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J. Biol. Chem., Vol. 280, Issue 29, 26649-26652, July 22, 2005

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(D)--Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G^*

Andrew K. P. Taggart¶, Jukka Kero||, Xiaodong Gan, Tian-Quan Cai, Kang Cheng, Marc Ippolito, Ning Ren, Rebecca Kaplan, Kenneth Wu, Tsuei-Ju Wu, Lan Jin, Chen Liaw**, Ruoping Chen**, Jeremy Richman**, Daniel Connolly**, Stefan Offermanns||, Samuel D. Wright, and M. Gerard Waters

From the Division of Cardiovascular Diseases, Merck Research Laboratories, Rahway, New Jersey 07065, the ^||Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany, and ^**Arena Pharmaceuticals Inc., San Diego, California 92121

As a treatment for dyslipidemia, oral doses of 1–3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease (Tavintharan, S., and Kashyap, M. L. (2001) Curr. Atheroscler. Rep. 3, 74–82). These benefits likely result from the ability of nicotinic acid to inhibit lipolysis in adipocytes and thereby reduce serum non-esterified fatty acid levels (Carlson, L. A. (1963) Acta Med. Scand. 173, 719–722). In mice, nicotinic acid inhibits lipolysis via PUMA-G, a G_i/o-coupled seven-transmembrane receptor expressed in adipocytes and activated macrophages (Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., and Offermanns, S. (2003) Nat. Med. 9, 352–355). The human ortholog HM74a is also a nicotinic acid receptor and likely has a similar role in anti-lipolysis. Endogenous levels of nicotinic acid are too low to significantly impact receptor activity, hence the natural ligands(s) of HM74a/PUMA-G remain to be elucidated. Here we show that the fatty acid-derived ketone body (D)--hydroxybutyrate ((D)--OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (D)--OHB inhibits mouse adipocyte lipolysis in a PUMA-G-dependent manner and is thus the first endogenous ligand described for this orphan receptor. These findings suggests a homeostatic mechanism for surviving starvation in which (D)--OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.

Received for publication, May 23, 2005

^* 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.

These authors contributed equally to this work.

^¶ To whom correspondence should be addressed: Dept. of Cardiovascular Diseases, Merck Research Laboratories, 126 E. Lincoln Ave., Rahway, NJ 07065. Tel.: 732-594-2358; Fax: 732-594-4620; E-mail: andy_taggart{at}merck.com.

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