Deorphanization of GPR109B as a receptor for the beta-oxidation intermediate 3-OH-octanoic acid and its role in the regulation of lipolysis.
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.
Ahmed
Kashan
K
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Tunaru
Sorin
S
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Langhans
Claus-Dieter
CD
Department of General Pediatrics, Division of Inherited Metabolic Disease, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Hanson
Julien
J
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.
Michalski
Christoph W
CW
Department of Surgery, Technical University Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
Kölker
Stefan
S
Department of General Pediatrics, Division of Inherited Metabolic Disease, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Jones
Patricia M
PM
Department of Pathology, University of Texas Southwestern Medical Center, Childrens Medical Center, Dallas, Texas 75235.
Okun
Jürgen G
JG
Department of General Pediatrics, Division of Inherited Metabolic Disease, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
Offermanns
Stefan
S
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.
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*
D002210:Caprylates; C473653:HCAR3 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; C101940:3-hydroxyoctanoic acid; D010100:Oxygen