Liu X, Pérusse F, Bukowiecki L J
Department of Physiology, Faculty of Medicine, Laval University, Québec City, Canada.
Am J Physiol. 1998 May;274(5):R1212-9. doi: 10.1152/ajpregu.1998.274.5.R1212.
Previous studies have demonstrated that chronic cold exposure activates the sympathetic nervous system, increases energy expenditure, improves glucose uptake in peripheral tissues [brown and white adipose tissues (BAT and WAT) and muscles] of normal rats. The goal of the present studies was to test whether the selective beta 3-adrenergic agonist CL-316243 (CL) would mimic the beneficial beneficial effects of cold exposure in lean and obese ZDF/Gmi-fa male (ZDF) rats, a new model of type II diabetes. In obese ZDF rats, chronic infusion of CL (1 mg.kg-1.day-1 for 14 days) significantly decreased body weight gain, food intake, and WAT weight. It also increased total tissue cytochrome oxidase activity, not only in BAT (15 times), but also in WAT (2-4) times, suggesting that it progressively enhanced mitochondriogenesis in adipose tissues. CL treatment normalized hyperglycemia and reduced hyperinsulinemia and circulating free fatty acid (FFA) levels. It also improved glucose tolerance and reduced insulin response during an intravenous glucose tolerance test. In general, the beneficial effects of CL were more pronounced in obese than in lean rats. Hyperinsulinemic-euglycemic glucose clamps combined with the [2-3H]deoxyglucose method revealed that CL markedly improved insulin responsiveness in obese rats (3-4 times) and increased glucose uptake in BAT (21 times), WAT (3 times), skeletal muscles (2-3 times), and in the diaphragm (2.8 times), but not in the heart. It is concluded that chronic CL treatment improves glucose tolerance and insulin responsiveness in obese ZDF rats by a mechanism similar to that induced by chronic cold exposure, i.e., by stimulating facultative thermaogenesis, mitochondriogenesis, and glucose utilization in BAT and WAT. In addition to this mechanism, the reduction in plasma FFA levels induced by chronic CL treatment may further contribute to enhance glucose uptake in skeletal muscles (a tissue that does not express typical beta 3-adrenoceptors) via the "glucose-fatty acid" cycle. The antiobesity and antidiabetic properties of CL suggest that selective beta 3-adrenergic agonists may represent useful agents for the treatment of type II diabetes.
先前的研究表明，长期暴露于寒冷环境会激活交感神经系统，增加能量消耗，改善正常大鼠外周组织[棕色和白色脂肪组织（BAT和WAT）以及肌肉]中的葡萄糖摄取。本研究的目的是测试选择性β3-肾上腺素能激动剂CL-316243（CL）是否能模拟寒冷暴露对瘦型和肥胖型ZDF/Gmi-fa雄性（ZDF）大鼠（一种II型糖尿病新模型）的有益作用。在肥胖的ZDF大鼠中，长期输注CL（1mg·kg-1·天-1，持续14天）显著降低了体重增加、食物摄入量和WAT重量。它还增加了总组织细胞色素氧化酶活性，不仅在BAT中增加了15倍，在WAT中也增加了2至4倍，这表明它逐渐增强了脂肪组织中的线粒体生成。CL治疗使高血糖正常化，并降低了高胰岛素血症和循环游离脂肪酸（FFA）水平。它还改善了葡萄糖耐量，并在静脉葡萄糖耐量试验中降低了胰岛素反应。总体而言，CL的有益作用在肥胖大鼠中比在瘦大鼠中更明显。高胰岛素-正常血糖葡萄糖钳夹结合[2-3H]脱氧葡萄糖方法显示，CL显著改善了肥胖大鼠的胰岛素反应性（3至4倍），并增加了BAT（21倍）、WAT（3倍）、骨骼肌（2至3倍）和膈肌（2.8倍）中的葡萄糖摄取，但对心脏没有影响。结论是，长期CL治疗通过类似于长期寒冷暴露所诱导的机制，即通过刺激BAT和WAT中的兼性产热、线粒体生成和葡萄糖利用，改善了肥胖ZDF大鼠的葡萄糖耐量和胰岛素反应性。除了这种机制外，长期CL治疗诱导的血浆FFA水平降低可能通过“葡萄糖-脂肪酸”循环进一步促进骨骼肌（一种不表达典型β3-肾上腺素能受体的组织）中的葡萄糖摄取。CL的抗肥胖和抗糖尿病特性表明，选择性β3-肾上腺素能激动剂可能是治疗II型糖尿病的有用药物。
