Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat heart

Diabetic rats have a deficiency in their heart ATP concentrations, and alth ough the mechanism remains to be elucidated, this deficiency may involve in creased uncoupling of oxidative phosphorylation, To investigate whether hea rt uncoupling proteins (UCPs) are subject to transcriptional regulation in diabetes, we examined changes in UCP mRNA expression in the heart of strept ozotocin-induced diabetic (STZ-DM) rats. Heart UCP3 mRNA expression signifi cantly increased by 9.4-fold in STZ-DIM rats, while levels of UCP3 mRNA exp ression were not significantly altered. Insulin supplementation in STZ-DM r ats returned UCP3 mRNA concentrations to control levels, The expression of UCP3 mRNA was similarly elevated in the heart of fasted rats, which also ha ve hypoinsulinemia and hyper-free fatty acidemia but, unlike the STZ-DM rat s, are hypoglycemic. Since hyperinsulinemia alone was previously reported t o not affect UCP3 gene expression in the muscle, these results indicate tha t hyper-free fatty acidemia is a potent enhancer of UCP3 gene expression in the diabetic rat heart. Interestingly, we? found no changes in UCP3 mRNA l evels in Zucker fatty (fa/fa) rats with excessive chronic hyper-free fatty acidemia, which suggests that upregulation of heart UCP3 mRNA may depend on an acute change in free fatty acid concentrations rather than on their sus tained elevation. High-energy ATP deficiencies in the diabetic rat heart ma y primarily result from proton leakage due to the upregulation of UCP3 expr ession.