Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1–7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
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Bibliographical noteFunding Information:
E.G.Y. has received institutional research funds from and is a consultant for Abbvie, Almirall, Amgen, Asana Biosciences, AstraZeneca, Boerhinger-Ingelhiem, Cara Therapeutics, Celgene, Elli Lilly, Galderma, Glenmark/Ichnos Sciences, Janssen, Kyowa Kirin, Leo Pharma, Pfizer, Regeneron, and UCB. E.G.Y. has received institutional research funds from AnaptysBio, Innovaderm, KAO, Kiniksa, Novan, Novartis, and Ralexar. E.G.Y. is a consultant for Arena, Aslan Pharmaceuticals, Bristol-Myers Squibb, Connect Pharma, EMD Serono, Evidera, Incyte, Pandion Therapeutics, RAPT Therapeutics, Sanofi, SATO Pharmaceutical, Siolta Therapeutics, Target Pharma Solutions, and Ventyx Biosciences. R.L.G. is a consultant and has equity interest in MatriSys Biosciences and Sente Inc. C.J.Y. is a Scientific Advisory Board member for and holds equity in Related Sciences and ImmunAI, a consultant for and holds equity in Maze Therapeutics, and a consultant for TReX Bio. C.J.Y. has received research support from Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, and Genentech. A.M. is a compensated cofounder, member of the boards of directors and a member of the scientific advisory boards of Spotlight Therapeutics and Arsenal Biosciences. A.M. is a cofounder, member of the boards of directors and a member of the scientific advisory board of Survey Genomics. A.M. is a compensated member of the scientific advisory board of NewLimit. A.M. owns stock in Arsenal Biosciences, Spotlight Therapeutics, NewLimit, Survey Genomics, PACT Pharma, and Merck. A.M. has received fees from PACT Pharma, Juno Therapeutics, Trizell, Vertex, Merck, Amgen, Genentech, AlphaSights, 23andMe, ALDA, Rupert Case Management and Bernstein. A.M. is an investor in and informal advisor to Offline Ventures and a client of EPIQ. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead and Anthem.
We thank A. Levine for advice and critical review of the manuscript; E. Marsh, B. Shy, S. Dodgson and B. Schaar for review of the manuscript; S. Pyle for scientific graphic illustration; Y. Dai, J. Alvarez, A. Cheng and Y. Zhang for technical assistance; and L. Ong, C. Brondos, J. Woo, J. Okano and J. Sawin for administrative assistance. We thank the Severe Asthma Research Program (SARP) for access to their patient data. S.P.B. was supported by U.S. National Institutes of Health (NIH) grants F30 DK096828, T32 GM007198, R38 HL143581 and K38 HL154202. J.L.S. and B.S.N. were supported by U.S. NIH grant P30GM127211. J.M.S. was supported by KAIST (N11210257) and the National Research Foundation of Korea (2017K1A1A2013124 and 2021R1A2C200757311). I.-K.L was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017R1A2B3006406). R.L.G. is supported by NIH grants U01AI52038, R01AI53185, R01AR076082, R01DK121760 and R37AI052453. L.E.C.A. was supported by an American Heart Association grant 16BGIA27790079 and a VA BLR&D Career Development Award 1IK2BX001313. R.M.E. holds the March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute, a SWCRF Investigator Award, and is supported by the NOMIS Foundation–Science of Health, and by U.S. NIH grants HL147835, HL105278, and CA014195. This research was made possible by funding from HHMI, the Foundation Leducq, the Don and Lorraine Freeberg Foundation, the Larry L. Hillblom foundation, and David C. Copley Foundation. Y.Z. was supported by the NOMIS Foundation, the Crohn’s and Colitis Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and the National Institute of Health (R01-AI107027, R01-AI1511123, R21-AI154919, S10-OD023689 and NCI CCSG P30-014195). A.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund, is an investigator at the Chan Zuckerberg Biohub, and is a recipient of the Cancer Research Institute (CRI) Lloyd J. Old STAR grant. The Marson laboratory has received funds from the Innovative Genomics Institute (IGI), the Simons Foundation, and the Parker Institute for Cancer Immunotherapy (PICI). The Marson laboratory has received gifts from the Byers family, B. Bakar, K. Jordan, and E. Radutzky. This work was also supported by National Cancer Institute funded Salk Institute Cancer Center core facilities (CA014195) and the James B. Pendleton Charitable Trust as well as the UCSF Parnassus Flow Cytometry Core funded in part by the Diabetes Research Center grant from the National Institutes of Health (P30 DK063720). Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number P42ES010337 and by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Numbers R01DK057978 and R01DK120480 (all to R.M.E.). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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