Deorphanization of GPR109B as a Receptor for the β-Oxidation Intermediate 3-OH-octanoic Acid and Its Role in the Regulation of Lipolysis

Kashan Ahmed,Sorin Tunaru,Claus-Dieter Langhans,Julien Hanson,Christoph W Michalski,Stefan Kölker,Patricia M Jones,Jürgen G Okun,Stefan Offermanns

doi:10.1074/jbc.m109.019455

Abstract

The orphan G-protein-coupled receptor GPR109B is the result of a recent gene duplication of the nicotinic acid and ketone body receptor GPR109A being found in humans but not in rodents. Like GPR109A, GPR109B is predominantly expressed in adipocytes and is supposed to mediate antilipolytic effects. Here we show that GPR109B serves as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid, which has antilipolytic activity on human but not on murine adipocytes. GPR109B is coupled to Gi-type G-proteins and is activated by 2- and 3-OH-octanoic acid with EC50 values of about 4 and 8 microM, respectively. Interestingly, 3-OH-octanoic acid plasma concentrations reach micromolar concentrations under conditions of increased beta-oxidation rates, like in diabetic ketoacidosis or under a ketogenic diet. These data suggest that the ligand receptor pair 3-OH-octanoic acid/GPR109B mediates in humans a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in beta-oxidation rates.

Highlights

Foundation. □S The on-line version of this article contains supplemental text and additional references. 1 Supported by “Fond National de la Recherche Scientifique” of Belgium and the Alexander von Humboldt Foundation. 2 To whom correspondence should be addressed
Besides insulin, which promotes the degradation of cAMP via activation of phosphodiesterase 3B [2, 5, 7], several antilipolytic stimuli decrease cAMP levels by activation of Gi-coupled receptors, which mediate an inhibition of adenylyl cyclase [5, 8]
The utilization of fatty acids as energy source requires their lipolytic formation from triacylglycerols stored in adipocytes and their subsequent degradation to acetyl CoA via ␤-oxidation cycles in mitochondria

Summary

Introduction

Foundation. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental text and additional references. 1 Supported by “Fond National de la Recherche Scientifique” of Belgium and the Alexander von Humboldt Foundation. 2 To whom correspondence should be addressed. These data suggest that the ligand receptor pair 3-OH-octanoic acid/GPR109B mediates in humans a negative feedback regulation of adipocyte lipolysis to counteract prolipolytic influences under conditions of physiological or pathological increases in ␤-oxidation rates. Mutation of the conserved arginine residue in position 111 to alanine completely abrogated the activation of GPR109B by OH-octanoic acid (data not shown), suggesting that similar to GPR109A arginine 111 in the third transmembrane helix functions as an important anchor point for the carboxylic acid ligands of both receptors [19].

Results

Conclusion