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

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

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.

Originalspracheenglisch
Seiten (von - bis)1948-1961
Seitenumfang14
FachzeitschriftCell Reports
Jahrgang23
Ausgabenummer7
DOIs
PublikationsstatusVeröffentlicht - 15 Mai 2018

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Type 3 Cyclic Nucleotide Phosphodiesterases
Insulin Resistance
Insulin
Knockout Mice
Fatty Acids
Glucose
White Adipose Tissue
Lipogenesis
Obesity
Phosphorylation
Sterol Esterase
Lipolysis
Hydrolases
Cyclic AMP-Dependent Protein Kinases
Adipocytes
Tissue
Medical problems
Aging of materials

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    ASJC Scopus subject areas

    • !!Biochemistry, Genetics and Molecular Biology(all)

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    Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance. / Xia, Wenmin; Pessentheiner, Ariane R.; Hofer, Dina C.; Amor, Melina; Schreiber, Renate; Schoiswohl, Gabriele; Eichmann, Thomas O.; Walenta, Evelyn; Itariu, Bianca; Prager, Gerhard; Hackl, Hubert; Stulnig, Thomas; Kratky, Dagmar; Rülicke, Thomas; Bogner-Strauss, Juliane G.

    in: Cell Reports, Jahrgang 23, Nr. 7, 15.05.2018, S. 1948-1961.

    Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

    Xia, W, Pessentheiner, AR, Hofer, DC, Amor, M, Schreiber, R, Schoiswohl, G, Eichmann, TO, Walenta, E, Itariu, B, Prager, G, Hackl, H, Stulnig, T, Kratky, D, Rülicke, T & Bogner-Strauss, JG 2018, 'Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance' Cell Reports, Jg. 23, Nr. 7, S. 1948-1961. https://doi.org/10.1016/j.celrep.2018.04.055
    Xia, Wenmin ; Pessentheiner, Ariane R. ; Hofer, Dina C. ; Amor, Melina ; Schreiber, Renate ; Schoiswohl, Gabriele ; Eichmann, Thomas O. ; Walenta, Evelyn ; Itariu, Bianca ; Prager, Gerhard ; Hackl, Hubert ; Stulnig, Thomas ; Kratky, Dagmar ; Rülicke, Thomas ; Bogner-Strauss, Juliane G. / Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance. in: Cell Reports. 2018 ; Jahrgang 23, Nr. 7. S. 1948-1961.
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    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.",
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    T1 - Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance

    AU - Xia, Wenmin

    AU - Pessentheiner, Ariane R.

    AU - Hofer, Dina C.

    AU - Amor, Melina

    AU - Schreiber, Renate

    AU - Schoiswohl, Gabriele

    AU - Eichmann, Thomas O.

    AU - Walenta, Evelyn

    AU - Itariu, Bianca

    AU - Prager, Gerhard

    AU - Hackl, Hubert

    AU - Stulnig, Thomas

    AU - Kratky, Dagmar

    AU - Rülicke, Thomas

    AU - Bogner-Strauss, Juliane G.

    PY - 2018/5/15

    Y1 - 2018/5/15

    N2 - 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.

    AB - 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.

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    KW - fatty acids

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    KW - lipolysis

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    KW - type 2 diabetes

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