Mice lacking ghrelin receptors resist the development of diet-induced obesity
Jeffrey M. Zigman, … , Bradford B. Lowell, Joel K. Elmquist
Jeffrey M. Zigman, … , Bradford B. Lowell, Joel K. Elmquist
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3564-3572. https://doi.org/10.1172/JCI26002.
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Research Article Metabolism

Mice lacking ghrelin receptors resist the development of diet-induced obesity

Abstract

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.

Authors

Jeffrey M. Zigman, Yoshihide Nakano, Roberto Coppari, Nina Balthasar, Jacob N. Marcus, Charlotte E. Lee, Juli E. Jones, Amy E. Deysher, Amanda R. Waxman, Ryan D. White, Todd D. Williams, Jennifer L. Lachey, Randy J. Seeley, Bradford B. Lowell, Joel K. Elmquist

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Body weights and body compositions of mice fed a Western-type HFD. Weekl...
Body weights and body compositions of mice fed a Western-type HFD. Weekly body weights (upper panels) of GHSR-null mice and wild-type littermates fed HFD for 19 weeks, beginning at 4 weeks of age, and their body composition at the end of the 19-week study, as determined both by carcass analysis (middle panels) and by DEXA (lower panels). Data for both female (left panels) and male (right panels) mice are presented. Data points and error bars correspond to the mean ± SEM. Body weight and DEXA mean values were calculated from 19–22 animals per group. Carcass analysis mean values were calculated from 8–13 animals per group. Significant differences between groups noted in the body composition analyses are denoted by asterisks; *P < 0.05.