Protective role of SIRT1 activation against insulin resistance and defective thermogenesis associated to inflammation in brown adipose tissue

Resumen

Nowadays, the global rate of obesity is increasing rapidly and has become the most frequent metabolic disease worldwide. This condition is considered by the Word Health Organization as a noncommunicable disease together with type 2 diabetes mellitus (T2DM) and several cancers. Numerous studies have clearly established that adipose tissue plays a relevant role in the chronic low grade inflammatory state associated to obesity since over-nutrition alters the functionality of adipocytes and induces the secretion of pro-inflammatory cytokines and reactive lipid species that negatively impact on whole body metabolism. Brown adipose tissue (BAT) plays a major role in the regulation of metabolic homeostasis by its ability to dissipate energy as heat. This fat depot is currently considered a therapeutic target against obesity due to its capacity of metabolize large amounts of lipids and glucose. In this Thesis we have analyzed insulin and β-adrenergic responses in BAT in two mouse models of inflammation: db/db mice as a genetic model of chronic inflammation linked to obesity and T2DM and in lean mice injected a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. Since sirtuin1 (SIRT1) has been related to the protection from metabolic damage associated to obesity, we also studied the potential beneficial effect of targeting SIRT1 under pro-inflammatory conditions Our results have provided evidences of the susceptibility of BAT from db/db mice to metabolic inflammation since activation of a pro-inflammatory signature of signaling cascades together with elevation of pro-inflammatory-related gene expression was found in this fat depot compared with the lean controls (db+). Furthermore, we demonstrated insulin resistance in BAT from db/db mice that might be due, at least in part, to alterations in the pattern of insulin receptor (IR) isoforms, revealing metabolic immaturity of the tissue. Moreover, mice with moderate overexpression of SIRT1 (SIRT1Tg+) were protected against the drop in insulin-mediated IR and AKT (protein kinase B) phosphorylation detected in LPS-injected wild-type (WT) mice. In line with these findings, differentiated brown adipocytes overexpressing SIRT1 (BA-SIRT1Tg+) upon stimulation with a pro-inflammatory medium showed similar protection as well as preserved insulin-mediated glucose uptake. Regarding the impact of inflammation in adrenergic responses in BAT, db/db mice treated with resveratrol, a SIRT1 activator, showed higher uncoupling protein 1 (UCP-1) levels in this tissue. Moreover, SIRT1Tg+ mice were protected against the deleterious effect of LPS in thermogenic-related parameters. Importantly, mice overexpressing SIRT1 attenuated the drop of T3 levels both in circulation and BAT after the exposure to LPS and cold. Cellular experiments in brown adipocytes (BA) from the two genotypes revealed that differentiation in the presence of high concentrations of T3, rosiglitazone and insulin increased SIRT1 activity favoring lipid accumulation in fat droplets, mitochondrial fission as well as potentiating the lipolytic response. In addition, BA from both genotypes maintained the induction of UCP-1 in response to norepinephrine (NE) under pro-inflammatory conditions, being this protection even higher in cells overexpressing SIRT1. Altogether, our results point to SIRT1 activation in BAT as a potential target against the low grade chronic inflammatory stage linked to obesity.