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

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 ␤-oxidation intermediate 3-OH-octanoic acid, which has antilipolytic activity on human but not on murine adipocytes. GPR109B is coupled to G i -type G-proteins and is activated by 2-and 3-OH-octanoic acid with EC 50 values of about 4 and 8 M, respectively. Interestingly, 3-OH-octanoic acid plasma concentrations reach micromolar concentrations under conditions of increased ␤-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 ␤-oxidation rates.

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

“…A chimera linking the N-terminal part of the HCA 3 receptor and the C-terminal part of the HCA 2 receptor at the interface between intracellular loop 2 and TM4 responded well to acifran (EC 50 ϭ 2 M) but was insensitive to nicotinic acid. The same chimera, studied in a later article, responded well to 2-oxo-octanoic acid, a close analog of the endogenous HCA 3 receptor ligand 3-hydroxy-octanoic acid, in a manner identical to the wild-type HCA 3 receptor (Ahmed et al, 2009a). The "reverse" chimera, in which the N-terminal half was from HCA 2 , did not respond to 2-oxo-octanoic acid.…”

“…Despite the high homology of HCA 2 and HCA 3 receptors, they show quite different binding properties for nicotinic acid and related substances, and various synthetic ligands specific for the HCA 3 receptor have been generated (see section V). 2-and 3-Hydroxylated medium-chain fatty acids, in particular 3-hydroxyoctanoate, have been shown to be specific agonists of HCA 3 , acting through the receptor with an EC 50 of 4 to 8 M (Ahmed et al, 2009a). 3-Hydroxy-octanoate was not able to activate HCA 1 or HCA 2 receptors, and a shortening or extension of the chain length of 3-hydroxyoctanoate by more than two carbon atoms resulted in a complete loss of activity at the HCA 3 receptor.…”

“…3-Hydroxy-hexanoate, 3-hydroxy-octanoate, and 3-hydroxydecanoate are intermediates of fatty acid ␤-oxidation. Under conditions of increased ␤-oxidation flux, during starvation, under ketogenic diet, or in patients with diabetic ketoacidosis, 3-hydroxy-octanoate plasma con- HCA RECEPTOR NOMENCLATURE 273 centrations reach levels sufficient to activate the HCA 3 receptor (Costa et al, 1998;Jones et al, 2002;Ahmed et al, 2009a).…”

Mice deficient in Group VIB phospholipase A2(iPLA2γ) exhibit relative resistance to obesity and metabolic abnormalities induced by a Western diet

“…This reduces production of stress signals from mitochondrial ␤-oxidative overload compared with WT mice. The identity of mitochondrion-derived signal(s) that link excessive ␤-oxidation to insulin resistance is not yet known, but specific ␤-oxidation intermediates (e.g., 3-hydroxyoctanoic acid) and shorter-chain hydroxycarboxylic acids are ligands of a subfamily of G protein-coupled receptors that regulate adipocyte lipolysis (1,2). Such compounds might be circulating mediators that coordinate metabolic activities of different tissues (1, 2) and represent candidate mitochondrion-derived signals of excessive ␤-oxidation.…”

“…SC-fed or WD-fed mice (age 6 mo) were euthanized with pentobarbital sodium, and the gastrocnemius muscle was excised. Oxidation of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate and of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]glucose by muscle homogenate was then performed as described (16). Briefly, gastrocnemius specimens (70 mg) were minced with scissors in homogenization buffer (200 l: 250 mM sucrose, 1 mM EDTA, 10 mM Tris·HCl, and 2 mM ATP, pH 7.4), diluted 20-fold, and transferred to a 3-ml Teflon-on-glass homogenization vessel.…”