Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal Yellow agouti mutation -: Usefulness of leptin for the treatment of obesity-associated diabetes
Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal Yellow agouti mutation -: Usefulness of leptin for the treatment of obesity-associated diabetes
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DOI：
10.2337/diabetes.48.8.1615
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发表时间：
1999-08-01
期刊：
影响因子：
7.7
通讯作者：
Nakao, K
中科院分区：
文献类型：
--
作者：
Masuzaki, H;Ogawa, Y;Nakao, K
瘦素是一种脂肪细胞来源的血液中的饱腹感因子，可以促进葡萄糖代谢。为了阐明瘦素对肥胖相关糖尿病的治疗意义，我们将我们最近开发的高表达瘦素的转基因瘦小鼠(Tg/+)与肥胖-糖尿病综合征的遗传模型致死黄色kka(Y)小鼠(A(Y)/+)杂交，并检测了F-1动物的代谢表型。6周龄时，携带A(Y)等位基因(TG/+：A(Y)/+)的TG/+小鼠血浆瘦素水平显著高于A(Y)/+小鼠。虽然TG/+：A(Y)/+小鼠、A(Y)/+小鼠和它们的野生型瘦肉仔鼠(+/+)之间的体重没有显著差异，但葡萄糖和胰岛素耐量试验显示，与A(Y)/+小鼠相比，TG/+：A(Y)/+小鼠的葡萄糖耐量和胰岛素敏感性增加。然而，在12周龄时，当A(Y)/+小鼠的血浆瘦素水平与TG/+：A(Y)/+小鼠相似时，TG/+：A(Y)/+小鼠出现了与A(Y)/+小鼠相似的肥胖-糖尿病综合征。通过3周的饮食限制，出生1周的TG/+：A(Y)/+和A(Y)/+小鼠的体重降低到+/+小鼠的体重；当TG/+：A(Y)/+小鼠的血浆瘦素浓度保持在较高水平，而A(Y)/+和+/+小鼠的血浆瘦素浓度显著降低时，TG/+：A(Y)/+小鼠的糖耐量和胰岛素敏感性明显改善。本研究表明，高瘦素血症可以延缓TG/+：A(Y)/+小鼠在热量限制下糖代谢受损的发生，加速糖尿病的恢复，从而提示瘦素与长期热量限制相结合治疗肥胖相关糖尿病具有潜在的实用价值。
Leptin acts as an adipocyte-derived blood-borne satiety factor that can increase glucose metabolism. To elucidate the therapeutic implications of leptin for obesity-associated diabetes, we crossed transgenic skinny mice overexpressing leptin (Tg/+), which we have developed recently, and lethal yellow KKA(y) mice (A(y)/+), a genetic model for obesity-diabetes syndrome, and examined the metabolic phenotypes of F-1 animals. At 6 weeks of age, plasma leptin concentrations in Tg/+ mice with the A(y) allele (Tg/+:A(y)/+) were significantly higher than those in A(y)/+ mice. Although no significant differences in body weight were noted among Tg/+:A(y)/+ mice, A(y)/+ mice, and their wild-type lean littermates (+/+), glucose and insulin tolerance tests revealed increased glucose tolerance and insulin sensitivity in Tg/+:A(y)/+ compared with A(y)/+ mice. However, at 12 weeks of age, when plasma leptin concentrations in A(y)/+ mice were comparable to those in Tg/+:A(y)/+ mice, Tg/+:A(y)/+ mice developed obesity-diabetes syndrome similar to that of A(y)/+ mice. Body weights of la-week-old Tg/+:A(y)/+ and A(y)/+ mice were reduced to those of +/+ mice by a 3-week food restriction; when plasma leptin concentrations remained high in Tg/+:A(y)/+ mice but were markedly reduced in A(y)/+ and +/+ mice, glucose tolerance and insulin sensitivity in Tg/+:A(y)/+ mice were markedly improved as compared with A(y)/+ and +/+ mice. The present study demonstrates that hyperleptinemia can delay the onset of impaired glucose metabolism and accelerate the recovery from diabetes during caloric restriction in Tg/+:A(y)/+ mice, thereby suggesting the potential usefulness of leptin in combination with a long-term caloric restriction for the treatment of obesity-associated diabetes.