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

Cell Reports
Wenmin XiaJuliane G Bogner-Strauss

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.

Citations

Mar 14, 2020·The Biochemical Journal·Alexander Yang, Emilio P Mottillo
Jun 5, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Jia ZhaoJiao Guo
Jul 9, 2020·Frontiers in Endocrinology·Ying LiBhagirath Chaurasia
Dec 2, 2020·Nutrition, Metabolism, and Cardiovascular Diseases : NMCD·Guotao HuangYongchun Zhang
Dec 9, 2020·Matrix Biology : Journal of the International Society for Matrix Biology·Irmgard Tegeder, Donat Kögel
Nov 21, 2021·Nature Metabolism·Gernot F GrabnerRudolf Zechner

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Datasets Mentioned

BETA
GSE16415
GSE98321

Methods Mentioned

BETA
PCR
co-immunoprecipitation

Software Mentioned

SPSS Statistics
GraphPad Prism

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