The E3 ubiquitin ligase Pellino3 protects against obesity-induced inflammation and insulin resistance

Shuo Yang, Bingwei Wang, Fiachra Humphries, Andrew E Hogan, Donal O'Shea, Paul N Moynagh

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)973-87
Number of pages15
JournalImmunity
Volume41
Issue number6
DOIs
Publication statusPublished - 18 Dec 2014

Keywords

  • Abdominal Fat
  • Adult
  • Aged
  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Diet, High-Fat
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inflammation
  • Insulin Resistance
  • Interleukin-1beta
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Obesity
  • TNF Receptor-Associated Factor 6
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Young Adult

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