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.

G 蛋白偶联受体 120 (GPR120) 和 PPARγ 激动剂均具有胰岛素增敏作用。但是，这两种途径是否在功能上相互作用并可以共同利用以显着改善胰岛素抵抗尚未得到探索。在这里，我们展示了用 PPARγ 激动剂罗格列酮 (Rosi) 加 GPR120 激动剂化合物 A 进行治疗会导致改善葡萄糖耐量和胰岛素敏感性的叠加效应，但 Rosi 剂量较低，从而避免了其已知的副作用。从机制上讲，我们表明 GPR120 是脂肪细胞中的 PPARγ 靶基因，而 GPR120 通过诱导内源性配体 15d-PGJ2 和阻断 ERK 介导的 PPARγ 抑制来增强 PPARγ 活性。更远，我们使用巨噬细胞 (MKO) 或脂肪细胞特异性 GPR120 KO (AKO) 小鼠来证明 GRP120 通过巨噬细胞具有抗炎作用，同时与脂肪细胞中的 PPARγ 一起工作以增加胰岛素敏感性。这些结果提出了一种在临床中增加胰岛素敏感性的更安全方法的前景。