The Free Fatty Acid Receptor G Protein-coupled Receptor 40 (GPR40) Protects from Bone Loss through Inhibition of Osteoclast Differentiation*

Wauquier, Fabien; Philippe, Claire; Léotoing, Laurent; Mercier, Sylvie; Davicco, Marie-Jeanne; Lebecque, Patrice; Guicheux, Jérôme; Pilet, Paul; Miot-Noirault, Élisabeth; Poitout, Vincent; Alquier, Thierry; Coxam, Véronique; Wittrant, Yohann

doi:10.1074/jbc.m112.429084

Cited by 75 publications

(63 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The activation of ERK with subsequent recruitment of the pro-apoptotic factor Bax to the outer membrane of the mitochondria was posited as the cause of TZD-related bone loss (125). In opposition to this mechanism, GW9508, a GPR40 agonist that blocks osteoclast differentiation in vitro , was found to prevent ovariectomy-induced bone loss in wildtype, but not Gpr40 −/− mice (126). …”

Section: Gpr40 and Pparγ An Integrated Two-receptor Signaling Patmentioning

confidence: 99%

PPARγ signaling and emerging opportunities for improved therapeutics

Wang

Dougherty

Danner

2016

Pharmacological Research

169

105

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPARγ are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPARγ signaling and to develop safer and more effective PPARγ-directed therapeutics. In addition to PPARγ itself, many PPARγ ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPARγ responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPARγ genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPARγ co-activator-1α, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPARγ-dependent transcription. Therefore in endothelium, GPR40 and PPARγ function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPARγ. Thus the role of GPR40 in PPARγ signaling may have important implications for drug development. Ligands that strongly activate PPARγ, but do not bind to or activate GPR40 may be safer than currently approved PPARγ agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPARγ, but not ERK1/2, avoiding its harmful effects on PPARγ signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.

show abstract

Section: Gpr40 and Pparγ An Integrated Two-receptor Signaling Patmentioning

confidence: 99%

PPARγ signaling and emerging opportunities for improved therapeutics

Wang

Dougherty

Danner

2016

Pharmacological Research

169

105

View full text Add to dashboard Cite

show abstract

“…The cells were then blocked in 4% nonfat milk and incubated with rabbit polyclonal anti-GPR40 (35,36) at 4°C overnight, followed by incubation for 1 h with FITC-conjugated anti-rabbit IgG. Fluorescence was visualized using a confocal microscope (LSM700, Carl Zeiss Microscopy, Jena, Germany).…”

Section: Methodsmentioning

confidence: 99%

A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-cis-12-octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40-MEK-ERK Pathway

Miyamoto

Mizukure

Park

et al. 2015

Journal of Biological Chemistry

201

143

View full text Add to dashboard Cite

Background:The physiological activity of gut microbial metabolites has recently attracted much attention. Results: A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid (HYA), ameliorates intestinal epithelial barrier impairments by regulating TNFR2 expression via the GPR40-MEK-ERK pathway. Conclusion: HYA-induced GPR40 signaling contributes to the intestinal homeostasis. Significance: Our findings indicate a novel function of GPR40 in the inflamed intestine.

show abstract

“…26,27 Recently, activation of FFAR1 and FFAR3 by endogeneous or synthetic ligands has been shown to inhibit NF-kB activation in both osteoclasts and macrophages. 19,28 In the light of these data, inhibition of NF-kB signaling pathways may contribute to explain the protective role of GPR40 in OA.…”

Section: Discussionmentioning

confidence: 99%

“…We recently demonstrated that GPR40 knock-out (GPR40 À/À ) mice exhibited osteoporotic features and that GPR40 stimulation preserved bone mass. 19 Regarding the close relationships between bone and cartilage tissues behavior, the role of GPR40 in cartilage physiopathology was investigated in the present study. First, we performed in vitro experiments to investigate the consequence of GPR40 deficiency on chondrocyte metabolism.…”

Section: Introductionmentioning

confidence: 99%

Featured Article: Deficiency of G-protein coupled receptor 40, a lipid-activated receptor, heightens in vitro- and in vivo-induced murine osteoarthritis

Monfoulet

Philippe

Mercier

et al. 2015

Exp Biol Med (Maywood)

Self Cite

View full text Add to dashboard Cite

Osteoarthritis (OA) is an age-related degenerative joint disease. To date, its management is focused on symptoms (pain and inflammation). Studies suggest that fatty acids can reduce the expression of inflammatory and catalytic mediators, and improve in vivo joint function. Free fatty acid receptors (FFARs) such as G-protein coupled receptor 40 (GPR40) are proposed as attractive therapeutic targets to counteract inflammation and cartilage degradation observed in OA. This study aims to elucidate the involvement of GPR40 in OA. In this study, we used an in vitro model of OA, and surgically induced OA by ligament transection and partial meniscectomy in wild-type and GPR40 deficient mice. OA phenotype was investigated in vivo by histology and genes expression. We demonstrate that IL-1b-treated GPR40 À/À chondrocytes secret more inflammatory mediators (nitric oxide, interleukin-6, prostaglandin E2) and active catabolic enzymes (metalloproteinase-2, -9 [MMP-2, MMP-9]), and show decreased anabolism (glycoaminoglycan) compared to GPR40 þ/þ cells. In accordance with these results, we show that GPR40 À/À mice exhibit an aggravated OA-induced phenotype characterized by higher tidemark exposure, frequency of osteophyte formation and subchondral bone sclerosis. Altogether our results demonstrate that GPR40 deficiency leads to an extended OA phenotype, providing evidence that increasing GPR40 activity, by natural or synthetic ligands, could be a new strategy in the management of OA.

show abstract

The Free Fatty Acid Receptor G Protein-coupled Receptor 40 (GPR40) Protects from Bone Loss through Inhibition of Osteoclast Differentiation*

Cited by 75 publications

References 38 publications

PPARγ signaling and emerging opportunities for improved therapeutics

PPARγ signaling and emerging opportunities for improved therapeutics

A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-cis-12-octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40-MEK-ERK Pathway

Featured Article: Deficiency of G-protein coupled receptor 40, a lipid-activated receptor, heightens in vitro- and in vivo-induced murine osteoarthritis

Contact Info

Product

Resources

About