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Obesity disrupts ILC2 metabolic and functional homeostasis by inhibiting mTORC1 signaling

Cellular & Molecular Immunology volume 23, pages 301–314 (2026)Cite this article

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Abstract

Group 2 innate lymphoid cells (ILC2s) play crucial roles in maintaining adipose tissue homeostasis. Recent studies indicate that ILC2s are dysregulated in obesity. However, the regulatory mechanisms governing adipose tissue ILC2 function remain inadequately explored. In this study, we demonstrated that mechanistic target of rapamycin complex 1 (mTORC1) activity is impaired in adipose tissue ILC2s from obese mice and humans. Deletion of Raptor, a critical adaptor protein in mTORC1, results in reduced numbers of ILC2s and diminished type 2 cytokine production in ILC2s, leading to increased adipose tissue inflammation and insulin resistance. Mechanistically, mTORC1 signaling upregulates PPARγ expression through HIF-1α, which promotes mitochondrial biogenesis and ST2 expression to sustain ILC2 metabolic and functional fitness. Together, our data identify mTORC1 as a crucial regulator that coordinates adipose tissue ILC2 metabolic and immunological homeostasis and prevents obesity-associated insulin resistance.

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Data availability

The raw reads from the RNA-seq data have been deposited at the Gene Expression Omnibus (GEO) repository under the accession numbers GSE225097 and GSE287676. All data supporting the conclusions are available from the authors upon reasonable request.

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Acknowledgements

We thank all the members from the Shen laboratory for their help and suggestions on this project. We thank the Flow Cytometry Facility at the Shanghai Institute of Immunology and Animal Facility at Shanghai Jiao Tong University School of Medicine for their service and assistance. This study was supported by grants 32250710147 and 81971487 (to L.S.) from the National Natural Science Foundation of China, grant 2020YFA0509200 (to L.S.) from the Ministry of Science and Technology of China, and grant 23ZR1455100 (to L.S.) from the Science and Technology Commission of Shanghai Municipality.

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  1. These authors contributed equally: Lin Hu, Dongdi Wang.

Authors and Affiliations

  1. Center for Immune-Related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lin Hu, Dongdi Wang, Youqin Zhang, Xiaohui Su, Jiping Sun & Lei Shen

  2. Department of Immunology and Microbiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lin Hu, Dongdi Wang, Youqin Zhang, Michelle Zhang, Xiaohui Su, Jiping Sun & Lei Shen

  3. Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lin Hu, Dongdi Wang, Youqin Zhang, Xiaohui Su, Jiping Sun & Lei Shen

  4. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Yue Chen, Jinxin Qiu & Ju Qiu

  5. Department of Endocrinology, Drum Tower Hospital affiliated with Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China

    Hongdong Wang

  6. Hainan Academy of Medical Sciences, Hainan Medical University, Hainan, China

    Lei Shen

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Contributions

LH and DW designed and performed the experiments, analyzed the data, and drafted the manuscript. YC, JQ, and MZ performed some of the experiments. H. contributed to human sample collection. YZ and JQ contributed to the discussion. LS and JS wrote the manuscript. LS conceived, designed, and supervised the project. All the authors discussed, revised, and approved the manuscript.

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Correspondence to Jiping Sun or Lei Shen.

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The authors declare that they have no conflicting interests. J.Q. is an editorial board member of Cellular & Molecular Immunology, but she has not been involved in peer review or decision-making related to the article.

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Hu, L., Wang, D., Chen, Y. et al. Obesity disrupts ILC2 metabolic and functional homeostasis by inhibiting mTORC1 signaling. Cell Mol Immunol 23, 301–314 (2026). https://doi.org/10.1038/s41423-026-01389-9

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