title: The E3 ubiquitin ligase Pellino3 protects against obesity-induced inflammation and insulin resistance.
abstract: Diet-induced obesity can induce low-level inflammation and insulin resistance. Interleukin-1β (IL-1β) is one of the key proinflammatory cytokines that contributes to the generation of insulin resistance and diabetes, but the mechanisms that regulate obesity-driven inflammation are ill defined. Here we found reduced expression of the E3 ubiquitin ligase Pellino3 in human abdominal adipose tissue from obese subjects and in adipose tissue of mice fed a high-fat diet and showing signs of insulin resistance. Pellino3-deficient mice demonstrated exacerbated high-fat-diet-induced inflammation, IL-1β expression, and insulin resistance. Mechanistically, Pellino3 negatively regulated TNF receptor associated 6 (TRAF6)-mediated ubiquitination and stabilization of hypoxia-inducible factor 1α (HIF1α), resulting in reduced HIF1α-induced expression of IL-1β. Our studies identify a regulatory mechanism controlling diet-induced insulin resistance by highlighting a critical role for Pellino3 in regulating IL-1β expression with implications for diseases like type 2 diabetes.
authors.affiliation: Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Bingwei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Fiachra
authors.initials: F
authors.lastname: Humphries
authors.affiliation: Education and Research Centre, St Vincent's University Hospital, University College Dublin, Dublin 4, Ireland.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Hogan
authors.affiliation: Education and Research Centre, St Vincent's University Hospital, University College Dublin, Dublin 4, Ireland.
authors.forename: Donal
authors.initials: D
authors.lastname: O'Shea
authors.affiliation: Institute of Immunology, Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland; Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, Northern Ireland, UK. Electronic address: paul.moynagh@nuim.ie.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Moynagh
mesh_terms: D050153:Abdominal Fat / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D007333:Insulin Resistance / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D048029:TNF Receptor-Associated Factor 6; C584081:PELI3 protein, mouse; D044767:Ubiquitin-Protein Ligases