495 subjects aged 20–74. Metabolically healthy subjects were free from hypertension, dyslipidaemia, impaired glucose regulation and insulin resistance. Metabolically unhealthy subjects had at least one of these four metabolic abnormalities. Results The prevalence of obesity was 29% in men and 34% in women. HMW adiponectin was positively correlated with HDL cholesterol and negatively correlated with triglycerides, obesity, insulin resistance and blood glucose. This effect was driven by metabolically unhealthy subjects in men, but by both metabolically healthy and metabolically unhealthy subjects in women. Metabolically healthy women had higher HMW adiponectin levels than metabolically unhealthy women. 12% of all obese subjects were metabolically healthy, and their HMW adiponectin levels were similar to normal weight subjects. Conclusions Obesity is more prevalent in Estonian adults than previously thought. HMW adiponectin levels were associated with various metabolic risk factors in metabolically healthy women but not in metabolically healthy men. For both genders, HMW adiponectin differentiates metabolically healthy obese subjects from metabolically unhealthy obese subjects.
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Affiliation(s)
- Triin Eglit
- Department of Internal Medicine, University of Tartu and Tartu University Hospital, Tartu, Estonia
- * E-mail:
| | - Inge Ringmets
- Department of Public Health, University of Tartu, Tartu, Estonia
| | - Margus Lember
- Department of Internal Medicine, University of Tartu and Tartu University Hospital, Tartu, Estonia
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30
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Krolow R, Noschang C, Arcego DM, Huffell AP, Marcolin ML, Benitz AN, Lampert C, Fitarelli RD, Dalmaz C. Sex-specific effects of isolation stress and consumption of palatable diet during the prepubertal period on metabolic parameters. Metabolism 2013; 62:1268-78. [PMID: 23664084 DOI: 10.1016/j.metabol.2013.04.009] [Citation(s) in RCA: 28] [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: 11/16/2012] [Revised: 04/08/2013] [Accepted: 04/09/2013] [Indexed: 12/18/2022]
Abstract
OBJECTIVES Social isolation during the prepubertal period may have long-term effects on metabolism. The exposure to stressful events is associated with increased palatable food intake, constituting reward-based eating. However, palatable food consumption in early life may lead to metabolic alterations later in life. We investigated whether isolation stress during early life can lead to metabolic alterations in male and female rats with or without exposure to a palatable diet. METHODS Animals were stressed by isolation during one week after weaning, with or without exposure to a palatable diet. RESULTS Stress and palatable diet induced increased caloric consumption. In females, there was a potentiation of consumption in animals exposed to stress and palatable diet, reflected by increased weight gain and triacylglycerol levels in juveniles, as well as increased adiponectin levels. Most of the effects had disappeared in the adults. Different effects were observed in males: in juveniles, stress increased unacylated ghrelin levels, and hypothalamic neuropeptide Y (NPY). Subsequently, adult males that were exposed to a palatable diet during prepuberty showed increased body weight and retroperitoneal fat deposition, increased glycemia, and decreased plasma adiponectin and hypothalamic NPY. Exposure to stress during prepuberty led to increased adrenals during adulthood, decreased LDL-cholesterol and increased triacylglycerol levels. CONCLUSION Isolation stress and consumption of palatable diet changes metabolism in a sex-specific manner. Prepuberty female rats were more prone to stress effects on food consumption, while males showed more long-lasting effects, being more susceptible to a metabolic programming after the consumption of a palatable diet.
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Affiliation(s)
- Rachel Krolow
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil.
