Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim M H, Skoda R C
Department of Pharmacology, Biozentrum, University of Basel, Switzerland.
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6231-5. doi: 10.1073/pnas.93.13.6231.
Leptin and its receptor, obese receptor (OB-R), comprise an important signaling system for the regulation of body weight. Splice variants of OB-R mRNA encode proteins that differ in the length of their cytoplasmic domains. We cloned a long isoform of the wild-type leptin receptor that is preferentially expressed in the hypothalamus and show that it can activate signal transducers and activators of transcription (STAT)-3, STAT-5, and STAT-6. A point mutation within the OB-R gene of diabetic (db) mice generates a new splice donor site that dramatically reduces expression of this long isoform in homozygous db/db mice. In contrast, an OB-R protein with a shorter cytoplasmic domain is present in both db/db and wild-type mice. We show that this short isoform is unable to activate the STAT pathway. These data provide further evidence that the mutation in OB-R causes the db/db phenotype and identify three STAT proteins as potential mediators of the anti-obesity effects of leptin.
瘦素及其受体——肥胖受体（OB-R），构成了调节体重的重要信号系统。OB-R mRNA的剪接变体编码的蛋白质，其胞质结构域长度不同。我们克隆了一种野生型瘦素受体的长亚型，它在下丘脑中优先表达，并表明它可以激活信号转导子和转录激活子（STAT）-3、STAT-5和STAT-6。糖尿病（db）小鼠OB-R基因内的一个点突变产生了一个新的剪接供体位点，这显著降低了纯合子db/db小鼠中这种长亚型的表达。相比之下，具有较短胞质结构域的OB-R蛋白在db/db小鼠和野生型小鼠中均存在。我们表明，这种短亚型无法激活STAT途径。这些数据进一步证明了OB-R中的突变导致了db/db表型，并确定了三种STAT蛋白作为瘦素抗肥胖作用的潜在介质。
