Purpose: GPR40, a free fatty acid receptor, has been shown both in vivo and in vitro to prevent from bone loss by mainly targeting osteoclast resorption activity with a synthetic agonist GW9508. Here, we questioned whether stimulation of the GPR40 receptor by high-fat diet enriched with long chain fatty acids, natural ligands of GPR40, may parallel with its described beneficial effects on bone. Methods: In this study, 9 week-old sham-operated and ovariectomized C57/BL6 wild-type and GPR40-/- mice were fed with control or ANC high-fat diets for 5 weeks. Bone mineral density, body composition, weigh, inflammation and serum circulating bone remodeling parameters were monitored. Results: Although ANC high-fat diet induced a decrease of BMD in sham-operated wild-type, under ovariectomy conditions, mice fed with ANC high-fat diet have a significant higher BMD than GPR40-/- mice. This effect seems to be due to a modulation of the osteoblast/osteoclast coupling by stimulation of GPR40 by fatty acids. Conclusions: In this study, wedemonstrated for the first time that GPR40 limits bone loss induced by ovariectomy upon high fat diet. Taken together; our results demonstrate that GPR40 could mediate beneficial effects of fatty acids mainly by targeting the bone cell coupling and subsequent osteoclastic bone resorption