Fabp4-Cre-mediated Sirt6 deletion impairs adipose tissue function and metabolic homeostasis in mice.
Fabp4-Cre-mediated Sirt6 deletion impairs adipose tissue function and metabolic homeostasis in mice.
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DOI：
10.1530/joe-17-0033
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Dong XC
中科院分区：
文献类型：
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作者：
Xiong X;Zhang C;Zhang Y;Fan R;Qian X;Dong XC
SIRT6是sirtuin脱乙酰酶家族的成员之一，参与基因组稳定、代谢稳态和抗炎等多种过程。然而，它在脂肪组织中的功能还不是很清楚。为了检测SIRT6在脂肪组织中的代谢功能，我们使用Cre-lox方法建立了两个SIRT6缺陷的小鼠模型。本研究选择了两个常用的由小鼠FABP4或ADIPOQ基因启动子驱动的Cre品系。与对照野生型小鼠相比，由FABP4-Cre系(Sirt6f/f：FABP4-Cre)产生的SIRT6基因敲除小鼠的体重和脂肪质量均显著增加，并表现出葡萄糖耐量和胰岛素抵抗。在分子水平上，Sirt6f/f：FABP4-Cre基因敲除小鼠在白色和棕色脂肪组织中炎症基因F4/80、肿瘤坏死因子α、IL-6和MCP-1的表达均增加。此外，基因敲除的小鼠在白色脂肪组织中脂联素基因的表达减少，在棕色脂肪组织中的UCP1基因表达减少。相比之下，由ADIPOQ-Cre品系(Sirt6f/f：ADIPOQ-Cre)产生的SIRT6基因敲除小鼠只有轻微的胰岛素抵抗。综上所述，我们的数据表明，除了成熟的脂肪细胞外，在表达FABP4-CRE的细胞中，SIRT6的功能在维持体重和代谢动态平衡方面发挥着关键作用。
SIRT6 is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis and anti-inflammation. However, its function in the adipose tissue is not well understood. To examine the metabolic function of Sirt6 in the adipose tissue, we generated two mouse models that are deficient in Sirt6 using the Cre-lox approach. Two commonly used Cre lines that are driven by either the mouse Fabp4 or Adipoq gene promoter were chosen for this study. The Sirt6-knockout mice generated by the Fabp4-Cre line (Sirt6f/f:Fabp4-Cre) had a significant increase in both body weight and fat mass and exhibited glucose intolerance and insulin resistance as compared with the control wild-type mice. At the molecular levels, the Sirt6f/f:Fabp4-Cre-knockout mice had increased expression of inflammatory genes including F4/80, TNFα, IL-6, and MCP-1 in both white and brown adipose tissues. Moreover, the knockout mice showed decreased expression of the adiponectin gene in the white adipose tissue and UCP1 in the brown adipose tissue, respectively. In contrast, the Sirt6 knockout mice generated by the Adipoq-Cre line (Sirt6f/f:Adipoq-Cre) only had modest insulin resistance. In conclusion, our data suggest that the function of SIRT6 in the Fabp4-Cre-expressing cells in addition to mature adipocytes plays a critical role in body weight maintenance and metabolic homeostasis.