Sirtuin 1 overexpression in mice preserves insulin and thermogenic responses in subcutaneous inguinal white adipose tissue under proinflammatory conditions.

Abstract

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.