Adipose sirtuin 6 drives macrophage polarization toward M2 through IL-4 production and maintains systemic insulin sensitivity in mice and humans
Adipose sirtuin 6 drives macrophage polarization toward M2 through IL-4 production and maintains systemic insulin sensitivity in mice and humans
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DOI：
10.1038/s12276-019-0256-9
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发表时间：
2019-05-21
影响因子：
12.8
通讯作者：
Park, Byung-Hyun
中科院分区：
文献类型：
--
作者：
Song, Mi-Young;Kim, Sang Hoon;Park, Byung-Hyun
脂肪组织炎症是肥胖和肥胖相关的胰岛素抵抗的一个可重复的特征。尽管sirtuin 6(SIRT6)缺乏曾被认为与饮食诱导的肥胖和全身性胰岛素抵抗有关，但SIRT6在正常饮食喂养的小鼠和人类脂肪组织炎症和全身性代谢功能障碍的调节中的脂肪细胞特异性作用仍然不清楚。在这里，我们利用ADIPOQ-Cre介导的脂肪细胞特异性SIRT6基因敲除(AS6KO)小鼠，探讨脂肪细胞SIRT6是否抑制脂肪组织炎症及其机制。饲喂正常饲料的aS6KO小鼠比野生型小鼠增加了更多的体重和脂肪质量，并表现出葡萄糖耐受和全身性胰岛素抵抗。血浆和组织细胞因子的测定以及脂肪基质血管细胞的流式细胞术分析表明，aS6KO小鼠脂肪组织中交替激活的M2巨噬细胞减少。在机制上，SIRT6以细胞自主的方式调节脂肪细胞表达规范的2型细胞因子IL-4，进而影响M2巨噬细胞的极化。与动物实验数据一致，体重指数、空腹血糖和糖化血红蛋白所反映的肥胖程度和胰岛素抵抗程度与人体内脏脂肪组织中SIRT6的表达呈负相关。总之，这些结果表明，脂肪细胞SIRT6调节体重增加和胰岛素敏感性不依赖于饮食，SIRT6增加IL-4的产生和脂肪组织巨噬细胞M2极化可能减弱脂肪组织的促炎反应。
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.