title: Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy.
abstract: Adiponectin (APN), an adipose-derived adipokine, offers cardioprotective effects although the precise mechanism of action remains unclear. This study was designed to examine the role of APN in high fat diet-induced obesity and cardiac pathology. Adult C57BL/6 wild-type and APN knockout mice were fed a low or high fat diet for 22weeks. After 40day feeding, mice were treated with 2mg/kg rapamycin or vehicle every other day for 42days on respective fat diet. Cardiomyocyte contractile and Ca(2+) transient properties were evaluated. Myocardial function was evaluated using echocardiography. Dual energy X-ray absorptiometry was used to evaluate adiposity. Energy expenditure, metabolic rate and physical activity were monitored using a metabolic cage. Lipid deposition, serum triglyceride, glucose tolerance, markers of autophagy and fatty acid metabolism including LC3, p62, Beclin-1, AMPK, mTOR, fatty acid synthase (FAS) were evaluated. High fat diet intake induced obesity, systemic glucose intolerance, cardiac hypertrophy, dampened metabolic ability, cardiac and intracellular Ca(2+) derangements, the effects of which were accentuated by APN knockout. Furthermore, APN deficiency augmented high fat diet-induced upregulation in the autophagy adaptor p62 and the decline in AMPK without affecting high fat diet-induced decrease in LC3II and LC3II-to-LC3I ratio. Neither high fat diet nor APN deficiency altered Beclin-1. Interestingly, rapamycin negated high fat diet-induced/APN-deficiency-accentuated obesity, cardiac hypertrophy and contractile dysfunction as well as AMPK dephosphorylation, mTOR phosphorylation and p62 buildup. Our results collectively revealed that APN deficiency may aggravate high fat diet-induced obesity, metabolic derangement, cardiac hypertrophy and contractile dysfunction possibly through decreased myocardial autophagy.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Subat
authors.initials: S
authors.lastname: Turdi
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods; D052242:Adiponectin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004452:Echocardiography / Q000379:methods; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005951:Glucose Tolerance Test / Q000379:methods; D006321:Heart / Q000503:physiopathology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; C490981:Gtf2h1 protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; D051758:Transcription Factor TFIIH; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D002118:Calcium