title: Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.
abstract: 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 obesity. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity and eosinophil and alternatively activated macrophage responses, and were recently identified in murine white adipose tissue (WAT) where they may act to limit the development of obesity. 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 expenditure. 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.
authors.affiliation: 1] Jill Roberts Institute for Research in IBD, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA [2] Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brestoff
authors.affiliation: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Saenz
authors.affiliation: Institute for Diabetes, Obesity and Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Stine
authors.affiliation: 1] Jill Roberts Institute for Research in IBD, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA [2] Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Monticelli
authors.affiliation: Jill Roberts Institute for Research in IBD, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Sonnenberg
authors.affiliation: 1] Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Thome
authors.affiliation: 1] Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA [3] Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California 91766, USA.
authors.forename: Kabirullah
authors.initials: K
authors.lastname: Lutfy
authors.affiliation: Institute for Diabetes, Obesity and Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Seale
authors.affiliation: 1] Jill Roberts Institute for Research in IBD, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, New York 10021, USA [2] Department of Microbiology and Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: David
authors.initials: D
authors.lastname: Artis
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D052436:Adipose Tissue, White / Q000166:cytology* / Q000276:immunology*; D000818:Animals; D004734:Energy Metabolism / Q000276:immunology; D004744:Enkephalin, Methionine / Q000096:biosynthesis / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology; D007473:Ion Channels / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000276:immunology* / Q000473:pathology; D019948:Receptors, Interleukin-4 / Q000276:immunology / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D007378:Interleukins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D019948:Receptors, Interleukin-4; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D004744:Enkephalin, Methionine