Sirtuin 1 overexpression in mice preserves insulin and thermogenic responses in subcutaneous inguinal white adipose...

Activation of brown adipose tissue (BAT) or subcutaneous adipose tissue (iWAT in mice) is a strategy to regulate metabolic homeostasis. The NAD⁺-dependent deacetylase Sirtuin 1 (SIRT1) plays an essential role in energy metabolism and inflammation and is a promising target to tackle obesity and associated comorbidities. We have previously reported the beneficial effect of moderate SIRT1 overexpression in protecting mice against inflammation-induced insulin resistance and impaired BAT thermogenesis. Here, we investigated the effect of an inflammatory environment on insulin sensitivity and thermogenic capacity in iWAT from wild-type (WT) or SIRT1 overexpressing mice (Sirt1^Tg+). We also analyzed in vitro responses to insulin and norepinephrine (NE) in subcutaneous white adipocytes (iWA) from both genotypes under proinflammatory conditions. Results showed higher UCP-1 levels in iWAT from Sirt1^Tg+ mice under thermoneutral conditions compared to WT mice, an effect also found in vitro in differentiated iWA. Cold-induced UCP-1 expression and insulin-induced Akt phosphorylation levels were reduced in iWAT from WT mice upon in vivo bacterial lipopolysaccharide (LPS) injection. However, these reductions were attenuated in iWAT from Sirt1^Tg+ mice. Likewise, in iWA exposed to the conditioned medium from LPS-stimulated Raw 264.7 macrophages (CM-LPS) both insulin signaling and NE-induced UCP-1 expression levels were preserved only in cells overexpressing SIRT1. LPS or CM-LPS increased SIRT1 levels in iWAT or iWA, respectively, an effect more evident upon SIRT1 overexpression. Collectively, our results suggest a SIRT1-dependent anti-inflammatory compensatory response that likely protects iWAT from the deleterious effects of inflammation.