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

J Biol Chem. 2005 Jul 22;280(29):26649-52. doi: 10.1074/jbc.C500213200. Epub 2005 Jun 1.

Abstract

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 Gi/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)-beta-hydroxybutyrate ((D)-beta-OHB) specifically activates PUMA-G/HM74a at concentrations observed in serum during fasting. Like nicotinic acid, (D)-beta-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)-beta-OHB negatively regulates its own production, thereby preventing ketoacidosis and promoting efficient use of fat stores.

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology*
  • Adipocytes / metabolism*
  • Animals
  • Cell Line
  • Feedback, Physiological
  • Humans
  • Hyperlipidemias / drug therapy
  • Hypolipidemic Agents / pharmacology
  • Ligands
  • Lipolysis / drug effects*
  • Mice
  • Nicotinic Agonists / pharmacology*
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic / drug effects*

Substances

  • HCAR2 protein, human
  • HCAR3 protein, human
  • Hcar2 protein, mouse
  • Hypolipidemic Agents
  • Ligands
  • Nicotinic Agonists
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • 3-Hydroxybutyric Acid