Adipokine IL-11/IL-11Ra constrains sphingolipid metabolism to limit the thermogenic capacity of beige adipocytes

  • Cell Metab. 2026 May 14:S1550-4131(26)00151-8. doi: 10.1016/j.cmet.2026.04.013.
Jiadai Liu  1 ,  Ronghui Gao  1 ,  Qianqian Kang  2 ,  Zhihan Wang  1 ,  Xuemin Peng  1 ,  Jing Ge  1 ,  Wenshe Wang  1 ,  Hongyan Deng  1 ,  Yuyu Xie  1 ,  Zengzhe Zhu  1 ,  Min Yang  1 ,  Rui He  1 ,  Huanyu Wang  3 ,  Yulian Liu  1 ,  Pema Maretich  4 ,  Yongsheng Chang  5 ,  Jichun Yang  6 ,  Shingo Kajimura  7 ,  Ruping Pan  8 ,  Yong Chen  9
Affiliations
  • 1. Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Laboratory of Endocrinology and Metabolism, Key Laboratory of Vascular Aging (Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2. Laboratory of Endocrinology and Metabolism, Key Laboratory of Vascular Aging (Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3. Laboratory of Endocrinology and Metabolism, Key Laboratory of Vascular Aging (Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4. Research Laboratory of Electronics, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 5. Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
  • 6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing, China.
  • 7. Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 8. Laboratory of Endocrinology and Metabolism, Key Laboratory of Vascular Aging (Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
  • 9. Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China; Laboratory of Endocrinology and Metabolism, Key Laboratory of Vascular Aging (Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Medical Research Center for Endocrinology & Metabolic Diseases, Wuhan, China; Branch of National Clinical Research Center for Metabolic Diseases, Wuhan, China. Electronic address: [email protected].
PMID: 42140185 DOI: 10.1016/j.cmet.2026.04.013
Abstract

Adipocytes exhibit cellular plasticity by secreting pro-inflammatory cytokines in response to an energy excess. Here, we identify that interleukin (IL)-11 is robustly induced and secreted from adipocytes, especially beige adipocytes upon adrenergic stimulation. IL-11 inhibits adipocyte thermogenesis through binding to IL-11 Receptor a (IL-11Ra) and serves as a "brake" to maintain energy homeostasis. Adipocyte-specific IL-11Ra-knockout mice exhibit enhanced whole-body energy consumption and improved glucose and lipid metabolism under a high-fat diet (HFD). Inhibition of IL-11/IL-11Ra signaling enhances sphingosine kinase 1 (SphK1)-driven production of sphingosine-1-phosphate (S1P), thus remodeling intracellular calcium cycling in beige adipocytes. Notably, treatment with a designed peptide against IL-11Ra in obese mice effectively alleviates fat accumulation and obesity-associated disorders. Taken together, our study defines a physiological and noncanonical mechanism of beige adipocyte-derived IL-11 in energy metabolism, which may serve as a promising target for the treatment of obesity.

Keywords
adipokine; calcium signaling; obesity; sphingolipid metabolism; thermogenesis.
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