title: The free fatty acid receptor G protein-coupled receptor 40 (GPR40) protects from bone loss through inhibition of osteoclast differentiation.
abstract: The mechanisms linking fat intake to bone loss remain unclear. By demonstrating the expression of the free fatty acid receptor G-coupled protein receptor 40 (GPR40) in bone cells, we hypothesized that this receptor may play a role in mediating the effects of fatty acids on bone remodeling. Using micro-CT analysis, we showed that GPR40(-/-) mice exhibit osteoporotic features suggesting a positive role of GPR40 on bone density. In primary cultures of bone marrow, we showed that GW9508, a GRP40 agonist, abolished bone-resorbing cell differentiation. This alteration of the receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation occurred via the inhibition of the nuclear factor κB (NF-κB) signaling pathway as demonstrated by decrease in gene reporter activity, inhibitor of κB kinase (IKKα/β) activation, inhibitor of κB (IkBα) phosphorylation, and nuclear factor of activated T cells 1 (NFATc1) expression. The GPR40-dependent effect of GW9508 was confirmed using shRNA interference in osteoclast precursors and GPR40(-/-) primary cell cultures. In addition, in vivo administration of GW9508 counteracted ovariectomy-induced bone loss in wild-type but not GPR40(-/-) mice, enlightening the obligatory role of the GPR40 receptor. Then, in a context of growing prevalence of metabolic and age-related bone disorders, our results demonstrate for the first time in translational approaches that GPR40 is a relevant target for the design of new nutritional and therapeutic strategies to counter bone complications.
authors: Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1019, Unité de Nutrition Humaine, Centre de Recherche en Nutrition Humaine Auvergne, F-63009 Clermont-Ferrand, France.
authors: Fabien
authors: F
authors: Wauquier
authors: Claire
authors: C
authors: Philippe
authors: Laurent
authors: L
authors: Léotoing
authors: Sylvie
authors: S
authors: Mercier
authors: Marie-Jeanne
authors: MJ
authors: Davicco
authors: Patrice
authors: P
authors: Lebecque
authors: Jérôme
authors: J
authors: Guicheux
authors: Paul
authors: P
authors: Pilet
authors: Elisabeth
authors: E
authors: Miot-Noirault
authors: Vincent
authors: V
authors: Poitout
authors: Thierry
authors: T
authors: Alquier
authors: Véronique
authors: V
authors: Coxam
authors: Yohann
authors: Y
authors: Wittrant
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010024:Osteoporosis / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011422:Propionates / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C473036:Ffar1 protein, mouse; C515630:GW9508; D008744:Methylamines; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D011422:Propionates; D053245:RANK Ligand; D043562:Receptors, G-Protein-Coupled; C505689:Tnfsf11 protein, mouse