Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK
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.
Authors
- Chunmei Xia (ORCID: https://orcid.org/0000-0001-9845-9685)
- Cen Xie (ORCID: https://orcid.org/0000-0002-4574-8456)
- Liya Jing
- Yi Zang (ORCID: https://orcid.org/0000-0001-9835-922X)
- Huan Ma
- Chang Peng (ORCID: https://orcid.org/0000-0002-8150-8134)
- Zhiqiang Lv (ORCID: https://orcid.org/0000-0002-3071-160X)
- Wen‐Biao Wu (ORCID: https://orcid.org/0009-0000-6598-2058)
- Hongyu Gu (ORCID: https://orcid.org/0000-0002-5478-132X)
- Bin Sun (ORCID: https://orcid.org/0000-0002-5082-3326)
- Erjiang Tang (ORCID: https://orcid.org/0000-0002-8042-5994)
- Shu‐Feng Lei (ORCID: https://orcid.org/0000-0003-1453-8082)
- Xiaotong Guan (ORCID: https://orcid.org/0000-0002-9813-2030)
- Min Wang (ORCID: https://orcid.org/0000-0001-6706-3418)
- Wenhua Yang
- Hanlin Wang (ORCID: https://orcid.org/0000-0003-0443-4378)
- Aili Wang (ORCID: https://orcid.org/0000-0002-9118-230X)
- Yutang Cao
- Xiaozhen Guo (ORCID: https://orcid.org/0000-0001-6852-6015)
- Haowen Jiang (ORCID: https://orcid.org/0000-0003-4419-7645)
- Rui Wu (ORCID: https://orcid.org/0009-0008-8707-4075)
- Jiayi Song (ORCID: https://orcid.org/0009-0008-2741-5915)
- Jia Li (ORCID: https://orcid.org/0000-0003-3224-001X)
- S B Yu
- Luyiyi Lu
Institutions
- Tongji University (CN)
- Nanjing University of Chinese Medicine (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
- Institute for Advanced Study (DE)
- Tongji Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Yangpu Hospital of Tongji University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1038/s41467-025-57044-w
- Citations
- 16
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 12.76
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Science and Technology Commission of Shanghai Municipality
- Chinese Academy of Medical Sciences
- University of Chinese Academy of Sciences