Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity1,2. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity3,4 and eosinophil and alternatively activated macrophage responses5, and were recently identified in murine white adipose tissue (WAT)5 where they may act to limit the development of obesity6. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)+ beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure7,8,9. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signalling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that, in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.
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The authors wish to thank members of the Artis laboratory for the critical reading of this manuscript. Research in the Artis laboratory is supported by the National Institutes of Health (AI061570, AI074878, AI095466, AI095608, AI102942, and AI097333 to D.A.), the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (D.A.) and Crohn’s & Colitis Foundation of America (D.A.). Additional funding was provided by NIH F30-AI112023 (J.R.B.), T32-AI060516 (J.R.B.), T32-AI007532 (L.A.M.), KL2-RR024132 (B.S.K.), DP5OD012116 (G.F.S.), P01AI06697 (D.L.F.), F31AG047003 (J.J.T.) and DP2OD007288 (P.S.) and by the Searle Scholars Award (P.S.). We thank M. A. Lazar for scientific and technical advice, D. E. Smith for providing Il33−/− mice, A. Goldrath for providing Id2−/− chimaeras, and A. Bhandoola for providing Tcf7−/− mice. We also thank the Mouse Phenotyping, Physiology & Metabolism Core at the Diabetes Research Center (DRC) of the Institute for Diabetes, Obesity & Metabolism (IDOM) as well as the Penn Diabetes Endocrine Research Center Grant (P30DK19525). In addition, we thank the Matthew J. Ryan Veterinary Hospital Pathology Laboratory, the Penn Microarray Facility, and the Mucosal Immunology Studies Team (MIST) of the NIH NIAID for shared expertise and resources. The authors would also like to thank the Abramson Cancer Center Flow Cytometry and Cell Sorting Resource Laboratory for technical advice and support. The ACC Flow Cytometry and Cell Sorting Shared Resource is partially supported by NCI Comprehensive Cancer Center Support Grant (no. 2-P30 CA016520). This work was supported by the NIH/NIDDK P30 Center for Molecular Studies in Digestive and Liver Diseases (P30-DK050306), its pilot grant program and scientific core facilities (Molecular Pathology and Imaging, Molecular Biology, Cell Culture and Mouse), as well as the Joint CHOP-Penn Center in Digestive, Liver and Pancreatic Medicine and its pilot grant program. In addition, we would like to acknowledge and thank the New York Organ Donor Network, the Cooperative Human Tissue Network-Eastern Division and especially the donors and their families. We apologize to colleagues whose work we were unable to quote owing to space constraints.
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