PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AND RECEPTOR-ALPHA MEDIATE IN-VIVO REGULATION OF UNCOUPLING PROTEIN (UCP-1, UCP-2, UCP-3) GENE-EXPRESSION

A role for peroxisome proliferator-activated receptors, PPAR gamma and PPAR alpha, as regulators of energy homeostasis and lipid metabolism, has been suggested. Recently, three distinct uncoupling protein isofo rms, UCP-1, UCP-2, and UCP-3, have also been identified and implicated as mediators of thermogenesis. Here, we examined whether in vivo PPAR gamma or PPAR alpha activation regulates the expression of all three UCP isoforms. Rats or lean and db/db mice were treated with PPAR gamma [thiazolidinedione (TZD)] or PPAR alpha (WY-14643) agonists, followed by measurement of messenger RNAs (mRNAs) for UCP-1, UCP-2, and UCP-3 in selected tissues where they are expressed. TZD treatment (AD 5075 a t 5 mg/kg day) of rats (14 days) increased brown adipose tissue (BAT) depot size and induced the expression of each UCP mRNA (3x control lev els for UCP-1 and UCP-2, 2.5x control for UCP-3). In contrast, UCP-2 a nd UCP-3 mRNA levels were not affected in white adipose tissue or skel etal muscle. Chronic (30 days) low-dose (0.3 mg/kg.day) TZD treatment induced UCP-1 mRNA and protein in BAT (2.5x control). In contrast, chr onic TZD treatment (30 mg/kg day) suppressed UCP-1 mRNA (>80%) and pro tein (50%) expression in BAT. This was associated with further inducti on of UCP-2 expression (>10-fold) and an increase in the size of lipid vacuoles, a decrease in the number of lipid vacuoles in each adipocyt e, and an increase in the size of the adipocytes. TZD treatment of db/ db mice (BRL 49653 at 10 mg/kg day for 10 days) also induced UCP-1 and UCP-3 (but not UCP-2) expression in BAT. PPAR alpha is present in BAT , as well as liver. Treatment of rats or db/db mice with WY-14643 did not affect expression of UCP-1, -2, or -3 in BAT. Hepatic UCP-8 mRNA w as increased (4x control level) in db/db and lean mice, although this effect was not observed in rats. Thus, in vivo PPAR gamma activation c an induce expression of UCP-1, -2, and -3 in BAT; whereas chronic-inte nse PPAR gamma activation may cause BAT to assume white adipose tissue -like phenotype with increased UCP-8 levels. PPAR alpha activation in mice is sufficient to induce liver UCP-2 expression.