GPR40 mediates potential positive effects of a saturated fatty acid enriched diet on bone

Mol Nutr Food Res. 2017 Feb;61(2). doi: 10.1002/mnfr.201600219. Epub 2016 Nov 11.


Scope: The stimulation of the free fatty acid receptor G-protein coupled receptor (GPR) 40 by GW9508 prevents bone loss by inhibiting osteoclast activity, both in vitro and in vivo. Here, we questioned whether the stimulation of the GPR40 receptor by dietary fatty acids may lead to the same beneficial effect on bone.

Methods and results: We investigated (i) the impact of a fatty acid enriched diet (high-fat diet [HFD]) on bone health in C57/BL6 female mice depending on (ii) the estrogen status (ovariectomy) and (iii) the genotype (GPR40+/+ or GPR40-/- ). Bone mineral density (BMD), body composition, weight, inflammation and bone remodeling parameters were monitored. HFD decreased BMD in HFD-SH-GPR40+/+ mice but OVX failed to further impact BMD in HFD-OVX-GPR40+/+ mice, while additional bone loss was observed in HFD-OVX-GPR40-/- animals. These data suggest that when stimulated by fatty acid enriched diets GPR40 contributes to counteract ovariectomy-induced bone alteration. The sparing effect is supported by the modulation of both the osteoprotegerin/receptor activator of nuclear factor kappa-B ligand (OPG/RANKL) ratio in blood stream and the expression level of inflammatory markers in adipose tissues. Bone preservation by GPR40 stimulation is dependent on the presence of long-chain saturated fatty acids.

Conclusion: GPR40 contributes to counter ovariectomy-induced bone loss in a context of saturated fatty acid enrichment.

Keywords: Free fatty acid receptor; GPR40; High-fat diet; Nutrition; Osteoporosis.

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Fatty Acids / pharmacology*
  • Female
  • Methylamines / pharmacology
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Osteoporosis / diet therapy*
  • Osteoporosis / etiology
  • Osteoporosis / prevention & control
  • Ovariectomy / adverse effects
  • Panniculitis / etiology
  • Panniculitis / pathology
  • Propionates / pharmacology
  • RANK Ligand / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*


  • Fatty Acids
  • Ffar1 protein, mouse
  • GW9508
  • Methylamines
  • Propionates
  • RANK Ligand
  • Receptors, G-Protein-Coupled
  • Tnfsf11 protein, mouse