Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity
Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity
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DOI：
10.1016/j.cmet.2020.04.020
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发表时间：
2020-06-02
期刊：
影响因子：
29
通讯作者：
Oh, Da Young
中科院分区：
文献类型：
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作者：
Paschoal, Vivian A.;Walenta, Evelyn;Oh, Da Young
G蛋白偶联受体120（GPR 120）和PPAR γ激动剂各自具有胰岛素增敏作用。但这两种途径是否在功能上相互作用，并可以一起利用，以显着改善胰岛素抵抗尚未探讨。在这里，我们表明用PPAR γ激动剂罗格列酮（Rosi）加GPR 120激动剂化合物A治疗导致改善葡萄糖耐量和胰岛素敏感性的累加效应，但在较低剂量的Rosi下，从而避免其已知的副作用。从机制上讲，我们表明GPR 120是脂肪细胞中的PPAR γ靶基因，而GPR 120通过诱导内源性配体15 d-PGJ 2和阻断ERK介导的对PPAR γ的抑制来增强PPAR γ活性。此外，我们使用巨噬细胞（MKO）或脂肪细胞特异性GPR 120 KO（AKO）小鼠来显示GRP 120通过巨噬细胞具有抗炎作用，同时与脂肪细胞中的PPAR γ一起工作以增加胰岛素敏感性。这些结果提高了临床上增加胰岛素增敏的更安全方法的前景。
G protein-coupled receptor 120 (GPR120) and PPAR gamma 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 PPAR gamma 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 PPAR gamma target gene in adipocytes, while GPR120 augments PPAR gamma activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPAR gamma. 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 PPAR gamma in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic.