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J. Biol. Chem. 284 (5): 2811-2822

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81*

Formula

Changlu Liu1, Jiejun Wu, Jessica Zhu, Chester Kuei, Jingxue Yu, Jonathan Shelton, Steven W. Sutton, Xiaorong Li, Su Jin Yun, Taraneh Mirzadegan, Curt Mazur2, Fredrik Kamme3, , and Timothy W. Lovenberg

Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121

Abstract: Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1–20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders.

Received for publication August 19, 2008. Revision received October 25, 2008.

* 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.


Formula

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1–3 and Figs. 1–6.

2 Present address: Isis Pharmaceuticals, Inc., 1896 Rutherford Rd., Carlsbad, CA 92008.

3 Present address: Cyntellect, 6620 Mesa Ridge Rd., San Diego, CA 92121.

1 To whom correspondence should be addressed: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121. Tel.: 858-784-3059; Fax: 858-450-2090; E-mail: cliu9{at}its.jnj.com.

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