Adipose sirtuin 6 drives macrophage polarization toward M2 through IL-4 production and maintains systemic insulin sensitivity in mice and humans

Abstract

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.

Regulation of adipose tissue inflammation and systemic metabolism in murine obesity by polymer implants loaded with lentiviral vectors encoding human interleukin‐4

“…We chose vector dosing based on prior studies in similar models by our group (Park, Decker, Margul et al, 2018; Park, Decker, Smith et al, 2018) but different dosing regimens, including the study of intermediate time‐points between 2 and 10 weeks, and repeated implant dosing, are opportunities for optimization. We studied viral vectors encoding hIL‐4, given well‐established effects of IL‐4 in inducing an “M2” macrophage phenotype associated with decreased obesity‐associated inflammation and insulin resistance (Balducci et al, 2010; Lumeng et al, 2007; Mills, 2012; Ricardo‐Gonzalez et al, 2010; Song et al, 2019), but vectors encoding other cytokines implicated in metabolic health such as IL‐10 (Cintra et al, 2008), or combinations of cytokines, may yield higher efficacy. Prior data demonstrate cross‐species reactivity of human IL‐4 on leukocyte functions (Baumhofer, Beinhauer, & Wang, 1998; Fukushi, Ono, Morikawa, Iwamoto, & Kuwano, 2000; Luzina et al, 2011; Volpert et al, 1998), but the study of murine cytokines may optimize in vivo effects in this murine model.…”

“…Our goal in this study was to extend these results into a murine model of obesity and test the utility of PLG implants engineered to deliver lentiviral vectors expressing the human cytokine interleukin‐4 (hIL‐4) in modulating local adipose tissue inflammation and systemic metabolism. We elected to study IL‐4 given substantial prior published data demonstrating the role of this cytokine in inducing an anti‐inflammatory M2 macrophage phenotype associated with improved insulin resistance (Balducci et al, 2010; Lumeng, Bodzin, & Saltiel, 2007; Mills, 2012; Ricardo‐Gonzalez et al, 2010; Song et al, 2019). We hypothesized that the transplantation of hIL‐4 implants into adipose tissue of mice would attenuate tissue inflammation and systemic insulin resistance.…”

“…We elected to study IL-4 given substantial prior published data demonstrating the role of this cytokine in inducing an antiinflammatory M2 macrophage phenotype associated with improved insulin resistance (Balducci et al, 2010;Lumeng, Bodzin, & Saltiel, 2007;Mills, 2012;Ricardo-Gonzalez et al, 2010;Song et al, 2019). We hypothesized that the transplantation of hIL-4 implants into adipose tissue of mice would attenuate tissue inflammation and systemic insulin resistance.…”

Loss of Sirt6 in adipocytes impairs the ability of adipose tissue to adapt to intermittent fasting

“…1a ). aS6KO mice ( Sirt6 flox/flox ; Adipoq-Cre ) were generated by crossing Sirt6 flox/flox mice (B6;129- Sirt6 tm1Ygu /J) and Adipoq-Cre mice (B6.FVB-Tg( Adipoq-cre )1Evdr/J ) as previously described 30 . Myeloid- 28 and hepatocyte-specific Sirt6 KO mice 25 were generated by crossing Sirt6 flox/flox mice (B6;129- Sirt6 tm1Ygu /J) with LysM-Cre mice (B6.129P2- lyz2 tm(cre)lfo /) and Albumin-Cre mice (B6.Cg-Tg( alb-Cre )21Mgn/J), respectively.…”

Emerging roles of SIRT6 in human diseases and its modulators

“…SIRT6 plays an essential role in pancreatic β‐cell function. Impairment of glucose‐stimulated insulin secretion (GSIS) is commonly found in SIRT6 KO pancreatic β‐cells and in vivo 177,179–181 . Mechanistic analysis indicates that SIRT6‐stimulated nuclear extrusion of FoxO1 subsequently relieves a molecular blockage on the expression of glucose sensing genes Pdx1, which in turn augments GLUT2 expression and GSIS 177 .…”