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; Alexander Marson

doi:10.1038/s41586-022-04536-0

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, Alexander Marson

Research output: Contribution to journal › Article › peer-review

175 Scopus citations

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 system^1–7, 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 (T_H2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent T_H17 inflammation. We also observed divergent responses to biologic therapies targeting T_H2 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 T_H2 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 T_H response towards a T_H2-predominant state and prevent aberrant non-T_H2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of T_H17 pathology and unlocked therapeutic responsiveness to targeted anti-T_H2 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.

Original language	English
Pages (from-to)	337-342
Number of pages	6
Journal	Nature
Volume	604
Issue number	7905
DOIs	https://doi.org/10.1038/s41586-022-04536-0
State	Published - Apr 14 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

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.

Funders	Funder number
Don and Lorraine Freeberg Foundation
March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute
IDEX HEALTH and SCIENCE	HL147835, HL105278, CA014195
VA BLR&D	1IK2BX001313
National Institutes of Health (NIH)	K38 HL154202, P30 DK063720, R01-AI107027, T32 GM007198, P30GM127211, S10-OD023689, R21-AI154919, F30 DK096828, R01-AI1511123
Howard Hughes Medical Institute
National Heart, Lung, and Blood Institute (NHLBI)	R38HL143581
National Childhood Cancer Registry – National Cancer Institute	CCSG P30-014195
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK120480, R01DK057978
National Institutes of Health/National Institute of Environmental Health Sciences	P42ES010337
Burroughs Wellcome Fund
Children's Cancer Research Institute, Vienna
Simons Foundation
American the American Heart Association	16BGIA27790079
Larry L. Hillblom Foundation
Genentech Incorporated
Leona M. and Harry B. Helmsley Charitable Trust
University of California San Francisco
James B. Pendleton Charitable Trust
Crohn's and Colitis Foundation of America
David C. Copley Foundation
Innovative Genomics Institute
Parker Institute for Cancer Immunotherapy
Fondation Leducq
Ministry of Science, ICT and Future Planning	U01AI52038, R01DK121760, NRF-2017R1A2B3006406, R37AI052453, R01AI53185, R01AR076082
National Research Foundation of Korea	2021R1A2C200757311, 2017K1A1A2013124
Korea Advanced Institute of Science and Technology	N11210257
NOMIS Stiftung

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

General

Access to Document

10.1038/s41586-022-04536-0

Cite this

Bapat, S. P., Whitty, C., Mowery, C. T., Liang, Y., Yoo, A., Jiang, Z., Peters, M. C., Zhang, L. J., Vogel, I., Zhou, C., Nguyen, V. Q., Li, Z., Chang, C., Zhu, W. S., Hastie, A. T., He, H., Ren, X., Qiu, W., Gayer, S. G., ... Marson, A. (2022). Obesity alters pathology and treatment response in inflammatory disease. Nature, 604(7905), 337-342. https://doi.org/10.1038/s41586-022-04536-0

@article{124c51e994384a4bbb13573f330b2ae6,

title = "Obesity alters pathology and treatment response in inflammatory disease",

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.",

author = "Bapat, \{Sagar P.\} and Caroline Whitty and Mowery, \{Cody T.\} and Yuqiong Liang and Arum Yoo and Zewen Jiang and Peters, \{Michael C.\} and Zhang, \{Ling juan\} and Ian Vogel and Carmen Zhou and Nguyen, \{Vinh Q.\} and Zhongmei Li and Christina Chang and Zhu, \{Wandi S.\} and Hastie, \{Annette T.\} and Helen He and Xin Ren and Wenli Qiu and Gayer, \{Sarah G.\} and Chang Liu and Choi, \{Eun Jung\} and Marlys Fassett and Cohen, \{Jarish N.\} and Sturgill, \{Jamie L.\} and \{Crotty Alexander\}, \{Laura E.\} and Suh, \{Jae Myoung\} and Christopher Liddle and Atkins, \{Annette R.\} and Yu, \{Ruth T.\} and Michael Downes and Sihao Liu and Nikolajczyk, \{Barbara S.\} and Lee, \{In Kyu\} and Emma Guttman-Yassky and Ansel, \{K. Mark\} and Woodruff, \{Prescott G.\} and Fahy, \{John V.\} and Dean Sheppard and Gallo, \{Richard L.\} and Ye, \{Chun Jimmie\} and Evans, \{Ronald M.\} and Ye Zheng and Alexander Marson",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = apr,

day = "14",

doi = "10.1038/s41586-022-04536-0",

language = "English",

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Bapat, SP, Whitty, C, Mowery, CT, Liang, Y, Yoo, A, Jiang, Z, Peters, MC, Zhang, LJ, Vogel, I, Zhou, C, Nguyen, VQ, Li, Z, Chang, C, Zhu, WS, Hastie, AT, He, H, Ren, X, Qiu, W, Gayer, SG, Liu, C, Choi, EJ, Fassett, M, Cohen, JN, Sturgill, JL, Crotty Alexander, LE, Suh, JM, Liddle, C, Atkins, AR, Yu, RT, Downes, M, Liu, S, Nikolajczyk, BS, Lee, IK, Guttman-Yassky, E, Ansel, KM, Woodruff, PG, Fahy, JV, Sheppard, D, Gallo, RL, Ye, CJ, Evans, RM, Zheng, Y & Marson, A 2022, 'Obesity alters pathology and treatment response in inflammatory disease', Nature, vol. 604, no. 7905, pp. 337-342. https://doi.org/10.1038/s41586-022-04536-0

TY - JOUR

T1 - Obesity alters pathology and treatment response in inflammatory disease

AU - Bapat, Sagar P.

AU - Whitty, Caroline

AU - Mowery, Cody T.

AU - Liang, Yuqiong

AU - Yoo, Arum

AU - Jiang, Zewen

AU - Peters, Michael C.

AU - Zhang, Ling juan

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AU - Nguyen, Vinh Q.

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AU - Sturgill, Jamie L.

AU - Crotty Alexander, Laura E.

AU - Suh, Jae Myoung

AU - Liddle, Christopher

AU - Atkins, Annette R.

AU - Yu, Ruth T.

AU - Downes, Michael

AU - Liu, Sihao

AU - Nikolajczyk, Barbara S.

AU - Lee, In Kyu

AU - Guttman-Yassky, Emma

AU - Ansel, K. Mark

AU - Woodruff, Prescott G.

AU - Fahy, John V.

AU - Sheppard, Dean

AU - Gallo, Richard L.

AU - Ye, Chun Jimmie

AU - Evans, Ronald M.

AU - Zheng, Ye

AU - Marson, Alexander

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N2 - 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.

AB - 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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Obesity alters pathology and treatment response in inflammatory disease

Abstract

Bibliographical note

Funding

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Obesity alters pathology and treatment response in inflammatory disease

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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