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PNAS 101 (4): 1045-1050

Copyright © 2004 by the National Academy of Sciences.

MEDICAL SCIENCES

Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41

Yumei Xiong *, Norimasa Miyamoto *, Kenji Shibata *, Mark A. Valasek *, Toshiyuki Motoike * {dagger}, Rafal M. Kedzierski *, and Masashi Yanagisawa * {dagger} {ddagger}

*Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050; and {dagger}Exploratory Research for Advanced Technology, Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo 135-0064, Japan

Communicated by Joseph L. Goldstein, University of Texas Southwestern Medical Center, Dallas, TX, October 29, 2003

Received for publication March 5, 2003.

Abstract: Leptin is an adipose-derived hormone that regulates a wide variety of physiological processes, including feeding behavior, metabolic rate, sympathetic nerve activity, reproduction, and immune response. Circulating leptin levels are tightly regulated according to energy homeostasis in vivo. Although mechanisms for the regulation of leptin production in adipocytes are not well understood, G protein-coupled receptors may play an important role in this adipocyte function. Here we report that C2–C6 short-chain fatty acids, ligands of an orphan G protein-coupled receptor GPR41, stimulate leptin expression in both a mouse adipocyte cell line and mouse adipose tissue in primary culture. Acute oral administration of propionate increases circulating leptin levels in mice. The concentrations of short-chain fatty acids required to stimulate leptin production are within physiological ranges, suggesting the relevance of this pathway in vivo.

Abbreviations: GPCR, G protein-coupled receptor; SCFA, short-chain fatty acid; siRNA, short interfering RNA.

{ddagger} To whom correspondence should be addressed at: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Room Y5.210, Dallas, TX 75390-9050. E-mail: masashi.yanagisawa{at}utsouthwestern.edu.

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