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Chang CY, Chen MJ, Yang WS, Yeh CY, Ho HN, Chen SU, Yang YS. Hypoadiponectinemia: a useful marker of dyslipidemia in women with polycystic ovary syndrome. Taiwan J Obstet Gynecol 2013; 51:583-90. [PMID: 23276562 DOI: 10.1016/j.tjog.2012.09.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2012] [Indexed: 10/27/2022] Open
Abstract
OBJECTIVE Adiponectin plays a role in obesity, lipid metabolism, and anti-inflammation. Women with polycystic ovary syndrome (PCOS) are also at risk for dyslipidemia. Therefore, we investigated the association between adiponectin levels and the lipid profile including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TGs) in women with PCOS and contemplated what role adiponectin might play in dyslipidemia with PCOS. MATERIALS AND METHODS We recruited 118 young Taiwanese women with PCOS. The women enrolled were not taking any medication and those with other systemic diseases of nonovarian origin, which could have affected the hypothalamic-pituitary-ovarian axis, were excluded. The serum lipid profile, metabolic and hormonal parameters, and adiponectin were measured. The lipid profile and adiponectin were analyzed and adjusted for age, body mass index (BMI), homeostasis model assessment-insulin resistance (HOMA-IR), and sex hormone-binding globulin (SHBG). RESULTS In a simple linear regression, adiponectin was significantly inversely related to LDL-C and TGs, but positively related to HDL-C (all p < 0.001) after logarithmic transformation. In the multiple linear regression, adiponectin was significantly related to HDL-C (p < 0.001) independent of age, BMI, HOMA-IR, and SHBG after logarithmic transformation. Using a logistic regression, the odds ratio was 0.088 between the association of increased adiponectin and abnormal HDL-C (≤ 50 mg/dL). CONCLUSIONS We demonstrated that adiponectin is an independent biomarker that is positively and evidently related to HDL-C and TGs in women with PCOS. Hypoadiponectinemia may be a useful marker of dyslipidemia in women with PCOS.
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Affiliation(s)
- Chih-Yuan Chang
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
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High-resolution identification of human adiponectin oligomers and regulation by pioglitazone in type 2 diabetic patients. Anal Biochem 2013; 437:150-60. [DOI: 10.1016/j.ab.2013.02.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 02/03/2013] [Accepted: 02/07/2013] [Indexed: 11/24/2022]
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Zhang L, Zhang Q, Fang Y, Zhu KX, Li Z. Relationship between serum adiponectin and non-alcoholic steatohepatitis in young men. Shijie Huaren Xiaohua Zazhi 2013; 21:1256-1260. [DOI: 10.11569/wcjd.v21.i13.1256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between serum adiponectin and non-alcoholic steatohepatitis (NASH) in young men.
METHODS: The body mass index (BMI), alanine aminotransferase, aspartate aminotransferase, total cholesterol (TCHO), triglyceride, high-density lipoprotein, low-density lipoprotein (LDL), fasting plasma glucose and fasting plasma insulin were examined in 64 NASH patients and 46 healthy controls. The levels of adiponectin and high molecular weight (HMW) adiponectin were determined by ELISA and Western blot. The data were analyzed using SPSS19.0.
RESULTS: The level of total adiponectin and the ratio of HMW to total adiponectin were decreased in men with NASH, compared with controls (total adiponectin: 0.92 ± 0.17 vs 1.02 ± 0.16, P < 0.01; HMW/total: 0.39 ± 0.14 vs 0.47 ± 0.11, P < 0.01). The level of total adiponectin was decreased with the increase in the severity of NASH. Furthermore, the level of total adiponectin inversely correlated with TCHO (r = -0.358, P < 0.01) and LDL (r =- 0.339, P < 0.05). The ratio of HMW to total adiponectin was inversely correlated with BMI (r = -0.279, P < 0.05), but positively correlated with HDL (r = 0.266, P < 0.05).
CONCLUSION: The level of total adiponectin and the ratio of HMW to total adiponectin are directly related to NASH in young men. Adiponectin may play an important role in the development of NASH.
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Tanianskiĭ DA, Denisenko AD. [Molecular forms of adiponectin: comparative evaluation of their correlations with parameters of carbohydrate and lipid metabolism]. BIOMEDIT︠S︡INSKAI︠A︡ KHIMII︠A︡ 2013; 58:457-66. [PMID: 23413690 DOI: 10.18097/pbmc20125804457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Interrelationship between total, multimer (MM) and oligomer (OM) adiponectin blood concentrations with some metabolic parameters has been investigated in 49 men and 49 women (mean age of 57.3 +/- 10.1 years). We have found negative correlations between total blood adiponectin and its MM form content with body mass index, waist circumference, the insulin resistance index HOMA, with blood concentrations of insulin, glucose, free fatty acids, triglycerides and also positive correlations with high density lipoprotein cholesterol content. There was a poor correlation between OM adiponectin concentration with any parameter studied. According to the regression analysis, concentration of total adiponectin but not its MM form was an independent determinant of the HOMA index in women and free fatty acid concentration in men. In the group of men with the low level of adiponectin its MM form but not total adiponectin reversely correlated with the HOMA index and was its independent determinant. Thus, correlation between blood adiponectin concentration and metabolic parameters is associated with its MM rather than OM form. Study of the role of adiponectin in development of metabolic disorders may be limited to determination of total blood adiponectin concentration except a group of male patients characterized by a low level of this adipokine. In these patients concentrations of the MM form should be determined.
