Kim Jason K, Kim Hyo-Jeong, Park So-Young, Cederberg Anna, Westergren Rickard, Nilsson Daniel, Higashimori Takamasa, Cho You-Ree, Liu Zhen-Xiang, Dong Jianying, Cline Gary W, Enerback Sven, Shulman Gerald I
Yale University School of Medicine, Department of Internal Medicine, Section of EndocrinologyMetabolism, The Anlyan Center, S269C, 300 Cedar St., P.O. Box 208020, New Haven, CT 06520-8020, USA.
Diabetes. 2005 Jun;54(6):1657-63. doi: 10.2337/diabetes.54.6.1657.
Insulin resistance plays a major role in the development of type 2 diabetes and may be causally associated with increased intracellular fat content. Transgenic mice with adipocyte-specific overexpression of FOXC2 (forkhead transcription factor) have been generated and shown to be protected against diet-induced obesity and glucose intolerance. To understand the underlying mechanism, we examined the effects of chronic high-fat feeding on tissue-specific insulin action and glucose metabolism in the FOXC2 transgenic (Tg) mice. Whole-body fat mass were significantly reduced in the FOXC2 Tg mice fed normal diet or high-fat diet compared with the wild-type mice. Diet-induced insulin resistance in skeletal muscle of the wild-type mice was associated with defects in insulin signaling and significant increases in intramuscular fatty acyl CoA levels. In contrast, FOXC2 Tg mice were completely protected from diet-induced insulin resistance and intramuscular accumulation of fatty acyl CoA. High-fat feeding also blunted insulin-mediated suppression of hepatic glucose production in the wild-type mice, whereas FOXC2 Tg mice were protected from diet-induced hepatic insulin resistance. These findings demonstrate an important role of adipocyte-expressed FOXC2 on whole-body glucose metabolism and further suggest FOXC2 as a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.
胰岛素抵抗在2型糖尿病的发生发展中起主要作用，并且可能与细胞内脂肪含量增加存在因果关系。已培育出脂肪细胞特异性过表达FOXC2（叉头转录因子）的转基因小鼠，这些小鼠表现出对饮食诱导的肥胖和葡萄糖不耐受具有抵抗力。为了解其潜在机制，我们研究了长期高脂喂养对FOXC2转基因（Tg）小鼠组织特异性胰岛素作用和葡萄糖代谢的影响。与野生型小鼠相比，喂食正常饮食或高脂饮食的FOXC2 Tg小鼠的全身脂肪量显著降低。野生型小鼠骨骼肌中饮食诱导的胰岛素抵抗与胰岛素信号缺陷及肌内脂肪酰基辅酶A水平显著升高有关。相比之下，FOXC2 Tg小鼠完全免受饮食诱导的胰岛素抵抗和肌内脂肪酰基辅酶A积累的影响。高脂喂养还减弱了野生型小鼠中胰岛素介导的肝葡萄糖生成抑制作用，而FOXC2 Tg小鼠则免受饮食诱导的肝胰岛素抵抗。这些发现证明了脂肪细胞表达的FOXC2在全身葡萄糖代谢中的重要作用，并进一步表明FOXC2是治疗胰岛素抵抗和2型糖尿病的新治疗靶点。
