Respiratory uncoupling lowers blood pressure through a leptin-dependent mechanism in genetically obese mice
Respiratory uncoupling lowers blood pressure through a leptin-dependent mechanism in genetically obese mice
复制标题
DOI：
10.1161/01.atv.0000019404.65403.71
复制
发表时间：
2002-06-01
影响因子：
8.7
通讯作者：
Semenkovich, CF
中科院分区：
文献类型：
--
作者：
Bernal-Mizrachi, C;Weng, S;Semenkovich, CF
胰岛素抵抗通常与高血压有关，高血压是一种导致肥胖和2型糖尿病患者血管疾病的疾病。高血压与胰岛素抵抗的关系尚不清楚。为了确定呼吸解偶联是否可以预防胰岛素抵抗相关的高血压，我们将骨骼肌中表达解偶联蛋白1（UCP 1）的转基因小鼠与致死性黄（A（y）/a）小鼠杂交，黄小鼠是已知具有高血压的遗传肥胖动物。尽管食物摄入量增加，但UCP-A（y）/a小鼠的体重低于其A（y）/a同窝出生的小鼠。UCP-A（y）/a小鼠的代谢率高于A（y）/a小鼠，并且不会损害它们响应温度变化而改变耗氧量的能力，这是一种涉及交感神经系统活动的适应。与同窝出生的非转基因小鼠相比，UCP-A（y）/a小鼠的空腹胰岛素、葡萄糖、甘油三酯和胆固醇水平较低，对胰岛素更敏感。血压，血清瘦素，尿中的儿茶酚胺水平也较低的非偶联小鼠。与交感神经系统活动无关，低剂量外周瘦素输注增加了UCP-A（y）/a小鼠的血压，但在A（y）/a同窝出生的小鼠中没有。这些数据表明，骨骼肌呼吸解偶联逆转胰岛素抵抗，降低遗传性肥胖的血压，而不影响体温调节。数据还表明，解偶联可以降低2型糖尿病患者动脉粥样硬化的风险。
Insulin resistance is commonly associated with hypertension, a condition that causes vascular disease in people with obesity and type 2 diabetes. The mechanisms linking hypertension and insulin resistance are poorly understood. To determine whether respiratory uncoupling can prevent insulin resistance-related hypertension, we crossed transgenic mice expressing uncoupling protein 1 (UCP1) in skeletal muscle with lethal yellow (A(y)/a) mice, genetically obese animals known to have elevated blood pressure. Despite increased food intake, UCP-A(y)/a mice weighed less than their A(y)/a littermates. The metabolic rate was higher in UCP-A(y)/a mice than in A(y)/a mice and did not impair their ability to alter oxygen consumption in response to temperature changes, an adaptation involving sympathetic nervous system activity. Compared with their nontransgenic littermates, UCP-A(y)/a mice had lower fasting insulin, glucose, triglyceride, and cholesterol levels and were more insulin sensitive. Blood pressure, serum leptin, and urinary catecholamine levels were also lower in uncoupled mice. Independent of sympathetic nervous system activity, low-dose peripheral leptin infusion increased blood pressure in UCP-A(y)/a mice but not in their A(y)/a littermates. These data indicate that skeletal muscle respiratory uncoupling reverses insulin resistance and lowers blood pressure in genetic obesity without affecting thermoregulation. The data also suggest that uncoupling could decrease the risk of atherosclerosis in type 2 diabetes.