Content area
Full Text
OBJECTIVE-Ghrelin is the only known peripheral hormone to increase ingestive behavior. However, its role in the physiological regulation of energy homeostasis is unclear because deletion of ghrelin or its receptor does not alter food intake or body weight in mice fed a normal chow diet. We hypothesized that overexpression of ghrelin in its physiological tissues would increase food intake and body weight.
RESEARCH DESIGN AND METHODS-We used bacterial artificial chromosome transgenesis to generate a mouse model with increased ghrelin expression and production in the stomach and brain. We investigated the effect of ghrelin overexpression on food intake and body weight. We also measured energy expenditure and detennined glucose tolerance, glucose stimulated insulin release, and peripheral insulin sensitivity.
RESULTS-Ghrelin transgenic (Tg) mice exhibited increased circulating bioactive ghrelin, which was associated with hyperphagia, increased energy expenditure, glucose intolerance, decreased glucose stimulated insulin secretion, and reduced leptin sensitivity.
CONCLUSIONS-This is the first report of a Tg approach suggesting that ghrelin regulates appetite under normal feeding conditions and provides evidence that ghrelin plays a fundamental role in regulating β-cell function. Diabetes 58:840-846, 2009
Ghrelin is a 28-aa peptide that is expressed at high levels in the stomach. It is the endogenous ligand for the growth hormone secretagogue receptor and increases growth hormone secretion from the pituitary (1). Ghrelin also increases food intake and adiposity, suggesting a role in the control of energy homeostasis (2). Consistent with this, plasma ghrelin levels have been shown to increase before a meal and during fasting (3). Ghrelin circulates in two forms: the biologically active octanoylated form and the des-octanoyl form, which is thought to be biologically inactive (4). Recent data show that ghrelin a-acyltransferase (GOAT), a membrane-bound enzyme, is responsible for octanoylation of the serine 3 residue of ghrelin and confers biological activity (5,6).
Despite unequivocal pharmacological data, the evidence for a physiological role for ghrelin in the control of appetite is much less clear. Mice with targeted deletion of either ghrelin or the growth hormone secretagogue receptor exhibit an essentially normal metabolic phenotype when fed a regular chow diet, suggesting that ghrelin may have a redundant role in the regulation of food intake (7,8). When fed a high-fat diet, these mice are resistant to diet-induced obesity, exhibiting reduced adiposity and increased...