title: Deorphanization of GPR109B as a receptor for the beta-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 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.
authors: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Kashan
authors: K
authors: Ahmed
authors: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors: Sorin
authors: S
authors: Tunaru
authors: Department of General Pediatrics, Division of Inherited Metabolic Disease, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors: Claus-Dieter
authors: CD
authors: Langhans
authors: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Department of Medicinal Chemistry, Centre Interfacultaire de Recherche du Médicament, University of Liège, 4000 Liège, Belgium.
authors: Julien
authors: J
authors: Hanson
authors: Department of Surgery, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
authors: Christoph W
authors: CW
authors: Michalski
authors: Department of General Pediatrics, Division of Inherited Metabolic Disease, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Kölker
authors: Department of Pathology, University of Texas Southwestern Medical Center, Childrens Medical Center, Dallas, Texas 75235.
authors: Patricia M
authors: PM
authors: Jones
authors: Department of General Pediatrics, Division of Inherited Metabolic Disease, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors: Jürgen G
authors: JG
authors: Okun
authors: Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Parkstrasse 1, 61231 Bad Nauheim, Germany.
authors: Stefan
authors: S
authors: Offermanns
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002210:Caprylates / Q000737:chemistry*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008066:Lipolysis; D051379:Mice; D008954:Models, Biological; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000737:chemistry*
chemical_list: D002210:Caprylates; C473653:HCAR3 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C101940:3-hydroxyoctanoic acid; D010100:Oxygen