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

Rafael Mayoral, Olivia Osborn, Joanne McNelis, Andrew M. Johnson, Dayoung 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

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)378-391
Number of pages14
JournalMolecular Metabolism
Volume4
Issue number5
DOIs
StatePublished - Jan 1 2015

Fingerprint

Sirtuin 1
Adipogenesis
PPAR gamma
Adipocytes
Insulin Resistance
Obesity
Knockout Mice
Adipose Tissue
Acetylation
Inflammation
Histone Deacetylase 1
Phosphorylation
Insulin
Gene Expression
Glucose
Glucose Intolerance
High Fat Diet
Transcription Factors
Down-Regulation

Keywords

  • Glucose homeostasis
  • Insulin resistance
  • Obesity
  • Phosphorylation
  • PPAR03B3
  • SIRT1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. / Mayoral, Rafael; Osborn, Olivia; McNelis, Joanne; Johnson, Andrew M.; Oh, Dayoung; Izquierdo, Cristina Llorente; Chung, Heekyung; Li, Pingping; Traves, Paqui G.; Bandyopadhyay, Gautam; Pessentheiner, Ariane R.; Ofrecio, Jachelle M.; Cook, Joshua R.; Qiang, Li; Accili, Domenico; Olefsky, Jerrold M.

In: Molecular Metabolism, Vol. 4, No. 5, 01.01.2015, p. 378-391.

Research output: Contribution to journalArticle

Mayoral, R, Osborn, O, McNelis, J, Johnson, AM, Oh, D, Izquierdo, CL, Chung, H, Li, P, Traves, PG, Bandyopadhyay, G, Pessentheiner, AR, Ofrecio, JM, Cook, JR, Qiang, L, Accili, D & Olefsky, JM 2015, 'Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity', Molecular Metabolism, vol. 4, no. 5, pp. 378-391. https://doi.org/10.1016/j.molmet.2015.02.007
Mayoral, Rafael ; Osborn, Olivia ; McNelis, Joanne ; Johnson, Andrew M. ; Oh, Dayoung ; Izquierdo, Cristina Llorente ; Chung, Heekyung ; Li, Pingping ; Traves, Paqui G. ; Bandyopadhyay, Gautam ; Pessentheiner, Ariane R. ; Ofrecio, Jachelle M. ; Cook, Joshua R. ; Qiang, Li ; Accili, Domenico ; Olefsky, Jerrold M. / Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. In: Molecular Metabolism. 2015 ; Vol. 4, No. 5. pp. 378-391.
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AU - Osborn, Olivia

AU - McNelis, Joanne

AU - Johnson, Andrew M.

AU - Oh, Dayoung

AU - Izquierdo, Cristina Llorente

AU - Chung, Heekyung

AU - Li, Pingping

AU - Traves, Paqui G.

AU - Bandyopadhyay, Gautam

AU - Pessentheiner, Ariane R.

AU - Ofrecio, Jachelle M.

AU - Cook, Joshua R.

AU - Qiang, Li

AU - Accili, Domenico

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N2 - 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.

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