Calorie Restriction and SIRT1 Overexpression Induce Different Gene Expression Profiles in White Adipose Tissue in Association with Metabolic Improvement

Abstract

Introduction Calorie restriction (CR) exerts multiple effects on health, including the amelioration of systemic insulin resistance. Although the precise mechanisms by which CR improves glucose homeostasis remain poorly defined, SIRT1 has been suggested to act as a central mediator of the cellular responses to CR. Here, we aim at identifying the mechanisms by which CR and SIRT1 modulate white adipose tissue (WAT) function, a key tissue in the control of glucose homeostasis. Material and Methods A gene expression profiling study using DNA microarrays is conducted in WAT of control and SIRT1 transgenic mice fed ad libitum (AL) and mice subjected to 40% CR. Results Gene expression profiling reveals a relatively low degree of overlap between the transcriptional programs regulated by SIRT1 and CR. Gene networks related to extracellular matrix appear commonly downregulated by SIRT1/CR, whereas mitochondrial biogenesis is enhanced exclusively by CR. Moreover, WAT inflammation is reduced by CR and SIRT1, although their anti‐inflammatory effects appeared to be achieved by regulating different gene networks related to the immune system. Concluding Remarks In WAT, SIRT1 does not mediate most of the effects of CR on gene expression. Still, gene networks differentially regulated by SIRT1 and CR converge to reduce WAT inflammation.

Sirtuins: Key players in obesity-associated adipose tissue remodeling

“…Interestingly, loss of SIRT1 leads to compensatory SIRT6 deacetylase activity on H3K9, demonstrating that SIRT1 and SIRT6 act on NF-κB through different mechanisms ( 40 ). Moderate SIRT1 overexpression ameliorates the effects of LPS on brown AT inflammation by the reduced acetylation of NF-κB, STAT3, and p38 MAPK ( 29 , 39 , 123 ). It is generally believed that the cluster of differentiation 40 (CD40)/CD40 ligand (CD40L) pathway is an integral part of the onset and maintenance of inflammatory reactions in obesity.…”

“…Pathway analysis revealed SIRT1-dependent key transcription factors, including PPARα, sterol regulatory element-binding transcription factor 1/2 (SREBF1/2), and PGC-1α ( 51 ). Moreover, SIRT1 overexpression downregulates the genes related to ECM remodeling (i.e., collagens, metalloproteases, and integrins) accompanied by a lower degree of inflammation-related fibrosis in visceral AT ( 39 ).…”

Ketogenic Diet Increases Serum and White Adipose Tissue SIRT1 Expression in Mice

“…Accordingly, SIRT1-null mice showed reduction in uncoupling protein 1 (UCP1) in white SAT, without showing differences in BAT, supporting the essential activity of SIRT1 for WAT browning [66]. Intriguingly, the brown adipocytes in SIRT1-transgenic mice accumulate less lipids [38], and no changes in BAT weight, apart from larger mitochondrial size, were observed in KD-fed mice [71]. The lack of SIRT1 changes in BAT suggest that, under ketogenic stimulation, SIRT1 exerts its activity predominantly in white fat.…”

“…In line with this assumption, we recently found that SIRT1 shows a continuous, inverse pattern of expression which follows the whole spectrum of adiposity, from anorexia nervosa to obesity [20], and that blood SIRT1 assumes a trend consistent with that of circulating adipokines such as adiponectin and leptin [36]. SIRT1 is a nutrient-sensing (NAD)-dependent deacetylase associated with the response to calorie restriction (CR) and weight loss, in these conditions increased SIRT1 levels in rodents and humans have been observed [13,[37][38][39]. Interestingly, SIRT1 reduces VAT deposition in animal models of obesity, and fat cell hypertrophy occurs when SIRT1 mRNA expression is low [40].…”

Moderate calorie restriction ameliorates reproduction via attenuating oxidative stress-induced apoptosis through SIRT1 signaling in obese mice

“…A recent study showed that the activation of SIRT1 can alleviate oxidative stress, DNA damage, and protect the testes from lipotoxicity (3). It has been also reported that SIRT1 acts as a central mediator of the cellular responses to CR (33). CR protected the ageing kidney include increasing SIRT1 levels, AMP-activated protein kinase and autophagy, reducing mammalian target of rapamycin, inflammation and oxidative stress (34).…”