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

Abstract

ObjectiveAdipose 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).MethodsTo 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/flxaP2Cre+ (ATKO) and Sirt1flx/flxaP2Cre- (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.ResultsOn 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.ConclusionTogether, 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.

NAMPT-Mediated NAD + Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

“…Given previous findings suggesting that hyperacetylation of PPARγ at lysines 293 also leads to an increase in Ser273 phosphorylation (Qiang et al, 2012), it is likely that NAMPT-mediated NAD + biosynthesis and SIRT1 together regulate PPARγ Ser273 phosphorylation by modulating CDK5 phosphorylation and PPARγ acetylation. Consistent with this idea, adipocyte-specific Sirt1 knockout mice have increased acetylation and Ser273 phosphorylation of PPARγ in adipose tissue (Mayoral et al, 2015). In addition, several independent groups have reported that adipocyte-specific Sirt1 knockdown/knockout is causatively related to adipose tissue dysfunction and systemic metabolic complications (Chalkiadaki and Guarente, 2012; Gillum et al, 2011; Mayoral et al, 2015).…”

“…Consistent with this idea, adipocyte-specific Sirt1 knockout mice have increased acetylation and Ser273 phosphorylation of PPARγ in adipose tissue (Mayoral et al, 2015). In addition, several independent groups have reported that adipocyte-specific Sirt1 knockdown/knockout is causatively related to adipose tissue dysfunction and systemic metabolic complications (Chalkiadaki and Guarente, 2012; Gillum et al, 2011; Mayoral et al, 2015). Nonetheless, we cannot exclude the possibility that other sirtuins and NAD + -consuming enzymes, such as poly(ADP-ribose) polymerases (Belenky et al, 2007; Canto et al, 2015; Imai and Yoshino, 2013), also mediate effects induced by the defects in NAPMPT-mediated NAD + biosynthesis in ANKO mice.…”

“…In addition, VAT from ANKO mice displayed increased lysine acetylation of PPARγ (Fig. 3C), indicating that hyperacetylation of PPARγ could also be involved in the observed increase in PPARγ phosphorylation(Mayoral et al, 2015; Qiang et al, 2012). We next evaluated VAT expression of obesity-linked target genes that are known to be the most sensitive to PPARγ phosphorylation (Ser273) (Choi et al, 2010).…”

Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

“…In 3T3-L1 adipocytes genetic or pharmacological Sirt1 inhibition increased the expression of inflammatory cytokines upon tumor necrosis factor 1 alpha stimulation, whereas Sirt1 activation had the opposite effect [133]. In agreement, genetic or antisense oligonucleotide mediated Sirt1 deficiency in rodents leads to elevated inflammation characterized by increased macrophage infiltration and mRNA expression of inflammatory cytokines in WAT under normal [107] and HFD conditions [101], [115], [117], [134]. However, during long-term HFD adipocyte specific Sirt1 deletion reduced WAT inflammation in contrast to the other findings [115].…”

Caffeine with Links to NAFLD and Accelerated Brain Aging

“…Sirt 1 is involved in food intake regulation [47,48], gluconeogenesis in the liver [49], fat mobilization from white adipose tissue, cholesterol metabolism, and energy metabolism [50,51]. In adipose tissue, Sirt 1 activates fat mobilization by inhibiting peroxisome proliferator-activated receptor gamma (PPAR-gamma) [52,53] and in the pancreas Sirt 1 repression decreases insulin secretion with effects on beta cell uncoupling protein 2 levels [54]. Sirt 1 influences mitochondrial biogenesis in the adipose tissue and liver with relevance to NAFLD [10].…”