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Liu Y, Turdi S, Park T, Morris NJ, Deshaies Y, Xu A, Sweeney G. Adiponectin corrects high-fat diet-induced disturbances in muscle metabolomic profile and whole-body glucose homeostasis. Diabetes 2013; 62:743-52. [PMID: 23238294 PMCID: PMC3581202 DOI: 10.2337/db12-0687] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We provide here a detailed and comprehensive analysis of skeletal muscle metabolomic profiles in response to adiponectin in adiponectin knockout (AdKO) mice after high-fat-diet (HFD) feeding. Hyperinsulinemic-euglycemic clamp studies showed that adiponectin administration corrected HFD-induced defects in post/basal insulin stimulated R(d) and insulin signaling in skeletal muscle. Lipidomic profiling of skeletal muscle from HFD-fed mice indicated elevated triacylglycerol and diacylglycerol species (16:0-18:1, 18:1, and 18:0-18:2) as well as acetyl coA, all of which were mitigated by adiponectin. HFD induced elevated levels of various ceramides, but these were not significantly altered by adiponectin. Adiponectin corrected the altered branched-chain amino acid metabolism caused by HFD and corrected increases across a range of glycerolipids, fatty acids, and various lysolipids. Adiponectin also reversed induction of the pentose phosphate pathway by HFD. Analysis of muscle mitochondrial structure indicated that adiponectin treatment corrected HFD-induced pathological changes. In summary, we show an unbiased comprehensive metabolomic profile of skeletal muscle from AdKO mice subjected to HFD with or without adiponectin and relate these to changes in whole-body glucose handling, insulin signaling, and mitochondrial structure and function. Our data revealed a key signature of relatively normalized muscle metabolism across multiple metabolic pathways with adiponectin supplementation under the HFD condition.
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MESH Headings
- Adiponectin/genetics
- Adiponectin/metabolism
- Adipose Tissue, White/metabolism
- Adipose Tissue, White/ultrastructure
- Animals
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/etiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/pathology
- Diet, High-Fat/adverse effects
- Energy Metabolism
- Hyperlipidemias/blood
- Hyperlipidemias/etiology
- Hyperlipidemias/metabolism
- Hyperlipidemias/pathology
- Insulin/metabolism
- Insulin Resistance
- Male
- Metabolic Syndrome/blood
- Metabolic Syndrome/etiology
- Metabolic Syndrome/metabolism
- Metabolic Syndrome/pathology
- Metabolomics/methods
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Muscle/metabolism
- Mitochondria, Muscle/ultrastructure
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/ultrastructure
- Obesity/blood
- Obesity/etiology
- Obesity/metabolism
- Obesity/pathology
- Recombinant Proteins/metabolism
- Signal Transduction
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Affiliation(s)
- Ying Liu
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Subat Turdi
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Taesik Park
- Department of Life Science, Gachon University, Sungnam, Republic of Korea
| | | | | | - Aimin Xu
- Department of Pharmacology, University of Hong Kong, Hong Kong, China
| | - Gary Sweeney
- Department of Biology, York University, Toronto, Ontario, Canada
- Corresponding author: Gary Sweeney,
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Eglit T, Lember M, Ringmets I, Rajasalu T. Gender differences in serum high-molecular-weight adiponectin levels in metabolic syndrome. Eur J Endocrinol 2013; 168:385-91. [PMID: 23230211 DOI: 10.1530/eje-12-0688] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The objective of this study was to estimate gender-specific associations between metabolic syndrome (MS) and high-molecular-weight (HMW) adiponectin in an Estonian adult population. METHODS Plasma HMW adiponectin was measured in 458 subjects (191 men) who participated in a population-based cross-sectional multicenter study (n=495) on the prevalence of metabolic disorders in Estonia. MS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS Median HMW adiponectin levels (μg/ml) were significantly lower among all subjects with MS compared with subjects without MS: 2.1 vs 2.8 in men (P=0.002) and 3.1 vs 5.1 in women (P<0.001). In a fully adjusted, logistic regression model containing HMW adiponectin, homeostasis model assessment of insulin resistance (HOMA-IR), BMI, and age, HMW adiponectin was significantly associated with MS only in women. Comparison of HMW adiponectin and HOMA-IR as markers for MS indicated that HOMA-IR predicted MS better than did HMW adiponectin in both genders. However, after adjusting for age and BMI, HOMA-IR was a significantly better predictor only in men. HMW adiponectin and HOMA-IR predicted the presence of MS at the same level in women. Areas under the receiver operating characteristic curves for HMW adiponectin and HOMA-IR were 0.833 vs 0.88 in men (P=0.02) and 0.897 vs 0.907 in women (P=0.5). CONCLUSIONS These data suggest that the association between low HMW adiponectin levels and presence of MS might be stronger in women compared with men.
