Wu-Peng X S, Chua S C, Okada N, Liu S M, Nicolson M, Leibel R L
Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, New York 10021, USA.
Diabetes. 1997 Mar;46(3):513-8. doi: 10.2337/diab.46.3.513.
The obese phenotypes of the diabetes (db) mouse and fatty fa) rat are due to functional null mutations of the leptin receptor (Lepr). The recessive mutation in the Koletsky (f) obese rat maps to the same genetic intervals as db and fa and fails to complement the fa mutation. Comparison of the sequence of brain Lepr cDNA from +/+ and f/f animals reveals a T2349A transversion resulting in a Tyr763Stop nonsense mutation in the gene just before the transmembrane domain. Virtual absence of Lepr mRNA in whole brain from f/f animals is consistent with the presence of a null mutation. The predicted reduced cerebrospinal fluid (CSF) transport of leptin in both f/f and fa/fa mutants is reflected in the approximately 10-fold lower ratio of CSF/plasma leptin concentration in the obese versus lean animals. However, equivalent CSF leptin concentration between lean and obese rats (fa/fa, f/f) indicates that leptin can enter the CSF through a non-Lepr-mediated mechanism, which may be saturated at normal physiological plasma leptin concentration.
糖尿病（db）小鼠和肥胖（fa）大鼠的肥胖表型是由于瘦素受体（Lepr）的功能性无效突变所致。科莱茨基（f）肥胖大鼠中的隐性突变定位于与db和fa相同的基因区间，且不能与fa突变互补。对野生型（+/+）和f/f动物脑Lepr cDNA序列的比较显示，存在一个T2349A颠换，导致该基因在跨膜结构域之前出现一个Tyr763Stop无义突变。f/f动物全脑中几乎不存在Lepr mRNA，这与无效突变的存在一致。在f/f和fa/fa突变体中，预测的脑脊液（CSF）中瘦素转运减少反映在肥胖动物与瘦动物相比，CSF/血浆瘦素浓度比值约低10倍。然而，瘦大鼠和肥胖大鼠（fa/fa，f/f）之间CSF瘦素浓度相当，这表明瘦素可以通过非Lepr介导的机制进入CSF，这种机制在正常生理血浆瘦素浓度下可能会饱和。
