Ação da grelina acilada sobre o metabolismo energético no tecido adiposo branco de camundongos jovens e adultos hiperalimentados no início da vida

Abstract

Obesity is a major public health problem that is growing worldwide, due to an imbalance between food intake and energy expenditure. The increase adiposity leads to is a major risk factor for the development of most prevalent chronic diseases as dyslipidemias, heart disease and type 2 diabetes. Ghrelin is a hormone synthesized by the stomach that acts in different tissues via a specific receptor (GHS-R1a). Ghrelin modulates energy stores and expenditure in the adipocytes, proving to be of great importance in the maintenance of energy metabolism. Therefore, considering that overnutrition in the postnatal period lead obesity in adulthood by mechanisms not yet fully elucidated, in this study we investigated the effects of acylated ghrelin on energy metabolism of WAT in mice overnutrition during lactation. To induce overnutrition during lactation, the litter size was reduced from three male pups at the third day, overnutrition group (OG). The control group (CG) remained with 9 pups per litter at lactation until weaning. At 21 and 120 days of age, the mice received an intraperitoneal injection of either acylated ghrelin or saline. We evaluated the body mass and visceral adipose tissue mass, liver and brown adipose tissue weight. Biochemical and hormonal parameters such as glycemia, insulin, acylated ghrelin, liver glycogen content, triglycerides and total cholesterol. Through Western blotting and real-time PCR we evaluated the proteins involved in insulin signaling and energy metabolism. We analyzed the CG and OG At 21 and 120 days of age. Our data demonstrated that overnutrition during early life induces significant increases in body weight, visceral fat weight, blood glucose, increase insulin and decrease acylated ghrelin circulating levels at 21 and 120 days; At 21 days overnutrition during lactation decreased CPT1, decreased substrate oxidation and increased 4HNE; decreased CD36 at 21 and 120 days. In addition at 120 days OG showed a decrease pAKT/AKT, Glut4 expression, ratio pAMPK/AMPK, increase FAS, CPT-1 and UCP2 expression, reduced OXPHOS with palmitoyl-L-carnitine and ATP levels. After ghrelin administration, in CG at 21 days, increased blood glucose, insulin levels, decrease acylated ghrelin circulating, increase AKT, GLUT4 and CPT1 gene expression. In OG at 21 days, ghrelin administration increased CD36, UCP2 gene expression, substrate oxidation and ATP levels. At 120 days, ghrelin administration in GC increased blood glucose, liver glycogen content, decreased acylated ghrelin circulating, increased GLUT4 gene expression and protein content of FAS, decreased ATP levels and increased UCP2 gene expression. In OG at 120 days, ghrelin administration decreased blood glucose and liver glycogen content. In addition, ghrelin administration increased acylated ghrelin circulating, decreased GHSR1a, increased IRβ, PI3K, pAKT and GLUT-4. Moreover, ghrelin administration increased CD36 e PPAR gamma. In summary, our data provide evidence that overnutrition during lactation lead to hormonal changes that influence glucose metabolism, lipid metabolism and predispose the mitochondria of adipose tissue to oxidative stress and reduce the oxidation capacity of energy substrates. Such modifications, in addition to promoting the weight gain, last until adulthood. Acylated ghrelin promotes increased oxidation of energetic substrates, improved insulin sensitivity, and reduced total cholesterol levels in OG. In addition, acylated ghrelin develops a double action on glycemic homeostasis according to animal age and nutritional status, reinforcing that ghrelin is an important modulator of energy metabolism in WAT.