Ishizuka T, Ernsberger P, Liu S, Bedol D, Lehman T M, Koletsky R J, Friedman J E
Departments of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
J Nutr. 1998 Dec;128(12):2299-306. doi: 10.1093/jn/128.12.2299.
The genetically obese Koletsky rat (SHROB, fak) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentration was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.
遗传性肥胖的科列茨基大鼠（SHROB，fak）在瘦素受体的第763位氨基酸处发生了一种新的点突变，导致瘦素受体细胞外结构域出现提前终止密码子。这意味着该模型中所有瘦素受体亚型都应不存在。我们研究了这种突变对SHROB及其瘦型SHR同窝仔鼠下丘脑和外周组织中瘦素及瘦素受体mRNA的表型影响。尽管存在突变，但长型（ObRa）和短型（ObRb）瘦素受体mRNA在SHROB和SHR的脑及外周组织中的表达水平相当。与SHR相比，SHROB脂肪组织中瘦素mRNA水平高两到三倍（P < 0.01），而循环瘦素浓度比SHR同窝仔鼠高170倍（P < 0.01），提示SHROB存在极端的瘦素抵抗。在SHR和SHROB的脑脊液（CSF）中也检测到了瘦素（分别为13.8和27.2 pmol/L）；然而，SHR中瘦素的脑脊液/血浆比值比SHROB高32倍。为了评估瘦素和瘦素受体对胰岛素介导的葡萄糖转运的假定作用，将SHR和SHROB的肌肉在体外与重组人瘦素一起孵育。瘦素可使SHR骨骼肌中胰岛素介导的葡萄糖转运直接降低50%，但在缺乏所有形式瘦素受体的肥胖SHROB大鼠中则无此作用。这些结果表明，SHROB中天然的瘦素受体敲除代表了一种独特的大鼠模型，可用于确定瘦素在中枢和外周能量代谢中的功能作用。
