Mice With Hyperghrelinemia Are Hyperphagic and Glucose Intolerant and Have Reduced Leptin Sensitivity

Mice With Hyperghrelinemia Are Hyperphagic and Glucose Intolerant and Have Reduced Leptin Sensitivity Gavin A. Bewick , Aysha Kent , Daniel Campbell , Michael Patterson , Mohammed A. Ghatei , Stephen R. Bloom and James V. Gardiner Department of Investigative Medicine, Hammersmith Campus, Imperial College London, London, U.K. Corresponding author: Stephen R. Bloom, s.bloom{at}imperial.ac.uk . Abstract 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 determined 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received October 16, 2008. Accepted January 8, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.