Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance

Wenmin Xia, Ariane R. Pessentheiner, Dina C. Hofer, Melina Amor, Renate Schreiber, Gabriele Schoiswohl, Thomas O. Eichmann, Evelyn Walenta, Bianca Itariu, Gerhard Prager, Hubert Hackl, Thomas Stulnig, Dagmar Kratky, Thomas Rülicke, Juliane G. Bogner-Strauss

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that α/β-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone-sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance. Xia et al. show that ABHD15 stabilizes PDE3B and, thereby, impacts the anti-lipolytic action of insulin. Loss of ABHD15 reduces PDE3B protein and leads to unrestrained fatty acid mobilization. Concomitantly, glucose uptake and de novo lipogenesis are reduced in Abhd15-knockout mice, which develop insulin resistance upon aging and dietary challenges.

Original languageEnglish
Pages (from-to)1948-1961
Number of pages14
JournalCell Reports
Volume23
Issue number7
DOIs
Publication statusPublished - 15 May 2018

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Keywords

  • ABHD15
  • adipose tissue
  • fatty acids
  • insulin resistance
  • lipolysis
  • PDE3B
  • type 2 diabetes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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