Bezafibrate reduces mRNA levels of adipocyte markers and increases fatty acid oxidation in primary culture of adipocytes

The molecular mechanisms by which peroxisome proliferator-activated recepto r (PPAR) activation by fibrates reduces fat deposition and improves insulin sensitivity are not completely understood. We report that exposure of a ra t primary culture of adipocytes for 24 h to the PPAR activator bezafibrate increased the mRNA levels of crucial genes involved in peroxisomal and mito chondrial beta -oxidation. The mRNA levels of the peroxisomal beta -oxidati on rate-limiting enzyme acyl-CoA oxidase and of the muscle-type carnitine p almitoyl transferase I (M-CPT-I), which determines the flux of mitochondria l beta -oxidation, increased by 1.6-fold (P < 0.02) and 4.5-fold (P = 0.001 ), respectively. These changes were accompanied by an increase in the trans cript levels of the uncoupling protein-2 (UCP-2; 1.5-fold induction; P < 0. 05) and UCP-3 (3.7-fold induction; P < 0.001), mitochondrial proteins that reduce ATP yield and may facilitate the oxidation of fatty acids. Furthermo re, bezafibrate increased the mRNA levels of the fatty acid translocase (2- fold induction; P < 0.01), suggesting a higher fatty acid uptake into adipo cytes. In agreement with these changes, bezafibrate caused a 1.9-fold induc tion (P < 0.02) in 9,10-[H-3]palmitate oxidation. Moreover, bezafibrate red uced the mRNA expression of several adipocyte markers, including PPAR gamma (30% reduction; P = 0.05), tumor necrosis factor-alpha (33% reduction; P < 0.05), and the ob gene (26% reduction). In contrast, adipocyte fatty acid binding protein mRNA levels increased (1.5-fold induction; P < 0.01), point ing to a mobilization of fatty acids to mitochondria and peroxisomes. The r eduction of the adipocyte markers caused by bezafibrate was accompanied by an increase in the mRNA levels of the preadipocyte marker Pref-1 (1.6-fold induction; P < 0.01). Some of the changes observed in the primary culture o f rat adipocytes also were studied in the epididymal white adipose tissue o f bezafibrate-treated rats for 7 days. In vivo, M-CPT-I mRNA levels increas ed (4.5-fold induction; P = 0.001) in epididymal white adipose tissue of be zafibrate-treated rats. Similarly, fatty acid translocase (2.6-fold inducti on; P = 0.002) and Pref-1 (5.6-fold induction) mRNA levels increased, altho ugh differences in the latter were not significant because of huge individu al variations. These results indicate that exposure of adipocytes to bezafi brate, independent of its hepatic effects, increases the degradation of fat ty acids, reducing their availability to synthesize triglycerides. As a res ult, some degree of dedifferentiation of adipocytes to preadipocyte-like ce lls is achieved. These changes may be involved in the reduction in fat depo ts and in the improvement of insulin sensitivity observed after bezafibrate treatment.