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

Jing Yan, Yuemei Zhang, Hairong Yu, Yicen Zong, Daixi Wang, Jiangfei Zheng, Li Jin, Xiangtian Yu, Caizhi Liu, Yi Zhang, Feng Jiang, Rong Zhang, Xiangnan Fang, Ting Xu, Mingyu Li, Jianzhong Di, Yan Lu, Xinran Ma, Jian Zhang, Weiping Jia and Cheng Hu ()
Additional contact information
Jing Yan: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yuemei Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Hairong Yu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yicen Zong: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Daixi Wang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jiangfei Zheng: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Li Jin: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xiangtian Yu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Caizhi Liu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yi Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Feng Jiang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Rong Zhang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xiangnan Fang: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Ting Xu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Mingyu Li: Shanghai Jiao Tong University School of Medicine
Jianzhong Di: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yan Lu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xinran Ma: East China Normal University
Jian Zhang: Shanghai Jiao Tong University School of Medicine
Weiping Jia: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Cheng Hu: Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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 Gαi3/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.

Date: 2022
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DOI: 10.1038/s41467-022-34998-9

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