Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes
Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes
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DOI：
10.2337/diabetes.50.6.1440
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发表时间：
2001-06-01
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：
Ebihara, K;Ogawa, Y;Nakao, K
脂肪萎缩性糖尿病是由脂肪组织缺乏引起的，其特征是严重的胰岛素抵抗、低肽血症和摄食过多。A-ZIP/F-1小鼠（A-ZIPTg/+）是严重脂肪萎缩性糖尿病的模型，具有胰岛素抵抗、低肽血症、摄食过多，并显示严重的肝脂肪变性。我们还产生了转基因“瘦”小鼠，其具有瘦素（LepTg/+）的肝脏过表达，并且没有脂肪细胞甘油三酯储存，并且是低吞噬的并且显示出增加的胰岛素敏感性。为了探索瘦素在脂肪萎缩性糖尿病中的病理生理学和治疗作用，我们将LepTg/+和A-ZIPTg/+小鼠杂交，产生几乎缺乏脂肪组织但瘦素水平大大升高的双转基因小鼠（LepTg/+：A-ZIPTg/+）。LepTg/+：A-ZIPTg/+小鼠是低吞噬的，并且显示出改善的肝脂肪变性。葡萄糖和胰岛素耐受性测试显示出增加的胰岛素敏感性，与LepTg/+小鼠相当。这些影响在至少6个月龄内是稳定的。将A-ZIPTg/+小鼠配对喂养至LepTg/+消耗的食物量：A-ZIPTg/+小鼠没有改善其胰岛素抵抗、糖尿病或肝脂肪变性，表明瘦素的有益作用不是由于食物摄入减少。持续给予瘦素，使血浆瘦素浓度升高至LepTg/+：A-ZIPTg/+小鼠的水平，也有效地改善了A-ZTP/F-1小鼠的肝脂肪变性和糖脂代谢紊乱。这些数据表明，瘦素可以改善严重脂肪萎缩性糖尿病小鼠模型的胰岛素抵抗和糖尿病，表明瘦素可能在脂肪萎缩性糖尿病的长期治疗中是治疗上有用的。
Lipoatrophic diabetes is caused by a deficiency of adipose tissue and is characterized by severe insulin resistance, hypoleptinemia, and hyperphagia. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe Lipoatrophic diabetes and is insulin resistant, hypoleptinemic, hyperphagic, and shows severe hepatic steatosis. We have also produced transgenic "skinny" mice that have hepatic overexpression of leptin (LepTg/+) and no adipocyte triglyceride stores, and are hypophagic and show increased insulin sensitivity. To explore the pathophysiological and therapeutic roles of leptin in lipoatrophic diabetes, we crossed LepTg/+ and A-ZIPTg/+ mice, producing doubly transgenic mice (LepTg/+:A-ZIPTg/+) virtually lacking adipose tissue but having greatly elevated leptin levels. The LepTg/+:A-ZIPTg/+ mice were hypophagic and showed improved hepatic steatosis, Glucose and insulin tolerance tests revealed increased insulin sensitivity, comparable to LepTg/+ mice. These effects were stable over at least 6 months of age. Pair-feeding the A-ZIPTg/+ mice to the amount of food consumed by LepTg/+:A-ZIPTg/+ mice did not improve their insulin resistance, diabetes, or hepatic steatosis, demonstrating that the beneficial effects of leptin were not due to the decreased food intake. Continuous leptin administration that elevates plasma leptin concentrations to those of LepTg/+:A-ZIPTg/+ mice also effectively improved hepatic steatosis and the disorder of glucose and lipid metabolism in A-ZTP/F-1 mice. These data demonstrate that leptin can improve the insulin resistance and diabetes of a mouse model of severe lipoatrophic diabetes, suggesting that leptin may be therapeutically useful in the long-term treatment of lipoatrophic diabetes.