Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Diabetes. 2013 Jan;62(1):158-69. doi: 10.2337/db12-0256. Epub 2012 Sep 6.
Regulation of energy metabolism is critical for the prevention of obesity, diabetes, and hepatic steatosis. Here, we report an important role for the pleckstrin homology-related domain family member, T-cell death-associated gene 51 (TDAG51), in the regulation of energy metabolism. TDAG51 expression was examined during adipocyte differentiation. Adipogenic potential of preadipocytes with knockdown or absence of TDAG51 was assessed. Weight gain, insulin sensitivity, metabolic rate, and liver lipid content were also compared between TDAG51-deficient (TDAG51(-/-)) and wild-type mice. In addition to its relatively high expression in liver, TDAG51 was also present in white adipose tissue (WAT). TDAG51 was downregulated during adipogenesis, and TDAG51(-/-) preadipocytes exhibited greater lipogenic potential. TDAG51(-/-) mice fed a chow diet exhibited greater body and WAT mass, had reduced energy expenditure, displayed mature-onset insulin resistance (IR), and were predisposed to hepatic steatosis. TDAG51(-/-) mice had increased hepatic triglycerides and SREBP-1 target gene expression. Furthermore, TDAG51 expression was inversely correlated with fatty liver in multiple mouse models of hepatic steatosis. Taken together, our findings suggest that TDAG51 is involved in energy homeostasis at least in part by regulating lipogenesis in liver and WAT, and hence, may constitute a novel therapeutic target for the treatment of obesity and IR.
能量代谢的调节对于预防肥胖、糖尿病和肝脂肪变性至关重要。在这里，我们报告了一个重要的角色，即血小板反应蛋白同源结构域家族成员，T 细胞死亡相关基因 51（TDAG51），在能量代谢的调节中的作用。在脂肪细胞分化过程中检查了 TDAG51 的表达。用 TDAG51 敲低或缺失的前脂肪细胞的成脂潜力进行了评估。还比较了 TDAG51 缺陷型（TDAG51（-/-））和野生型小鼠之间的体重增加、胰岛素敏感性、代谢率和肝脂质含量。除了在肝脏中表达较高外，TDAG51 也存在于白色脂肪组织（WAT）中。在脂肪生成过程中，TDAG51 下调，TDAG51（-/-）前脂肪细胞表现出更大的脂肪生成潜力。用标准饮食喂养的 TDAG51（-/-）小鼠表现出更大的体重和 WAT 质量，能量消耗减少，表现出成熟型胰岛素抵抗（IR），并且容易发生肝脂肪变性。TDAG51（-/-）小鼠的肝甘油三酯和 SREBP-1 靶基因表达增加。此外，TDAG51 的表达与多种肝脂肪变性小鼠模型中的脂肪肝呈负相关。总之，我们的研究结果表明，TDAG51 至少部分通过调节肝脏和 WAT 的脂肪生成参与能量平衡，因此，可能构成肥胖和 IR 治疗的新的治疗靶点。
