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

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

Mol Metab. 2015 Mar 5;4(5):378-91. doi: 10.1016/j.molmet.2015.02.007. eCollection 2015 May.

Authors

Rafael Mayoral¹, Olivia Osborn², Joanne McNelis², Andrew M Johnson², Da Young Oh², Cristina Llorente Izquierdo³, Heekyung Chung², Pingping Li², Paqui G Traves⁴, Gautam Bandyopadhyay², Ariane R Pessentheiner⁵, Jachelle M Ofrecio², Joshua R Cook⁶, Li Qiang⁶, Domenico Accili⁶, Jerrold M Olefsky²

Affiliations

¹ Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA ; Networked Biomedical Research Center, Hepatic and Digestive Diseases (CIBERehd), Monforte de Lemos 3-5, ISC-III, 28029 Madrid, Spain.
² Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
³ Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
⁴ Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.
⁵ Institute of Biochemistry, Humboldtstrasse 46/3, 8010 Graz, Austria.
⁶ Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.

Abstract

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. Sirt1 (flx/flx) aP2Cre (+) (ATKO) and Sirt1 (flx/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.

Keywords: Glucose homeostasis; Insulin resistance; Obesity; PPAR03B3; Phosphorylation; SIRT1.

Abstract

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