IMPAIRED GHRELIN SECRETION IN OBESITY: THE KEY ROLE OF INSULIN RESISTANCE

Abstract

Background: The stomach-derived hormone, ghrelin, has emerged as a key player in the neuro-endocrine regulation of appetite and energy storage. Ghrelin increases food intake and adiposity through its action on the ghrelin receptor in appetite-regulating neurons of the hypothalamus. Ghrelin levels increase during periods of fasting and decrease after a meal is consumed. Although obesity is commonly associated with increases in food intake, basal concentration of ghrelin was found to be decreased in obese individuals. These findings suggest that obesity is linked with a dysregulation in ghrelin secretion. Objective: The goal of the present study was to investigate the putative mechanisms underlying dysregulation of ghrelin secretion in obesity using the diet-induced obesity (DIO) mouse model. Methods: We used the mouse model of high fat-diet induced obesity to investigate the glucose-suppressing effect of ghrelin secretion in normal weight and obese mice. We further delineated the intracellular pathways involved using primary culture of ghrelin cells. Since increased adipose tissue-derived inflammatory cytokines was linked with insulin resistance, we investigated the role of TNF-α in ghrelin secretion. Results: Oral glucose significantly suppressed ghrelin secretion in normal weight mice by 60% at 30 min and 70% at 60 min (p<0.001, p<0.001 respectively, n=6), but failed to do so in obese animals. In primary cultures of gastric cells from lean mice, 10 nM insulin reduced ghrelin secretion by 40% (P< 0.05, n=6). In contrast, the effect of insulin was lost in gastric mucosal cells derived from DIO mice (n =6). The effect of insulin was found to be linked with decreased activation of Akt phosphorylation. Pre-treatment of ghrelin cells with TNF-α (10ng/mL) abolished the inhibitory effect of insulin (10 nM) on ghrelin secretion. Conclusion: We demonstrate that impaired ghrelin suppression found in obesity is due to insulin resistance occurring at the level of ghrelin cells and involves adipose tissue-derived inflammatory cytokines.