title: Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function.
abstract: Obesity is often associated with reduced plasma insulin-like growth factor 1 (IGF-1) levels, oxidative stress, mitochondrial damage, and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high-fat diet-induced oxidative, myocardial, geometric, and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low- (10%) or high-fat (45%) diet to induce obesity. High-fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin 6, insulin, and triglyceride, as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end-systolic and end-diastolic diameter, increased wall thickness, and cardiac hypertrophy in high-fat-fed FVB mice. High-fat diet promoted reactive oxygen species generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca(2+) dysregulation (including depressed peak shortening and maximal velocity of shortening/relengthening), prolonged duration of relengthening, and dampened intracellular Ca(2+) rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor and postreceptor signaling molecules insulin receptor substrate 1 (tyrosine/serine phosphorylation), Akt, glycogen synthase kinase 3β, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-γ coactivator 1α and uncoupling protein 2. Intriguingly, IGF-1 mitigated high-fat-diet feeding-induced alterations in reactive oxygen species, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca(2+) handling, and insulin signaling but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high-fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high-fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly because of preserved cell survival, mitochondrial function, and insulin signaling.
authors.affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Bradley
authors.forename: Feng
authors.initials: F
authors.lastname: Dong
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006332:Cardiomegaly / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004036:Diet, Atherogenic / Q000009:adverse effects*; D004195:Disease Models, Animal; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000473:pathology; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I