The E3 Ubiquitin Ligase Pellino3 Protects against Obesity-Induced Inflammation and Insulin Resistance

• Published in: Immunity (Cambridge, Mass.) Vol. 41; no. 6; pp. 973 - 987
• Main Authors: Yang, Shuo, Wang, Bingwei, Humphries, Fiachra, Hogan, Andrew E., O’Shea, Donal, Moynagh, Paul N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.12.2014; Elsevier Limited
• Subjects: Abdominal Fat - metabolism; Abdominal Fat - pathology; Adult; Aged; Animals; Cell Differentiation - genetics; Cells, Cultured; Diabetes; Diet, High-Fat; Female; Gene expression; Glucose; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inflammation - etiology; Inflammation - immunology; Insulin; Insulin resistance; Insulin Resistance - genetics; Interleukin-1beta - metabolism; Kinases; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Obesity; Obesity - complications; Obesity - immunology; Phosphorylation; Proteins; Rodents; Software; TNF Receptor-Associated Factor 6 - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination - genetics; Young Adult
• DOI: 10.1016/j.immuni.2014.11.013
• ISSN: 1074-7613; 1097-4180

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. •Loss of Pellino3 exacerbates diet-induced inflammation and insulin resistance•Pellino3 inhibits TRAF6-mediated ubiquitination and stabilization of HIF-1α•Pellino3 regulates HIF-1α-induced IL-1β expression to prevent insulin resistance IL-1β is one of the key proinflammatory cytokines that contributes to diet-induced insulin resistance and diabetes, but the mechanisms that regulate obesity-driven inflammation are ill defined. Moynagh and colleagues show that the E3 ubiquitin ligase Pellino3 negatively regulates IL-1β expression to control diet-induced insulin resistance.