Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts, USA.
Diabetes. 2010 Jun;59(6):1424-34. doi: 10.2337/db09-1212. Epub 2010 Mar 18.
Thioredoxin interacting protein (Txnip), a regulator of cellular oxidative stress, is induced by hyperglycemia and inhibits glucose uptake into fat and muscle, suggesting a role for Txnip in type 2 diabetes pathogenesis. Here, we tested the hypothesis that Txnip-null (knockout) mice are protected from insulin resistance induced by a high-fat diet.
Txnip gene-deleted (knockout) mice and age-matched wild-type littermate control mice were maintained on a standard chow diet or subjected to 4 weeks of high-fat feeding. Mice were assessed for body composition, fat development, energy balance, and insulin responsiveness. Adipogenesis was measured from ex vivo fat preparations, and in mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes after forced manipulation of Txnip expression.
Txnip knockout mice gained significantly more adipose mass than controls due to a primary increase in both calorie consumption and adipogenesis. Despite increased fat mass, Txnip knockout mice were markedly more insulin sensitive than controls, and augmented glucose transport was identified in both adipose and skeletal muscle. RNA interference gene-silenced preadipocytes and Txnip(-/-) MEFs were markedly adipogenic, whereas Txnip overexpression impaired adipocyte differentiation. As increased adipogenesis and insulin sensitivity suggested aspects of augmented peroxisome proliferator-activated receptor-gamma (PPARgamma) response, we investigated Txnip's regulation of PPARgamma function; manipulation of Txnip expression directly regulated PPARgamma expression and activity.
Txnip deletion promotes adiposity in the face of high-fat caloric excess; however, loss of this alpha-arrestin protein simultaneously enhances insulin responsiveness in fat and skeletal muscle, revealing Txnip as a novel mediator of insulin resistance and a regulator of adipogenesis.
硫氧还蛋白相互作用蛋白（Txnip）是细胞氧化应激的调节剂，它可被高血糖诱导，并抑制脂肪和肌肉摄取葡萄糖，这表明 Txnip 在 2 型糖尿病发病机制中起作用。在这里，我们检验了这样一个假设，即 Txnip 基因缺失（敲除）的小鼠可以免受高脂肪饮食引起的胰岛素抵抗。
将 Txnip 基因缺失（敲除）的小鼠和年龄匹配的野生型同窝对照小鼠维持在标准的饲料饮食或接受 4 周的高脂肪喂养。评估小鼠的身体成分、脂肪发育、能量平衡和胰岛素反应性。从体外脂肪制备物中测量脂肪生成，并在强制操纵 Txnip 表达后的小鼠胚胎成纤维细胞（MEFs）和 3T3-L1 前脂肪细胞中测量脂肪生成。
与对照组相比，Txnip 敲除小鼠的脂肪量显著增加，这主要是由于热量摄入和脂肪生成的增加。尽管脂肪量增加，但 Txnip 敲除小鼠的胰岛素敏感性明显高于对照组，并且在脂肪和骨骼肌中都发现了葡萄糖转运的增强。RNA 干扰基因沉默的前脂肪细胞和 Txnip（-/-）MEFs 明显具有脂肪生成能力，而 Txnip 过表达则损害脂肪细胞分化。由于增加的脂肪生成和胰岛素敏感性表明过氧化物酶体增殖物激活受体-γ（PPARγ）反应的增强，我们研究了 Txnip 对 PPARγ 功能的调节；操纵 Txnip 表达直接调节 PPARγ 的表达和活性。
Txnip 缺失在面对高脂肪热量过剩时促进肥胖；然而，这种α-抑制蛋白的缺失同时增强了脂肪和骨骼肌的胰岛素反应性，揭示了 Txnip 是胰岛素抵抗的新介质和脂肪生成的调节剂。
