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Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice

Author

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  • Martina Schweiger

    (Institute of Molecular Biosciences, University of Graz)

  • Matthias Romauch

    (Institute of Molecular Biosciences, University of Graz)

  • Renate Schreiber

    (Institute of Molecular Biosciences, University of Graz)

  • Gernot F. Grabner

    (Institute of Molecular Biosciences, University of Graz)

  • Sabrina Hütter

    (Institute of Molecular Biosciences, University of Graz)

  • Petra Kotzbeck

    (Institute of Molecular Biosciences, University of Graz)

  • Pia Benedikt

    (Institute of Molecular Biosciences, University of Graz)

  • Thomas O. Eichmann

    (Institute of Molecular Biosciences, University of Graz)

  • Sohsuke Yamada

    (Institute of Molecular Biosciences, University of Graz)

  • Oskar Knittelfelder

    (Institute of Molecular Biosciences, University of Graz)

  • Clemens Diwoky

    (Institute of Molecular Biosciences, University of Graz)

  • Carina Doler

    (Institute of Organic Chemistry, Graz University of Technology)

  • Nicole Mayer

    (Institute of Organic Chemistry, Graz University of Technology)

  • Werner De Cecco

    (Institute of Chemistry, University of Graz)

  • Rolf Breinbauer

    (Institute of Organic Chemistry, Graz University of Technology)

  • Robert Zimmermann

    (Institute of Molecular Biosciences, University of Graz)

  • Rudolf Zechner

    (Institute of Molecular Biosciences, University of Graz)

Abstract

Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.

Suggested Citation

  • Martina Schweiger & Matthias Romauch & Renate Schreiber & Gernot F. Grabner & Sabrina Hütter & Petra Kotzbeck & Pia Benedikt & Thomas O. Eichmann & Sohsuke Yamada & Oskar Knittelfelder & Clemens Diwok, 2017. "Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14859
    DOI: 10.1038/ncomms14859
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    Cited by:

    1. Johanna M. Kohlmayr & Gernot F. Grabner & Anna Nusser & Anna Höll & Verina Manojlović & Bettina Halwachs & Sarah Masser & Evelyne Jany-Luig & Hanna Engelke & Robert Zimmermann & Ulrich Stelzl, 2024. "Mutational scanning pinpoints distinct binding sites of key ATGL regulators in lipolysis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Yuhui Wang & Hai P. Nguyen & Pengya Xue & Ying Xie & Danielle Yi & Frances Lin & Jennie Dinh & Jose A. Viscarra & Nnejiuwa U. Ibe & Robin E. Duncan & Hei S. Sul, 2024. "ApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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