INDUCTION OF UNCOUPLING PROTEIN IN BROWN ADIPOSE-TISSUE - SYNERGY BETWEEN NOREPINEPHRINE AND PIOGLITAZONE, AN INSULIN-SENSITIZING AGENT

Insulin resistance and obesity in rodent models of non-insulin-depende nt diabetes mellitus have been correlated with ablated or defective br own adipose tissue (BAT) function. The mitochondrial uncoupling protei n (UCP) allows BAT to perform its unique role in facultative energy ex penditure. In this study, we observed an increase in both BAT mass and the expression of UCP mRNA in BAT from obese diabetic mice and their lean littermates following treatment with the thiazolidinedione piogli tazone, a novel insulin-sensitizing agent. Thus, we wanted to ascertai n if pioglitazone directly induces BAT differentiation. We found that treatment for 48 hr with pioglitazone caused a 32-fold increase in UCP mRNA, whereas a 7-hr treatment with norepinephrine caused a 24-fold i ncrease in expression. Cells treated with pioglitazone for 48 hr, with norepinephrine added during the last 7 hr, demonstrated a 59-fold inc rease in UCP mRNA. However, simultaneous treatment with pioglitazone a nd repeated treatment norepinephrine for 48 hr yielded a greater than 200-fold increase in UCP mRNA. Examination of UCP protein levels demon strated a similar time-dependent increase with pioglitazone and/or nor epinephrine treatment, as well as a synergistic increase with concurre nt pioglitazone and norepinephrine treatment. This study shows that pi oglitazone exerts a direct effect on BAT cells in vitro by increasing UCP mRNA and protein levels, and that it also synergizes with norepine phrine perhaps by inducing and stabilizing UCP mRNA and/or preventing proteolysis of UCP protein.