Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity

G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic. [Display omitted] •GPR120 is a PPARγ target gene in adipocytes•GPR120 activation blocks the inhibitory phosphorylation of PPARγ at S273•GPR120 activation increases the endogenous PPARγ ligand 15d-PGJ2 in adipose tissue•Combined PPARγ and GPR120 agonism potentiates insulin sensitivity in diabetic mice Paschoal et al. explore the molecular interactions between the GPR120 and PPARγ pathways in vitro and in vivo. They also report that dual agonism of GPR120 and PPARγ additively improves insulin resistance in obese diabetic mice while avoiding the unwanted side effects of targeting PPARγ, potentially paving the way to re-expand the use PPARγ agonists in the clinic.