HUMAN OBESE GENE-EXPRESSION - ALTERNATIVE SPLICING OF MESSENGER-RNA AND RELATION TO ADIPOSE-TISSUE LOCALIZATION

Background: The adipocyte-specific protein leptin signals the size of the adipose tissue mass to hypothalamic regions, thereby influencing f ood intake and energy metabolism. Human obesity is often associated wi th high leptin levels implying leptin resistance or defective leptin f unction. Two leptin mRNA species differing only by the presence or abs ence of a CAG codon encoding glutamine at position 49 of the mature pr otein arise from alternative splicing owing to two splice acceptor sit es immediately following each other at the intron 2 - exon 3 junction. Since glutamine 49 is part of a highly conserved region, we studied p ossible functional implications of alternative splicing for human obes ity. Methods: We determined, in lean and obese individuals, the relati ve abundance of both mRNA species in intra-and extraperitoneal adipose tissue in relation to ob gene transcript abundance and plasma leptin levels. Results: Leptin mRNA levels in adipose tissue and concentratio ns of leptin in plasma were significantly higher in obese subjects tha n 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 s ize. In all tissue samples, the predominant ob gene transcript contain ed the codon for glutamine 49 and the molar ratio of the two leptin mR NA species was similar in patients and controls. No correlation was ob served between splice site usage and leptin mRNA abundance or leptin c oncentration in plasma in our study group. Conclusions: Differences in the primary structure of leptin due to the presence or absence of glu tamine 49 are unlikely to contribute to the apparent 'leptin resistanc e' commonly observed in obese individuals.