Modulation of uncoupling protein 2 and uncoupling protein 3: regulation bydenervation, leptin and retinoic acid treatment

We recently reported that the leptin-induced increase in uncoupling protein 1 (UCP1) mRNA in brown adipose tissue (BAT) is prevented by the denervatio n of BAT. We also reported that retinoic acid (RA) increases UCP1 mRNA in B AT. To extend these finding to UCP2 and UCP3 in BAT, we examined UCP2 and U CP3 mRNA after unilateral denervation of BAT, as well as after leptin, beta (3)-adrenergic agonist, RA, and glucocorticoid administration to rats. UCP3 mRNA was 20% less in the denervated compared with the intact BAT, whereas UCP2 mRNA was unchanged with denervation. The beta(3)-adrenergic agonist, C GP-12177 (0.75 mg/kg), increased UPC3 mRNA by 40% in the innervated and by 85% in the denervated BAT. Leptin (0.9 mg/day for 3 days) increased both UC P2 and UCP3 mRNA by 30% in the innervated and, surprisingly, in the denerva ted BAT. RA (7.5 mg/kg) increased UCP1 mRNA but decreased UCP2 and UCP3 mRN A by 50%, whereas methylprednisolone (65 mg/kg, two doses 24 h apart) suppr essed all three uncoupling proteins by greater than 60%. The present findin gs indicate that: sympathetic innervation is necessary to maintain basal le vels of UCP3 mRNA; beta(3)-adrenergic agonist stimulation induces UCP3 mRNA ; leptin induces UCP2 and UCP3 mRNA and this induction is not dependent on sympathetic innervation; RA increases UCP1 but decreases UCP2 and UCP3 mRNA ; and methylprednisolone suppresses UCP1, UCP2, and UCP3 mRNA equally. Thes e data suggest that there are distinct patterns of regulation between UCP1, UCP2, and UCP3, and there may be at least two modes by which leptin could modulate thermogenesis in BAT; first, by increasing sympathetic stimulation of BAT and induction of UCP1 mRNA and, secondly, by increasing UCP2 and UC P3 mRNA by a mechanism independent of sympathetic stimulation.