title: Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborn
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: McNelis
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Johnson
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Cristina Llorente
authors.initials: CL
authors.lastname: Izquierdo
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Traves
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Institute of Biochemistry, Humboldtstrasse 46/3, 8010 Graz, Austria.
authors.forename: Ariane R
authors.initials: AR
authors.lastname: Pessentheiner
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Jachelle M
authors.initials: JM
authors.lastname: Ofrecio
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Cook
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qiang
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
keywords: Glucose homeostasis; Insulin resistance; Obesity; PPAR03B3; Phosphorylation; SIRT1