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Affiliation(s)
- Triin Eglit
- Departments of Internal Medicine, University of Tartu, 6 L. Puusepa Street, 51014 Tartu, Estonia.
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Finelli C, Tarantino G. What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 2013; 19:802-812. [PMID: 23430039 PMCID: PMC3574877 DOI: 10.3748/wjg.v19.i6.802] [Citation(s) in RCA: 134] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 12/03/2012] [Accepted: 12/15/2012] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries. Insulin resistance is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of insulin resistance or obesity. Adiponectin is the most abundant adipose-specific adipokine. There is evidence that adiponectin decreases hepatic and systematic insulin resistance, and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and the severity of NAFLD; however, to what extent this is a direct effect or related to the presence of more severe insulin resistance or obesity remains to be addressed. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are analyzed systematically.
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Vu V, Liu Y, Sen S, Xu A, Sweeney G. Delivery of adiponectin gene to skeletal muscle using ultrasound targeted microbubbles improves insulin sensitivity and whole body glucose homeostasis. Am J Physiol Endocrinol Metab 2013; 304:E168-75. [PMID: 23132298 PMCID: PMC3543570 DOI: 10.1152/ajpendo.00493.2012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Numerous studies have shown that adiponectin confers antidiabetic effects via both insulin-like and insulin-sensitizing actions. The majority of adiponectin in circulation is derived from adipocytes; however, other tissues such as skeletal muscle can produce adiponectin. This study was designed to investigate the functional significance of adiponectin produced by skeletal muscle. We encapsulated the adiponectin gene in lipid-coated microspheres filled with octafluoropropane gas that were injected into the systemic circulation and destroyed within the microvasculature of skeletal muscle using ultrasound. We first demonstrated safe and successful targeting of luciferase and green fluorescent protein reporter genes to skeletal muscle using this approach and then confirmed efficient overexpression of adiponectin mRNA and oligomeric protein forms. Glucose tolerance test indicated that overexpression of adiponectin in skeletal muscle was able to improve glucose intolerance induced by feeding mice a high-fat diet (HFD), and this correlated with improved skeletal muscle insulin signaling. We then performed hyperinsulinemic-euglycemic clamp studies and demonstrated that adiponectin overexpression attenuated the decreases in glucose infusion rate, glucose disposal, and increase in glucose appearance induced by HFD. Ultrasound-targeted microbubble destruction (UTMD) delivery of adiponectin to skeletal muscle also enhanced serum adiponectin levels and improved hepatic insulin sensitivity. In conclusion, our data show that UTMD efficiently delivers adiponectin to skeletal muscle and that this improves insulin sensitivity and glucose homeostasis.
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Affiliation(s)
- Vivian Vu
- Department of Biology, York University, Toronto, Canada
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McCourt HJ, Hunter SJ, Cardwell CR, Young IS, Murray LJ, Boreham CA, McEneny J, Woodside JV, McKinley MC. Adiponectin multimers, body weight and markers of cardiovascular risk in adolescence: Northern Ireland Young Hearts Project. Int J Obes (Lond) 2013; 37:1247-53. [PMID: 23318722 DOI: 10.1038/ijo.2012.214] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 10/23/2012] [Accepted: 11/28/2012] [Indexed: 12/29/2022]
Abstract
BACKGROUND Research examining the relationship between adiponectin (AN) isoforms, body weight and cardiovascular (CV) risk factors is limited, particularly in younger populations. OBJECTIVES To investigate the inter-relationships between AN isoforms and CV risk factors, and their dependence on body weight status, in adolescents. DESIGN Blood samples from 92 obese, 92 overweight and 92 normal weight age- and sex-matched adolescents were analysed for traditional cardiovascular disease (CVD) risk biomarkers and also total, high molecular weight (HMW), medium and low molecular weight (LMW) AN. RESULTS A significant inverse association was observed between total and HMW AN and waist-hip ratio (P=0.015, P=0.006, respectively), triglycerides (P=0.003, P=0.003, respectively) and systolic blood pressure (P=0.012, P=0.024, respectively) and a significant positive association with high-density lipoprotein (P<0.001, P<0.001, respectively) in multi-adjusted analyses. There was no evidence of a relationship between multimeric AN and high-sensitivity C-reactive protein. There was also little evidence of a relationship between LMW AN and CVD risk factors. There was a strong, body mass index (BMI)-independent, association between AN, CVD biomarkers and the hypertriglyceridemic waist phenotype. CONCLUSION Prominent, BMI-independent associations between total and HMW AN, but not LMW AN, and CVD risk factors were already evident in this young population. This research in adolescents supports the contention that AN subfractions may have different biological actions. These associations in apparently healthy adolescents suggest an important role for AN and its subfractions in the pathogenesis of metabolic syndrome traits and indicate that the potential for total or HMW AN to act as early universal biomarkers of CV risk warrants further study.
