Oberkofler H, Beer A, Breban D, Hell E, Krempler F, Patsch W
Department of Laboratory Medicine, Landeskrankenanstalten Salzburg, Austria.
Obes Surg. 1997 Oct;7(5):390-6. doi: 10.1381/096089297765555368.
The adipocyte-specific protein leptin signals the size of the adipose tissue mass to hypothalamic regions, thereby influencing food intake and energy metabolism. Human obesity is often associated with high leptin levels implying leptin resistance or defective leptin function. Two leptin mRNA species differing only by the presence or absence of a CAG codon encoding glutamine at position 49 of the mature protein arise from alternative splicing owing to two splice acceptor sites immediately following each other at the intron 2 - exon 3 junction. Since glutamine 49 is part of a highly conserved region, we studied possible functional implications of alternative splicing for human obesity.
We determined, in lean and obese individuals, the relative abundance of both mRNA species in intra- and extraperitoneal adipose tissue in relation to ob gene transcript abundance and plasma leptin levels.
Leptin mRNA levels in adipose tissue and concentrations of leptin in plasma were significantly higher in obese subjects than in controls. In both obese and control subjects, leptin mRNA levels were higher in extraperitoneal than in intraperitoneal adipose tissue. Furthermore, leptin mRNA abundance correlated with average fat cell size. In all tissue samples, the predominant ob gene transcript contained the codon for glutamine 49 and the molar ratio of the two leptin mRNA species was similar in patients and controls. No correlation was observed between splice site usage and leptin mRNA abundance or leptin concentration in plasma in our study group.
Differences in the primary structure of leptin due to the presence or absence of glutamine 49 are unlikely to contribute to the apparent 'leptin resistance' commonly observed in obese individuals.
脂肪细胞特异性蛋白瘦素将脂肪组织质量大小的信号传递至下丘脑区域，从而影响食物摄入和能量代谢。人类肥胖常与高瘦素水平相关，这意味着存在瘦素抵抗或瘦素功能缺陷。由于内含子2 - 外显子3连接处紧挨着两个剪接受体位点，成熟蛋白第49位编码谷氨酰胺的CAG密码子的有无导致了两种仅在这一点上存在差异的瘦素mRNA种类，这是选择性剪接的结果。由于谷氨酰胺49是高度保守区域的一部分，我们研究了选择性剪接对人类肥胖可能的功能影响。
我们测定了瘦人和肥胖个体腹膜内和腹膜外脂肪组织中两种mRNA种类的相对丰度，并将其与ob基因转录本丰度和血浆瘦素水平进行关联。
肥胖受试者的脂肪组织中瘦素mRNA水平和血浆中瘦素浓度显著高于对照组。在肥胖和对照受试者中，腹膜外脂肪组织中的瘦素mRNA水平均高于腹膜内脂肪组织。此外，瘦素mRNA丰度与平均脂肪细胞大小相关。在所有组织样本中，主要的ob基因转录本包含谷氨酰胺49的密码子，患者和对照组中两种瘦素mRNA种类的摩尔比相似。在我们的研究组中，未观察到剪接位点使用与瘦素mRNA丰度或血浆瘦素浓度之间的相关性。
由于谷氨酰胺49的存在或缺失导致的瘦素一级结构差异不太可能导致肥胖个体中常见的明显“瘦素抵抗”。
