Obesity alters pathology and treatment response in inflammatory disease

Sagar P. Bapat (), Caroline Whitty, Cody T. Mowery, Yuqiong Liang, Arum Yoo, Zewen Jiang, Michael C. Peters, Ling-juan Zhang, Ian Vogel, Carmen Zhou, Vinh Q. Nguyen, Zhongmei Li, Christina Chang, Wandi S. Zhu, Annette T. Hastie, Helen He, Xin Ren, Wenli Qiu, Sarah G. Gayer, Chang Liu, Eun Jung Choi, Marlys Fassett, Jarish N. Cohen, Jamie L. Sturgill, Laura E. Crotty Alexander, Jae Myoung Suh, Christopher Liddle, Annette R. Atkins, Ruth T. Yu, Michael Downes, Sihao Liu, Barbara S. Nikolajczyk, In-Kyu Lee, Emma Guttman-Yassky, K. Mark Ansel, Prescott G. Woodruff, John V. Fahy, Dean Sheppard, Richard L. Gallo, Chun Jimmie Ye, Ronald M. Evans (), Ye Zheng () and Alexander Marson ()
Additional contact information
Sagar P. Bapat: The Salk Institute for Biological Studies
Caroline Whitty: University of California, San Francisco
Cody T. Mowery: University of California, San Francisco
Yuqiong Liang: The Salk Institute for Biological Studies
Arum Yoo: University of California, San Francisco
Zewen Jiang: University of California, San Francisco
Michael C. Peters: University of California, San Francisco
Ling-juan Zhang: Xiamen University
Ian Vogel: University of California, San Francisco
Carmen Zhou: The Salk Institute for Biological Studies
Vinh Q. Nguyen: University of California, San Francisco
Zhongmei Li: University of California, San Francisco
Christina Chang: The Salk Institute for Biological Studies
Wandi S. Zhu: University of California, San Francisco
Annette T. Hastie: Wake Forest University
Helen He: Icahn School of Medicine at Mount Sinai
Xin Ren: University of California, San Francisco
Wenli Qiu: University of California, San Francisco
Sarah G. Gayer: University of California, San Francisco
Chang Liu: University of California, San Francisco
Eun Jung Choi: Kyungpook National University, Kyungpook National University Hospital
Marlys Fassett: University of California, San Francisco
Jarish N. Cohen: University of California, San Francisco
Jamie L. Sturgill: University of Kentucky
Laura E. Crotty Alexander: Veterans Affairs San Diego Healthcare System
Jae Myoung Suh: KAIST
Christopher Liddle: Westmead Hospital, University of Sydney
Annette R. Atkins: The Salk Institute for Biological Studies
Ruth T. Yu: The Salk Institute for Biological Studies
Michael Downes: The Salk Institute for Biological Studies
Sihao Liu: The Salk Institute for Biological Studies
Barbara S. Nikolajczyk: University of Kentucky
In-Kyu Lee: Kyungpook National University, Kyungpook National University Hospital
Emma Guttman-Yassky: Icahn School of Medicine at Mount Sinai
K. Mark Ansel: University of California, San Francisco
Prescott G. Woodruff: University of California
John V. Fahy: University of California
Dean Sheppard: University of California
Richard L. Gallo: Xiamen University
Chun Jimmie Ye: University of California, San Francisco
Ronald M. Evans: The Salk Institute for Biological Studies
Ye Zheng: The Salk Institute for Biological Studies
Alexander Marson: University of California, San Francisco

Nature, 2022, vol. 604, issue 7905, 337-342

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04536-0

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