Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK

Chang Peng, Haowen Jiang (), Liya Jing, Wenhua Yang, Xiaotong Guan, Hanlin Wang, Sike Yu, Yutang Cao, Min Wang, Huan Ma, Zan Lv, Hongyu Gu, Chunmei Xia, Xiaozhen Guo, Bin Sun, Aili Wang, Cen Xie, Wenbiao Wu, Luyiyi Lu, Jiayi Song, Saifei Lei, Rui Wu, Yi Zang, Erjiang Tang () and Jia Li ()
Additional contact information
Chang Peng: Chinese Academy of Sciences
Haowen Jiang: Chinese Academy of Sciences
Liya Jing: Chinese Academy of Sciences
Wenhua Yang: Chinese Academy of Sciences
Xiaotong Guan: University of Chinese Academy of Sciences
Hanlin Wang: Chinese Academy of Sciences
Sike Yu: University of Chinese Academy of Sciences
Yutang Cao: Chinese Academy of Sciences
Min Wang: Chinese Academy of Sciences
Huan Ma: Chinese Academy of Sciences
Zan Lv: Chinese Academy of Sciences
Hongyu Gu: Chinese Academy of Sciences
Chunmei Xia: Chinese Academy of Sciences
Xiaozhen Guo: Chinese Academy of Sciences
Bin Sun: Tongji University School of Medicine
Aili Wang: Tongji University School of Medicine
Cen Xie: Chinese Academy of Sciences
Wenbiao Wu: Chinese Academy of Sciences
Luyiyi Lu: University of Chinese Academy of Sciences
Jiayi Song: University of Chinese Academy of Sciences
Saifei Lei: University of Chinese Academy of Sciences
Rui Wu: University of Chinese Academy of Sciences
Yi Zang: Lingang Laboratory
Erjiang Tang: Tongji University School of Medicine
Jia Li: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Obesity is regarded as a chronic inflammatory disease involving adipose tissue macrophages (ATM), but whether immunometabolic reprogramming of ATM affects obesity remains unclarified. Here we show that in ATM glutaminolysis is the fundamental metabolic flux providing energy and substrate, bridging with AMP-activated protein kinase (AMPK) activity, succinate-induced interleukin-1β (IL-1β) production, and obesity. Abrogation of AMPKα in myeloid cells promotes proinflammatory ATM, impairs thermogenesis and energy expenditure, and aggravates obesity in mice fed with high-fat diet (HFD). Conversely, IL-1β neutralization or myeloid IL-1β abrogation prevents obesity caused by AMPKα deficiency. Mechanistically, ATP generated from glutaminolysis suppresses AMPK to decrease phosphorylation of the β subunit of succinyl-CoA synthetase (SUCLA2), thereby resulting in the activation of succinyl-CoA synthetase and the overproduction of succinate and IL-1β; by contrast, siRNA-mediated SUCLA2 knockdown reduces obesity induced by HFD in mice. Lastly, phosphorylated SUCLA2 in ATM correlates negatively with obesity in humans. Our results thus implicate a glutaminolysis/AMPK/SUCLA2/IL-1β axis of inflammation and obesity regulation in ATM.

Date: 2025
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DOI: 10.1038/s41467-025-57044-w

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