Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity

Rafael Mayoral; Olivia Osborn; Joanne McNelis; Andrew M. Johnson; Da Young Oh; Cristina Llorente Izquierdo; Heekyung Chung; Pingping Li; Paqui G. Traves; Gautam Bandyopadhyay; Ariane R. Pessentheiner; Jachelle M. Ofrecio; Joshua R. Cook; Li Qiang; Domenico Accili; Jerrold M. Olefsky

doi:10.1016/j.molmet.2015.02.007

Molecular Metabolism (May 2015)

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity

Rafael Mayoral,
Olivia Osborn,
Joanne McNelis,
Andrew M. Johnson,
Da Young Oh,
Cristina Llorente Izquierdo,
Heekyung Chung,
Pingping Li,
Paqui G. Traves,
Gautam Bandyopadhyay,
Ariane R. Pessentheiner,
Jachelle M. Ofrecio,
Joshua R. Cook,
Li Qiang,
Domenico Accili,
Jerrold M. Olefsky

Affiliations

Rafael Mayoral: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Olivia Osborn: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Joanne McNelis: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Andrew M. Johnson: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Da Young Oh: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Cristina Llorente Izquierdo: Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Heekyung Chung: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Pingping Li: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Paqui G. Traves: Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA
Gautam Bandyopadhyay: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Ariane R. Pessentheiner: Institute of Biochemistry, Humboldtstrasse 46/3, 8010 Graz, Austria
Jachelle M. Ofrecio: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA
Joshua R. Cook: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA
Li Qiang: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA
Domenico Accili: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA
Jerrold M. Olefsky: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA

DOI: https://doi.org/10.1016/j.molmet.2015.02.007
Journal volume & issue: Vol. 4, no. 5
pp. 378 – 391

Abstract

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Objective: Adipose tissue is the primary site for lipid deposition that protects the organisms in cases of nutrient excess during obesogenic diets. The histone deacetylase Sirtuin 1 (SIRT1) inhibits adipocyte differentiation by targeting the transcription factor peroxisome proliferator activated-receptor gamma (PPARγ). Methods: To assess the specific role of SIRT1 in adipocytes, we generated Sirt1 adipocyte-specific knockout mice (ATKO) driven by aP2 promoter onto C57BL/6 background. Sirt1flx/flx aP2Cre+ (ATKO) and Sirt1flx/flx aP2Cre- (WT) mice were fed high-fat diet for 5 weeks (short-term) or 15 weeks (chronic-term). Metabolic studies were combined with gene expression analysis and phosphorylation/acetylation patterns in adipose tissue. Results: On standard chow, ATKO mice exhibit low-grade chronic inflammation in adipose tissue, along with glucose intolerance and insulin resistance compared with control fed mice. On short-term HFD, ATKO mice become more glucose intolerant, hyperinsulinemic, insulin resistant and display increased inflammation. During chronic HFD, WT mice developed a metabolic dysfunction, higher than ATKO mice, and thereby, knockout mice are more glucose tolerant, insulin sensitive and less inflamed relative to control mice. SIRT1 attenuates adipogenesis through PPARγ repressive acetylation and, in the ATKO mice adipocyte PPARγ was hyperacetylated. This high acetylation was associated with a decrease in Ser273-PPARγ phosphorylation. Dephosphorylated PPARγ is constitutively active and results in higher expression of genes associated with increased insulin sensitivity. Conclusion: Together, these data establish that SIRT1 downregulation in adipose tissue plays a previously unknown role in long-term inflammation resolution mediated by PPARγ activation. Therefore, in the context of obesity, the development of new therapeutics that activate PPARγ by targeting SIRT1 may provide novel approaches to the treatment of T2DM.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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