Igel M, Becker W, Herberg L, Joost H G
Institut für Pharmakologie und Toxikologie der RWTH, Aachen, Germany.
Endocrinology. 1997 Oct;138(10):4234-9. doi: 10.1210/endo.138.10.5428.
New Zealand Obese (NZO) mice exhibit a polygenic syndrome of hyperphagia, obesity, hyperinsulinemia, and hyperglycemia similar to that observed in young diabetes mutant mice on the C57BLKS/J background (C57BLKS/J-Lepr(db)/Lepr(db)). Here we show that in NZO this syndrome is accompanied by a marked elevation of the leptin protein in adipose tissue and serum. The promoter region and the complementary DNA of the ob gene of NZO mice, including its 5'-untranslated region, are identical with the wild-type sequence (C57BL, BALB/c), except that the transcription start is located 5 bp upstream of the reported site. In contrast to C57BLKS/J+/+ and C57BL/6J-Lep(ob)/Lep(ob) mice, NZO mice failed to respond to recombinant leptin (7.2 microg/g) with a reduction of food intake. Leptin receptor messenger RNA as detected by PCR appears as abundant in hypothalamic tissue of NZO mice as in tissue from lean mice. Ten nucleotide polymorphisms are found in the complementary DNA of the leptin receptor, resulting in two conservative substitutions (V541I and V651I) in the extracellular part of the receptor and one nonconservative substitution (T1044I) in the intracellular domain between the presumed Jak and STAT binding boxes. However, these mutations are also present in the related lean New Zealand Black strain (body fat at 9 weeks: New Zealand Black, 6.2 +/- 1.3%; NZO, 17.0 +/- 1.7%). Thus, the polymorphic leptin receptor seems to play only a minor, if any, role in the obesity and hyperleptinemia of the NZO mouse. It is suggested that the main defect in NZO is located distal from the leptin receptor or at the level of leptin transport into the central nervous system.
新西兰肥胖（NZO）小鼠表现出多食、肥胖、高胰岛素血症和高血糖的多基因综合征，类似于在C57BLKS/J背景（C57BLKS/J-Lepr(db)/Lepr(db)）的年轻糖尿病突变小鼠中观察到的情况。在此我们表明，在NZO小鼠中，这种综合征伴随着脂肪组织和血清中瘦素蛋白的显著升高。NZO小鼠ob基因的启动子区域和互补DNA，包括其5'-非翻译区，与野生型序列（C57BL、BALB/c）相同，只是转录起始位点位于报道位点上游5 bp处。与C57BLKS/J+/+和C57BL/6J-Lep(ob)/Lep(ob)小鼠不同，NZO小鼠对重组瘦素（7.2微克/克）无反应，食物摄入量未减少。通过PCR检测到的瘦素受体信使RNA在NZO小鼠下丘脑组织中的含量与瘦小鼠组织中的含量一样丰富。在瘦素受体的互补DNA中发现了10个核苷酸多态性，导致受体细胞外部分有两个保守性替换（V541I和V651I），以及在假定的Jak和STAT结合框之间的细胞内结构域中有一个非保守性替换（T1044I）。然而，这些突变也存在于相关的瘦新西兰黑品系中（9周龄时体脂：新西兰黑，6.2±1.3%；NZO，17.0±1.7%）。因此，多态性瘦素受体在NZO小鼠的肥胖和高瘦素血症中似乎只起次要作用（如果有作用的话）。有人认为，NZO小鼠的主要缺陷位于瘦素受体远端或瘦素转运到中枢神经系统的水平。
