La. Foellmiadams et al., INDUCTION OF UNCOUPLING PROTEIN IN BROWN ADIPOSE-TISSUE - SYNERGY BETWEEN NOREPINEPHRINE AND PIOGLITAZONE, AN INSULIN-SENSITIZING AGENT, Biochemical pharmacology, 52(5), 1996, pp. 693-701
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.