What is the clinical evidence from this study?

Study design: Other. Population: Obesity and insulin resistance. Intervention: Adipocyte-specific SIRT1 knockout vs. Wild-type (WT) mice. Primary outcome: Glucose tolerance, insulin sensitivity, and inflammation.

March 5, 2015Molecular Metabolism166 citationsOpen Access

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

RMRafael MayoralMerck & Co., Inc., Rahway, NJ, USA (United States)OOOlivia OsbornUniversity of California, San Diego JMJoanne McNelisUniversity of California, San Diego

Key Result

Adipocyte-specific SIRT1 knockout in mice fed a chronic high-fat diet improved glucose tolerance, insulin sensitivity, and reduced inflammation compared to wild-type controls.

Structured PICO

Population

Sirt1 adipocyte-specific knockout mice and wild-type controls fed a high-fat diet for 5 or 15 weeks.

Intervention

High-fat diet (HFD) for 5 weeks (short-term) or 15 weeks (chronic-term)

Comparator

Sirt1 (flx/flx) aP2Cre (-) (WT) mice on the same diets

Outcome

Metabolic dysfunction, glucose tolerance, insulin sensitivity, and inflammationsurrogate

SIRT1 downregulation in adipose tissue improves insulin sensitivity and reduces inflammation during chronic high-fat diet via PPARγ activation.

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.

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