Uncoupling protein-3 gene expression: reduced skeletal muscle mRNA in obese humans during pronounced weight loss

Aims: Uncoupling protein-3 is a member of a protein family that serves to d issipate energy in the form of heat thereby modulating energy expenditure. Alternative processing of uncoupling protein-3 transcripts results in two m RNA species that encode a large and small protein, perhaps differing in fun ctional activity. Since obesity is associated with disrupted energy homeost asis, we measured muscle mRNA expression in morbidly obese and lean subject s. Methods: The two uncoupling protein-3 mRNA species were quantified in muscl e tissue using an RNase protection assay. Gene locus effects on mRNA expres sion were studied by quantitative allele-specific primer extension. Results: In both obese and lean subjects, the mRNA species encoding the sma ll protein isoform was twice as abundant as the mRNA species encoding the l arge protein isoform. Neither the total uncoupling protein-3 mRNA expressio n nor the molar abundance ratios of the two mRNA species differed between o bese and lean male or female subjects. Women who had lost 37 +/- 22 kg of w eight in response to dietary restriction and continued a hypocaloric diet d isplayed lower mRNA than obese (p < 0.005) or lean women (p < 0.05). Primer extension assays in lean and obese subjects showed similar allelic mRNA ab undance in all but one subject studied. Conclusion: Muscle expression of the two uncoupling protein-3 mRNA species is similar in obese and lean people. In obese patients, prolonged hypocalor ic diet downregulates uncoupling protein-3 mRNA expression in muscle and ca n thereby enhance its energy efficiency. Sequence substitutions at the gene locus may only be minor determinants of mRNA expression in muscle tissue.