Adipose tissue
inflammation is a reproducible feature of
obesity and
obesity-linked
insulin resistance. Although
sirtuin 6 (Sirt6) deficiency has previously been implicated in diet-induced
obesity and systemic
insulin resistance, the adipocyte-specific role of Sirt6 in the regulation of adipose tissue
inflammation and systemic metabolic dysfunction in mice fed normal chow and in humans remains elusive. Here, using Adipoq-Cre-mediated adipocyte-specific Sirt6 knockout (aS6KO) mice, we explored whether adipocyte Sirt6 inhibits adipose tissue
inflammation and its underlying mechanism. aS6KO mice fed normal chow gained more
body weight and fat mass than wild-type mice and exhibited
glucose intolerance and systemic
insulin resistance. Measurement of plasma and tissue
cytokines and flow cytometric analysis of adipose stromal vascular cells indicated a decrease in alternatively activated M2 macrophages in the adipose tissue of aS6KO mice. Mechanistically, Sirt6 regulated the expression of the canonical type 2
cytokine IL-4 by adipocytes in a cell autonomous manner, which in turn affects M2 macrophage polarization. Consistent with animal experimental data, the degree of
obesity and
insulin resistance demonstrated by the body mass index, fasting
blood glucose and HbA1c correlated negatively with the expression of Sirt6 in human visceral fat tissues. Collectively, these results suggest that adipocyte Sirt6 regulates
body weight gain and
insulin sensitivity independent of diet, and the increased
IL-4 production by Sirt6 and resultant M2 polarization of adipose tissue macrophages may attenuate proinflammatory responses in adipose tissue.