Tissue-specific activity of lipoprotein lipase in skeletal muscle regulates the expression of uncoupling protein 3 in transgenic mouse models

Uncoupling protein (UCP)-2 and UCP-3 an two recently discovered proteins si milar to UCP-1, which regulates thermogenesis in brown adipose tissue (BAT) . Whereas UCP-1 expression is restricted to BAT, UCP-2 is widely expressed. UCP-3 is found mainly in skeletal muscle and BAT. A large body of evidence exists that the expression of UCP-2 and UCP-3 in skeletal muscle of mice i s regulated by feediug/fasting, and some studies have suggested that this e ffect might be caused by the changing concentration of plasma non-esterifie d fatty acids (NEFAs). In an attempt to determine whether the increased imp ort of triacylglycerol-derived NEFAs can also affect UCP expression, we det ermined the mRNA levels of UCP-1, UCP-2 and UCP-3 in BAT and muscle of indu ced mutant mouse lines that overexpressed or lacked lipoprotein lipase (LPL ) in these tissues. The expression levels of UCP-1 and UCP-2 in BAT and in skeletal and cardiac muscle respectively were not affected by variations in tissue LPL activities. In contrast, UCP-3 mRNA levels were induced 3.4-fol d in mice with high levels of LPL in skeletal muscle, and down-regulated in mice that lacked LPL in skeletal muscle. The presence or absence of LPL in BAT had no effect on UCP-3 expression levels. The response of UCP-3 mRNA e xpression to variations in LPL activity in skeletal muscle was independent of the feeding status or of plasma NEFA concentrations. These findings indi cated that NEFAs as lipolytic products of LPL-mediated triacylglycerol hydr olysis markedly affect UCP-3 expression and that increased LPL activities o ccurring during fasting in skeletal muscle contribute to the induction of U CP-3 expression by promoting the increased uptake of NEFAs. In addition, ou r results demonstrate that UCP-2 and UCP-3 are differentially regulated in response to LPL-mediated NEFA uptake in skeletal muscle of mice.