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Affiliation(s)
- H J McCourt
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
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Kang SC, Kim BR, Lee SY, Park TS. Sphingolipid metabolism and obesity-induced inflammation. Front Endocrinol (Lausanne) 2013; 4:67. [PMID: 23761785 PMCID: PMC3671289 DOI: 10.3389/fendo.2013.00067] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/20/2013] [Indexed: 12/15/2022] Open
Abstract
Obesity is a metabolic disorder developed by overnutrition and a major cause for insulin resistance and cardiovascular events. Since adipose tissue is one of the major sites for the synthesis and secretion of cytokines, enlarged adipose tissue in obese condition alters inflammatory state leading to pathophysiological conditions such as type 2 diabetes and increased cardiovascular risk. A plausible theory for development of metabolic dysregulation is that obesity increases secretion of inflammatory cytokines from adipose tissue and causes a chronic inflammation in the whole body. Additionally accumulation of lipids in non-adipose tissues elevates the cellular levels of bioactive lipids that inhibit the signaling pathways implicated in metabolic regulation together with activated inflammatory response. Recent findings suggest that obesity-induced inflammatory response leads to modulation of sphingolipid metabolism and these bioactive lipids may function as mediators for increased risk of metabolic dysfunction. Importantly, elucidation of mechanism regarding sphingolipid metabolism and inflammatory disease will provide crucial information to development of new therapeutic strategies for the treatment of obesity-induced pathological inflammation.
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Affiliation(s)
- Se-Chan Kang
- Department of Life Science, Gachon University, Seongnam, South Korea
| | - Bo-Rahm Kim
- Department of Life Science, Gachon University, Seongnam, South Korea
| | - Su-Yeon Lee
- Department of Life Science, Gachon University, Seongnam, South Korea
| | - Tae-Sik Park
- Department of Life Science, Gachon University, Seongnam, South Korea
- *Correspondence: Tae-Sik Park, Department of Life Science, Gachon University, Jinrikwan 304B, Bokjeong-dong, Sujeong-gu, Seongnam, Gyeonggi-do 461-701, South Korea e-mail:
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Tabák AG, Carstensen M, Witte DR, Brunner EJ, Shipley MJ, Jokela M, Roden M, Kivimäki M, Herder C. Adiponectin trajectories before type 2 diabetes diagnosis: Whitehall II study. Diabetes Care 2012; 35:2540-7. [PMID: 22933430 PMCID: PMC3507593 DOI: 10.2337/dc11-2263] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes. RESEARCH DESIGN AND METHODS In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991-1993, 1997-1999, and 2003-2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year(0)) based on 755/5,095 (case/noncase) person-examinations. RESULTS Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187-10,304] vs. 8,818 [6,535-12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3% per year, P < 0.0001) at higher levels in women than in men (difference at year(0): 5,358 ng/mL, P < 0.0001). Female case and early-onset case (age at diagnosis <52 years) subjects had a steeper decline than control subjects (slope difference -1.1% per year, P = 0.001 in females, -1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity. CONCLUSIONS Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development.
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Affiliation(s)
- Adam G Tabák
- Department of Epidemiology and Public Health, University College London, London, UK.
