4.8 Article

GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages

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NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34998-9

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资金

  1. National Science Foundation of China [81800702, 81974118, 81925034]
  2. Shanghai Sailing Program [18YF1418900]
  3. National Key Research and Development Program of China [2018YFA0800402]
  4. Shanghai Outstanding Academic Leaders [20XD1433300]
  5. Shuguang Project [21SG11]
  6. Innovative research team of high-level local universities in Shanghai [SHSMU-ZDCX20212700]
  7. Shanghai Research Center for Endocrine and Metabolic Diseases [2022ZZ01002]

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This study reveals that GPSM1 is genetically associated with T2D and obesity. The authors demonstrate that myeloid GPSM1 promotes metabolic inflammation and accelerates T2D and obesity development. They also identify a small molecule compound that inhibits GPSM1 function, potentially making it a candidate for metabolic therapy.
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 G alpha(i3)/cAMP/PKA/CREB axis, thus inhibiting TLR4-induced NF-kappa B 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-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.

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