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HORMONES AND SIGNALING

Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure

¹Department of Psychiatry, Obesity Research Center and Genome Research Institute, University of Cincinnati College of Medicine, Cincinnati, Ohio; ²Department of Obstetrics, Yale University School of Medicine, New Haven, Connecticut; ³Department of Pharmacology, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany; and ⁴Regeneron Pharmaceuticals, Tarrytown, New York

Submitted 17 July 2007 ; accepted in final form 29 November 2007

Administration of chemically synthesized ghrelin (Ghr) peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous Ghr in the molecular control of energy metabolism is far less understood. Mice deficient for either Ghr or its receptor (the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high-fat diet-induced obesity but do not show a substantial metabolic phenotype on a standard diet. Here we present the first mouse mutant lacking both Ghr and the Ghr receptor. We demonstrate that simultaneous genetic disruption of both genes of the Ghr system leads to an enhanced energy metabolism phenotype. Ghr/Ghr receptor double knockout (dKO) mice exhibit decreased body weight, increased energy expenditure, and increased motor activity on a standard diet without exposure to a high caloric environment. Mice on the same genetic background lacking either the Ghr or the Ghr receptor gene did not exhibit such a phenotype on standard chow, thereby confirming earlier reports. No differences in food intake, meal pattern, or lean mass were observed between dKO, Ghr-deficient, Ghr receptor-deficient, and wild-type (WT) control mice. Only dKO showed a slight decrease in body length. In summary, simultaneous deletion of Ghr and its receptor enhances the metabolic phenotype of single gene-deficient mice compared with WT mice, possibly suggesting the existence of additional, as of yet unknown, molecular components of the endogenous Ghr system.

growth hormone secretagogue receptor, constitutive receptor activity; locomotion

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