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Xanthakos SA, Kohli R. Treating pediatric nonalcoholic fatty liver disease with cysteamine: is adiponectin the key? J Pediatr 2012; 161:579-81. [PMID: 22738945 DOI: 10.1016/j.jpeds.2012.05.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 05/23/2012] [Indexed: 12/25/2022]
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Development of a novel enzyme-linked immunosorbent assay (ELISA) for measurement of serum CTRP1: a pilot study: measurement of serum CTRP1 in healthy donors and patients with metabolic syndrome. Clin Biochem 2012; 46:73-8. [PMID: 23000311 DOI: 10.1016/j.clinbiochem.2012.09.006] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 09/01/2012] [Accepted: 09/04/2012] [Indexed: 11/22/2022]
Abstract
BACKGROUND Complement C1q tumor necrosis factor-related protein 1 (CTRP1), a recently identified adipokine, was found to stimulate aldosterone production. Obesity and metabolic syndrome are frequently associated with elevated levels of aldosterone. Therefore, it would be interesting to investigate whether the secretion of CTRP1 in human serum is associated with obesity as well as with hypertension. AIM This study evaluated serum CTRP1 concentrations in healthy individuals and patients with metabolic syndrome. METHODS Serum samples from 61 healthy individuals and 46 patients with metabolic syndrome were measured for CTRP1 by enzyme-linked immunosorbent assay (ELISA). RESULTS Correlation analyses showed that serum CTRP1 in healthy individuals did not correlate with BMI, leptin, TG, HDL-CH, and LDL-CH; however, in patients with metabolic syndrome, CTRP1 correlated with glucose, HbA1c and BMI. CTRP1 level was significantly higher in subjects with metabolic syndrome compared to healthy subjects. DISCUSSION Our results support the hypothesis that adipokine CTRP1 is associated with metabolic syndrome and obesity compared to healthy individuals.
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Wooldridge AA, Edwards HG, Plaisance EP, Applegate R, Taylor DR, Taintor J, Zhong Q, Judd RL. Evaluation of high–molecular weight adiponectin in horses. Am J Vet Res 2012; 73:1230-40. [DOI: 10.2460/ajvr.73.8.1230] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Kawamoto R, Tabara Y, Kohara K, Miki T, Kusunoki T, Abe M. γ-Glutamyl Transferase and High-Molecular-Weight Adiponectin Levels Are Synergistically Associated with Metabolic Syndrome and Insulin Resistance in Community-Dwelling Persons. Metab Syndr Relat Disord 2012; 10:83-91. [DOI: 10.1089/met.2011.0078] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Ryuichi Kawamoto
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
- Department of Internal Medicine, Seiyo Municipal Nomura Hospital, Ehime, Japan
| | - Yasuharu Tabara
- Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Katsuhiko Kohara
- Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tetsuro Miki
- Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Tomo Kusunoki
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
- Department of Internal Medicine, Seiyo Municipal Nomura Hospital, Ehime, Japan
| | - Masanori Abe
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan
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Dadson K, Liu Y, Sweeney G. Adiponectin action: a combination of endocrine and autocrine/paracrine effects. Front Endocrinol (Lausanne) 2011; 2:62. [PMID: 22649379 PMCID: PMC3355882 DOI: 10.3389/fendo.2011.00062] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 10/10/2011] [Indexed: 12/15/2022] Open
Abstract
The widespread physiological actions of adiponectin have now been well characterized as clinical studies and works in animal models have established strong correlations between circulating adiponectin level and various disease-related outcomes. Thus, conventional thinking attributes many of adiponectin's beneficial effects to endocrine actions of adipose-derived adiponectin. However, it is now clear that several tissues can themselves produce adiponectin and there is growing evidence that locally produced adiponectin can mediate functionally important autocrine or paracrine effects. In this review article we discuss regulation of adiponectin production, its mechanism of action via receptor isoforms and signaling pathways, and its principal physiological effects (i.e., metabolic and cardiovascular). The role of endocrine actions of adiponectin and changes in local production of adiponectin or its receptors in whole body physiology is discussed.
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Affiliation(s)
- Keith Dadson
- Department of Biology, York UniversityToronto, ON, Canada
| | - Ying Liu
- Department of Biology, York UniversityToronto, ON, Canada
| | - Gary Sweeney
- Department of Biology, York UniversityToronto, ON, Canada
- Institut Pasteur KoreaSeoul, South Korea
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Forsblom C, Thomas MC, Moran J, Saraheimo M, Thorn L, Wadén J, Gordin D, Frystyk J, Flyvbjerg A, Groop PH. Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes. J Intern Med 2011; 270:346-55. [PMID: 21615808 DOI: 10.1111/j.1365-2796.2011.02406.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. OBJECTIVE To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. DESIGN Multicentre prospective cohort study. SETTING Primary and tertiary care. SUBJECTS Finnish adults with type 1 diabetes (n= 2034). Main outcome measures. All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. RESULTS During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. CONCLUSIONS Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.
