Human Obese Gene Expression: Alternative Splicing of mRNA 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 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. Methods: 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. Results: 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. Conclusions: 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.