Mice with Hyperghrelinemia are Hyperphagic, Glucose Intolerant and have Reduced Leptin Sensitivity.

Abstract

Objective: Ghrelin is the only known peripheral hormone to increase ingestive behaviour. However, its role in the physiological regulation of energy homeostasis is unclear since deletion of ghrelin or its receptor does not alter food intake or body weight in mice fed a normal chow diet. We hypothesized over expression 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 stomach and brain. We investigated the effect of ghrelin over expression on food intake and body weight. In addition, we measured energy expenditure and determined glucose tolerance, glucose stimulated insulin release and peripheral insulin sensitivity.

Results: Ghrelin transgenic 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.

Conclusion: This is the first report of a transgenic approach suggesting ghrelin regulates appetite under normal feeding conditions and provides evidence that ghrelin plays a fundamental role in regulating β-cell function.