Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Endocrinology. 2012 Feb;153(2):583-91. doi: 10.1210/en.2011-1793. Epub 2011 Dec 6.
Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in the United States and is strongly associated with hepatic insulin resistance. We examined whether the thyroid hormone receptor-α (Thra) would be a potential therapeutic target to prevent diet-induced NAFLD and insulin resistance. For that purpose, we assessed insulin action in high-fat diet-fed Thra gene knockout (Thra-0/0) and wild-type mice using hyperinsulinemic-euglycemic clamps combined with (3)H/(14)C-labeled glucose to assess basal and insulin-stimulated rates of glucose and fat metabolism. Body composition was assessed by (1)H magnetic resonance spectroscopy and energy expenditure by indirect calorimetry. Relative rates of hepatic glucose and fat oxidation were assessed in vivo using a novel proton-observed carbon-edited nuclear magnetic resonance technique. Thra-0/0 were lighter, leaner, and manifested greater whole-body insulin sensitivity than wild-type mice during the clamp, which could be attributed to increased insulin sensitivity both in liver and peripheral tissues. Increased hepatic insulin sensitivity could be attributed to decreased hepatic diacylglycerol content, resulting in decreased activation of protein kinase Cε and increased insulin signaling. In conclusion, loss of Thra protects mice from high-fat diet-induced hepatic steatosis and hepatic and peripheral insulin resistance. Therefore, thyroid receptor-α inhibition represents a novel pharmacologic target for the treatment of NAFLD, obesity, and type 2 diabetes.
非酒精性脂肪性肝病（NAFLD）是美国最常见的慢性肝病，与肝胰岛素抵抗密切相关。我们研究了甲状腺激素受体-α（Thra）是否可能成为预防饮食诱导的 NAFLD 和胰岛素抵抗的潜在治疗靶点。为此，我们使用高胰岛素-正常血糖钳夹术结合（3）H/（14）C 标记的葡萄糖评估高脂肪饮食喂养的 Thra 基因敲除（Thra-0/0）和野生型小鼠的胰岛素作用，以评估基础和胰岛素刺激的葡萄糖和脂肪代谢率。通过（1）H 磁共振波谱法评估身体成分，通过间接热量法评估能量消耗。使用新型质子观察碳编辑核磁共振技术在体内评估肝葡萄糖和脂肪氧化的相对速率。在钳夹期间，Thra-0/0 比野生型小鼠更轻、更瘦，表现出更高的全身胰岛素敏感性，这归因于肝和外周组织中胰岛素敏感性的增加。肝胰岛素敏感性的增加可归因于二酰基甘油含量降低，导致蛋白激酶 Cε 的激活减少和胰岛素信号的增加。总之，Thra 的缺失可保护小鼠免受高脂肪饮食诱导的肝脂肪变性以及肝和外周胰岛素抵抗。因此，甲状腺受体-α 抑制代表了治疗非酒精性脂肪性肝病、肥胖症和 2 型糖尿病的新的药理学靶点。
