Deletion of Ghrelin Impairs neither Growth nor Appetite

Abstract

Pharmacological studies show that ghrelin stimulates growth hormone release, appetite, and fat deposition, but ghrelin's physiological role in energy homeostasis has not been established. Ghrelin was also proposed to regulate leptin and insulin release and to be important for the normal function of stomach, heart, kidney, lung, testis, and placenta. To help determine a definable physiological role for ghrelin, we generated ghrelin-null mice. In contrast to predictions made from the pharmacology of ghrelin, ghrelin-null mice are not anorexic dwarfs; their size, growth rate, food intake, body composition, reproduction, gross behavior, and tissue pathology are indistinguishable from wild-type littermates. Fasting produces identical decreases in serum leptin and insulin in null and wild-type mice. Ghrelin-null mice display normal responses to starvation and diet-induced obesity. As in wild-type mice, the administration of exogenous ghrelin stimulates appetite in null mice. Our data show that ghrelin is not critically required for viability, fertility, growth, appetite, bone density, and fat deposition and not likely to be a direct regulator of leptin and insulin. Therefore, antagonists of ghrelin are unlikely to have broad utility as antiobesity agents.

ACKNOWLEDGMENTS

The ghrelin ^−/− mice were generated in collaboration with Lexicon Genetics, Inc. (Woodlands, Tex.). We thank Adelina Gunawan for excellent technical assistance. We thank Fred Pereira, Mark Asnicar, Hui Zheng, Hong Jiang, and Lorena Betancourt for stimulating discussions during the study. We thank Michael R. Honig for help with the manuscript.

We gratefully acknowledge the support of National Institutes of Health grants RO1AG18895 and RO1AG19230, the Hankamer Foundation, and a postdoctoral fellowship for Yuxiang Sun from the Canadian Institutes of Health Research.