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Affiliation(s)
- C Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
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Marette A, Sweeney G. Cardiovascular complications of diabetes: recent insights in pathophysiology and therapeutics. Expert Rev Endocrinol Metab 2011; 6:689-696. [PMID: 30780882 DOI: 10.1586/eem.11.63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cardiovascular complications represent the principal cause of death in patients with Type 2 diabetes. It is therefore of great importance to dissect the genetic determinants and molecular mechanisms responsible for diabetic cardiovascular complications. New research is of particular importance since, somewhat unexpectedly, large-scale clinical trials have indicated that glycemic control does not appear to have the anticipated major influence as a factor dictating cardiovascular outcome in diabetics. Hence, additional pathophysiological factors such as dyslipidemia, as well as proinflammatory and proatherosclerotic mechanisms, need to be more carefully examined. In this article, we will focus on recent studies in both animal models and humans as well as cellular mechanistic studies that advance our knowledge on the role of dyslipidemia, inflammation and atherosclerotic events in the cardiovascular complications of diabetes. We also translate our focus on research insights to related therapeutic opportunities.
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Affiliation(s)
- André Marette
- a Department of Medicine, Quebec Heart and Lung Institute, Laval University, Québec, Canada
| | - Gary Sweeney
- b Institut Pasteur Korea, Seoul, South Korea.
- c Department of Biology, York University, Toronto, Canada
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Dahlman I, Arner P. Genetics of adipose tissue biology. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 94:39-74. [PMID: 21036322 DOI: 10.1016/b978-0-12-375003-7.00003-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Adipose tissue morphology and release of free fatty acids, as well as peptide hormones, are believed to contribute to obesity and related metabolic disorders. These adipose tissue phenotypes are influenced by adiposity, but there is also a strong hereditary impact. Polymorphisms in numerous adipose-expressed genes have been evaluated for association with adipocyte and clinical phenotypes. In our opinion, some results are convincing. Thus ADRB2 and GPR74 genes are associated with adipocyte lipolysis, GPR74 also with BMI; PPARG and SREBP1, which promote adipogenesis and lipid storage, are associated with T2D and possible adiposity; ADIPOQ and ARL15 are associated with circulating levels of adiponectin, ARL15 also with coronary heart disease. We anticipate that the use of complementary approaches such as expression profiling and RNAi screening, and studies of additional levels of gene regulation, that is, miRNA and epigenetics, will be important to unravel the genetics of adipose tissue function.
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Kawamoto R, Tabara Y, Kohara K, Abe M, Kusunoki T, Miki T. Association of serum high molecular weight adiponectin and blood pressure among non-diabetic community-dwelling men. Clin Exp Hypertens 2011; 33:336-44. [PMID: 21529312 DOI: 10.3109/10641963.2010.531847] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Adiponectin is one of the important molecules in the development of metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and cardiovascular disease. We aim to determine whether serum high-molecular weight (HMW) adiponectin, which is thought to represent the biological active form, was associated with a risk for the prevalence of prehypertension and hypertension. The cross-sectional study was carried out in 2002. A total of 614 men, aged 58 ± 14 (range, 20-89) years, and 779 women, aged 62 ± 12 (range, 21-88) years without medications for hypertension, diabetes, or dyslipidemia were recruited from a single community at the time of their annual health examination. In men, nonadjusted and age-adjusted mean serum HMW adiponectin were significantly lower in subjects with prehypertension and hypertension than those with normotension. In women, only nonadjusted values were higher in subjects with hypertension than those with normotension. Multiple linear regression analysis using systolic blood pressure (SBP) and diastolic blood pressure (DBP) as an objective variable, adjusted for risk factors as explanatory variables, showed that only in men, log serum HMW adiponectin were significantly and independently associated with SBP and DBP. In men, lower serum HMW adiponectin categories were positively associated with prehypertension and hypertension in an age-adjusted model, and hypertension in an age- and BMI-adjusted model. Serum HMW adiponectin concentrations were inversely associated with blood pressure (BP) in the general male population.
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Affiliation(s)
- Ryuichi Kawamoto
- Department of Community Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
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