Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity.
Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity.
复制标题
多基因肥胖 NZO/H1Lt 小鼠能量代谢失调对 2 型糖尿病发展的影响。
DOI：
10.1016/j.metabol.2003.12.024
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Leiter,EdwardH
中科院分区：
文献类型：
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作者：
Koza,RobertA;Flurkey,Kevin;Graunke,DawnM;Braun,Christopher;Pan,Huei-Ju;Reifsnyder,PeterC;Kozak,LeslieP;Leiter,EdwardH
新西兰肥胖 (NZO) 雄性小鼠会出现多基因幼年型肥胖以及成熟型高胰岛素血症和高血糖（糖尿病）。在此，我们报告了与 CL316,243 (CL)（一种 β3-肾上腺素能受体激动剂）的抗糖尿病作用相关的代谢和分子变化。断奶时开始的日粮 CL 治疗可减少青春期前后体重和肥胖的增加，同时促进生长而不抑制食欲过盛。肥胖的变化反过来又抑制了高胰岛素血症、高瘦素血症、高脂血症和高血糖的发生。这些 CL 诱导的改变反映在脂肪组织质量减少、解偶联蛋白 1 (UCP-1)、过氧化物酶体增殖物激活受体 α (PPARα)、过氧化物酶体增殖物激活受体辅激活物 1 (PGC-1) 转录物表达增加以及白色脂肪中棕色脂肪细胞功能的强劲发展。在食物摄入量增加但身体活动没有变化的情况下，药物介导的能量耗散增加导致全身温度升高 1.5°C。用 CL 治疗的小鼠的间接量热法显示能量消耗增加，并且呼吸交换比率显着的昼夜模式恢复，表明营养感应得到改善。我们的数据表明，CL 通过增强生热作用和以预防糖尿病的方式代谢重新分配能量，促进白色和棕色脂肪库中能量耗散的增加。这是第一份证明膳食 β3 激动剂在预防 2 型糖尿病多基因啮齿动物模型中糖尿病发病方面的作用的报告。
New Zealand Obese (NZO) male mice develop a polygenic juvenile-onset obesity and maturity-onset hyperinsulinemia and hyperglycemia (diabesity). Here we report on metabolic and molecular changes associated with the antidiabesity action of CL316,243 (CL), a β3-adrenergic receptor agonist. Dietary CL treatment initiated at weaning reduced the peripubertal rise in body weight and adiposity while promoting growth without suppressing hyperphagia. The changes in adiposity, in turn, suppressed development of hyperinsulinemia, hyperleptinemia, hyperlipidemia, and hyperglycemia. These CL-induced alterations were reflected by decreased adipose tissue mass, increased expression of transcripts for uncoupling protein-1 (UCP-1), peroxisome proliferator—activated receptor alpha (PPARα), peroxisome proliferater-activated receptor coactivator-1 (PGC-1), and robust development of brown adipocyte function in white fat. Increased drug-mediated energy dissipation elicited a 1.5°C increase in whole body temperature under conditions of increased food intake but with no change in physical activity. Indirect calorimetry of mice treated with CL showed both increased energy expenditure and a restoration of a prominent diurnal pattern in the respiratory exchange ratio suggesting improved nutrient sensing. Our data suggest that CL promotes increased energy dissipation in white and brown fat depots by augmenting thermogenesis and by metabolic re-partitioning of energy in a diabesity-protective fashion. This is the first report demonstrating the effects of dietary β3-agonist in preventing the onset of diabesity in a polygenic rodent model of type 2 diabetes.