Professor and Chair, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Endocrinology. 2011 Jan;152(1):69-81. doi: 10.1210/en.2010-0498. Epub 2010 Nov 17.
Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new animal model in which exon 17 of the leptin receptor (Lepr) protein was selectively deleted in somatotropes by Cre-loxP technology. Organ genotyping confirmed the recombination of the floxed LepR allele only in the pituitary. Deletion mutant mice showed a 72% reduction in pituitary cells bearing leptin receptor (LEPR)-b, a 43% reduction in LEPR proteins and a 60% reduction in percentages of immunopositive GH cells, which correlated with reduced serum GH. In mutants, LEPR expression by other pituitary cells was like that of normal animals. Leptin stimulated phosphorylated Signal transducer and activator of transcription 3 expression in somatotropes from normal animals but not from mutants. Pituitary weights, cell numbers, IGF-I, and the timing of puberty were not different from control values. Growth curves were normal during the first 3 months. Deletion mutant mice became approximately 30-46% heavier than controls with age, which was attributed to an increase in fat mass. Serum leptin levels were either normal in younger animals or reflected the level of obesity in older animals. The specific ablation of the Lepr exon 17 gene in somatotropes resulted in GH deficiency with a consequential reduction in lipolytic activity normally maintained by GH and increased adiposity.
瘦素是 Lep 基因的产物，向下丘脑和其他调节细胞（包括分泌 GH 的垂体生长激素细胞）报告脂肪含量。瘦素缺乏与生长激素细胞数量和功能下降有关，这表明瘦素可能对其维持很重要。这一假说在一种新的动物模型中得到了验证，该模型通过 Cre-loxP 技术选择性地在生长激素细胞中删除了瘦素受体（Lepr）蛋白的外显子 17。组织基因分型证实，只有在垂体中，LepR 基因的 floxed 等位基因发生了重组。缺失突变小鼠的垂体细胞中携带瘦素受体（LEPR）-b 的细胞减少了 72%，LEPR 蛋白减少了 43%，免疫阳性 GH 细胞的百分比减少了 60%，这与血清 GH 减少有关。在突变体中，其他垂体细胞的 LEPR 表达与正常动物相似。瘦素刺激正常动物生长激素细胞中磷酸化信号转导和转录激活因子 3 的表达，但不能刺激突变体生长激素细胞中的表达。突变体的垂体重量、细胞数量、IGF-I 和青春期的时间与对照值没有不同。在最初的 3 个月内，生长曲线正常。随着年龄的增长，突变小鼠比对照小鼠大约重 30-46%，这归因于脂肪量的增加。年轻动物的血清瘦素水平正常，或反映出老年动物肥胖的水平。生长激素细胞中 Lepr 外显子 17 基因的特异性缺失导致 GH 缺乏，导致 GH 通常维持的脂解活性降低和脂肪量增加。
