title: Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes.
abstract: The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4(+) T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.
authors.affiliation: 1] Department of Immunology, Genentech, South San Francisco, California 94080, USA [2].
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.affiliation: 1] Department of Immunology, Genentech, South San Francisco, California 94080, USA [2].
authors.forename: Naruhisa
authors.initials: N
authors.lastname: Ota
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Manzanillo
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Kates
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Zavala-Solorio
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Celine
authors.initials: C
authors.lastname: Eidenschenk
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA.
authors.forename: Jed
authors.initials: J
authors.lastname: Ross
authors.affiliation: Department of Pathology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Lauri
authors.initials: L
authors.lastname: Diehl
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: van Bruggen
authors.affiliation: 1] Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA [2].
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.affiliation: Department of Immunology, Genentech, South San Francisco, California 94080, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ouyang
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D044082:Citrobacter rodentium / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D003920:Diabetes Mellitus / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat; D005260:Female; D006943:Hyperglycemia / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism; D018928:Immunity, Mucosal / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D018123:Receptors, Interleukin / Q000172:deficiency / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007328:Insulin; D053759:Interleukin-23; D007378:Interleukins; D018123:Receptors, Interleukin; D054411:Receptors, Leptin; D000097043:Interleukin-22; C415369:interleukin-22 receptor