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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 3?, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-? coactivator 1? 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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3288378 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function.

Zhang Yingmei Y Yuan Ming M Bradley Katherine M KM Dong Feng F Anversa Piero P Ren Jun J

Hypertension (Dallas, Tex. : 1979) 20120123 3

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 ...[more]

PMID: 22275536

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Project description:Aims/hypothesisDespite a similar fat storing function, visceral (intra-abdominal) white adipose tissue (WAT) is detrimental, whereas subcutaneous WAT is considered to protect against metabolic disease. Recent findings indicate that thermogenic genes, expressed in brown adipose tissue (BAT), can be induced primarily in subcutaneous WAT. Here, we investigate the hypothesis that the Wilms tumour gene product (WT1), which is expressed in intra-abdominal WAT but not in subcutaneous WAT and BAT, suppresses a thermogenic program in white fat cells.MethodsHeterozygous Wt1 knockout mice and their wild-type littermates were examined in terms of thermogenic and adipocyte-selective gene expression. Glucose tolerance and hepatic lipid accumulation in these mice were assessed under normal chow and high-fat diet conditions. Pre-adipocytes isolated from the stromal vascular fraction of BAT were transduced with Wt1-expressing retrovirus, induced to differentiate and analysed for the expression of thermogenic and adipocyte-selective genes.ResultsExpression of the thermogenic genes Cpt1b and Tmem26 was enhanced and transcript levels of Ucp1 were on average more than tenfold higher in epididymal WAT of heterozygous Wt1 knockout mice compared with wild-type mice. Wt1 heterozygosity reduced epididymal WAT mass, improved whole-body glucose tolerance and alleviated severe hepatic steatosis upon diet-induced obesity in mice. Retroviral expression of WT1 in brown pre-adipocytes, which lack endogenous WT1, reduced mRNA levels of Ucp1, Ppargc1a, Cidea, Prdm16 and Cpt1b upon in vitro differentiation by 60-90%. WT1 knockdown in epididymal pre-adipocytes significantly lowered Aldh1a1 and Zfp423 transcripts, two key suppressors of the thermogenic program. Conversely, Aldh1a1 and Zfp423 mRNA levels were increased approximately five- and threefold, respectively, by retroviral expression of WT1 in brown pre-adipocytes.Conclusion/interpretationWT1 functions as a white adipocyte determination factor in epididymal WAT by suppressing thermogenic genes. Reducing Wt1 expression in this and other intra-abdominal fat depots may represent a novel treatment strategy in metabolic disease.

Project description:Obesity is associated with chronic inflammation which plays a critical role in the development of cardiovascular dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) in macrophages regulates innate immune responses via activation of pro-inflammatory cytokines, we hypothesize that CARD9 mediates the pro-inflammatory signaling associated with obesity en route to myocardial dysfunction. C57BL/6 wild-type (WT) and CARD9(-/-) mice were fed normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5months. At the end of 5-month HFD feeding, cardiac function was evaluated using echocardiography. Cardiomyocytes were isolated and contractile properties were measured. Immunofluorescence was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from isolated macrophages were collected to measure the concentrations of pro-inflammatory cytokines using ELISA kits. Western immunoblotting analyses were performed on heart tissue homogenates and isolated macrophages to explore the underlying signaling mechanism(s). CARD9 knockout alleviated HFD-induced insulin resistance and glucose intolerance, prevented myocardial dysfunction with preserved cardiac fractional shortening and cardiomyocyte contractile properties. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart with reduced myocardium-, plasma-, and macrophage-derived cytokines including IL-6, IL-1β and TNFα. Finally, CARD9 knockout abrogated the increase of p38 MAPK phosphorylation, the decrease of LC3BII/LC3BI ratio and the up-regulation of p62 expression in the heart induced by HFD feeding and restored cardiac autophagy signaling. In conclusion, CARD9 knockout ameliorates myocardial dysfunction associated with HFD-induced obesity, potentially through reduction of macrophage infiltration, suppression of p38 MAPK phosphorylation, and preservation of autophagy in the heart.

Dataset Information

Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function.

Publications

Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function.

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