Peroxisome proliferator-activated receptor alpha (PPAR alpha) activators, bezafibrate and Wy-14,643, increase uncoupling protein-3 mRNA levels without modifying the mitochondrial membrane potential in primary culture of rat preadipocytes

Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters wh ich act as pores for H+ ions, dissipating the electrochemical gradient that develops during mitochondrial respiration at the expense of ATP synthesis. We have studied the effects of two fibrates, bezafibrate and Wy-14,643, on UCP-3 and UCP-2 mRNA levels in primary monolayer cultures of rat adipocyte s and undifferentiated preadipocytes, Treatment with both PPAR alpha activa tors for 24 h upregulated UCP-3 mRNA levels. Thus, bezafibrate treatment re sulted in an 8-fold induction in UCP-3 mRNA levels in preadipocytes compare d with the 3.5-fold induction observed in adipocytes. Differences in the in duction of UCP-3 between these cells correlated well with the higher expres sion of PPARa and RXR alpha mRNA values in preadipocytes compared to adipoc ytes. Wy-14,643 caused similar effects on UCP-3 mRNA expression. In contras t to UCP-3, UCP-2 mRNA levels were only slightly modified by bezafibrate in adipocytes, The induction in UCP-3 expression was not accompanied by chang es in the mitochondrial membrane potential of rat primary preadipocytes aft er bezafibrate or Wy-14,643 treatment. Since it has been proposed that UCP- 3 could be involved in the regulation of the use of fatty acids as fuel sub strates, the UCP-3 induction achieved after bezafibrate and Wy-14,643 treat ment may indicate a higher oxidation of fatty acids, limiting their availab ility to be stored as triglycerides. This change may result in a reduced ra te of conversion of preadipocytes to adipocytes, which directly affects fat depots. (C) 2000 Academic Press.