Sinalização da grelina no coração de camundongos obesos após hipernutrição durante a lactação

• Autor(a) principal: Miranda, Glauciane Lacerda
• Data de Publicação: 2013
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/16137
• topic: Overnutrition; Heart; GHSR-1a; AKT; PI3K; Ghrelin; Overnutrition; Energy Metabolism; Heart; Obesity; Hipernutrição; Coração; GHSR-1a; AKT; PI3K; Grelina; Hipernutrição; Metabolismo Energético; Coração; Obesidade; CNPQ::CIENCIAS DA SAUDE::NUTRICAO::DESNUTRICAO E DESENVOLVIMENTO FISIOLOGICO

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. We examined key proteins of cardiomyocyte metabolism in heart left ventricle from overfed (OG) and control (CG) groups from adult mice (180 days) overfed during lactation. Obesity was induced by litter reduction. Therefore, the study was done in adult mice 180 days old (OG, obese group (n=10) and CG, control group (n=10). The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology. The content and phosphorylation of cardiac proteins: growth hormone secretagogue receptor 1a (GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK), mTOR and pmTOR, BAX, Bcl2 and actin was achieved by western blotting. GHSR-1a gene expression was analyzed to RT-PCR. We performed high-resolution respirometry of cardiomyocytes with OROBOROS® Oxygraph-2k. Statistical significance was determined by Student t-test for unpaired. P< 0.05 was considered statistical significant. Body weight, blood glucose, liver weight, and visceral fat weight were higher in OG than CG group. Obese mice had increased heart weight and heart weight/TL (tibia length) indicating cardiac remodeling and hypertrophy, increased GHSR-1a content and expression in the heart, associated to PI3K content, increased AKT content and phosphorylation (P< 0.05), decreased Bcl2 content. In contrast, AMPK and mTOR content and phosphorylation in heart were not different between the experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. The O2 consumption of OG with ghrelin was lower than in the CG with ghrelin. Incubation of cardiac fibers with ghrelin resulted in increased respiration after addition of cytochrome c in groups with ghrelin, indicating mitochondrial membrane damage and leakage of cytochrome c. CG with ghrelin and OG without ghrelin showed RCR lower compared to GC without ghrelin, indicating mitochondrial uncoupling. In this study, our results showing a decrease of ghrelin level and an increase of GHS-R1a expression for a down regulation that leads a higher sensibility of ghrelin in heart, occurring independently of any association with AMPK and mTOR in hearts of obese mice. That suggests a reduction in protective effects through ghrelin action on AMPK. In addition, our data demonstrated that remodeled myocardial in obese mice exclusively overnourished in early life are associated with GHSR-1a, PI3K and AKT phosphorylation but not with AMPK and mTOR in adulthood.