G-protein-signaling modulator 1 (GPSM1) exhibits strong genetic association with Type 2 diabetes (T2D) and Body Mass Index in population studies. However, how GPSM1 carries out such control and in which types of cells are poorly understood. Here, we demonstrate that myeloid GPSM1 promotes metabolic inflammation to accelerate T2D and obesity development. Mice with myeloid-specific GPSM1 ablation are protected against high fat diet-induced insulin resistance, glucose dysregulation, and liver steatosis via repression of adipose tissue pro-inflammatory states. Mechanistically, GPSM1 deficiency mainly promotes TNFAIP3 transcription via the Gα_i3/cAMP/PKA/CREB axis, thus inhibiting TLR4-induced NF-κB signaling in macrophages. In addition, we identify a small-molecule compound, AN-465/42243987, which suppresses the pro-inflammatory phenotype by inhibiting GPSM1 function, which could make it a candidate for metabolic therapy. Furthermore, GPSM1 expression is upregulated in visceral fat of individuals with obesity and is correlated with clinical metabolic traits. Overall, our findings identify macrophage GPSM1 as a link between metabolic inflammation and systemic homeostasis.

G 蛋白信号调节剂 1 ( GPSM1 ) 在人群研究中表现出与 2 型糖尿病 (T2D) 和体重指数的强烈遗传关联。然而，人们对 GPSM1 如何进行这种控制以及在哪些类型的细胞中进行控制知之甚少。在这里，我们证明骨髓 GPSM1 促进代谢性炎症以加速 T2D 和肥胖的发展。通过抑制脂肪组织促炎状态，骨髓特异性GPSM1消融小鼠可免受高脂肪饮食诱导的胰岛素抵抗、葡萄糖失调和肝脂肪变性。从机制上讲，GPSM1 缺陷主要通过 Gα _{i3促进 TNFAIP3 转录}/cAMP/PKA/CREB ​​轴，从而抑制巨噬细胞中 TLR4 诱导的 NF-κB 信号传导。此外，我们鉴定了一种小分子化合物 AN-465/42243987，它通过抑制 GPSM1 功能来抑制促炎表型，这可能使其成为代谢治疗的候选药物。此外，GPSM1表达在肥胖个体的内脏脂肪中上调，并且与临床代谢特征相关。总体而言，我们的研究结果将巨噬细胞 GPSM1 确定为代谢炎症和全身稳态之间的联系。