ABSTRACT: The molecular effects of the non-selective dietary PPARalpha agonists n-3 LCPUFAs were compared side-by-side with those of the selective synthetic PPARalpha agonist fenofibrate on whole-genome gene expression in peripheral blood mononuclear cells (PBMCs), white adipose tissue (WAT), and muscle in overweight and obese subjects. Eleven overweight and obese subjects participated in a randomized, double-blind, placebo-controlled intervention trial and received in random order 3.7 g/d n-3 fatty acids (providing 1.7 g/d EPA and 1.2 g/d DHA), 200 mg fenofibrate or placebo treatment for 6 weeks separated by a wash-out period of at least 2-weeks. Fenofibrate changed 5 of the analysed 64 PPARalpha target genes in PBMC, 4 in muscle, and 2 in WAT, whereas fish oil changed 2 genes in WAT only. Both treatments changed 17 out of 25 similar pathways in PBMCs, related to xenobiotic metabolism, biosynthesis of steroids, lipid metabolism, transcription, proteasome function, Th1 immunity, propanoate metabolism and nucleotide metabolism. The majority (18 out of 25) of downregulated pathways in WAT were similarly changed in PBMCs after fish oil and related to lipid metabolism and amino acid metabolism. Fenofibrate and fish oil hardly affected pathways in muscle. In PBMCs, fenofibrate and fish oil only regulated 9 similar genes in metabolic syndrome-related pathways, which were IL25, TICAM1, PRDX2, PTGS1, AGK, FDPS, LDLR, TNNI3, LMAN1 and PTGS1. Overall, 6-weeks treatment with n-3 LCPUFAs and fenofibrate hardly affected PPARalpha target genes in overweight and obese subjects. Pathway analyses suggested that gene expression profiles in PBMCs can provide information about regulated metabolic processes by fish oil and fenofibrate in WAT, but not muscle. Expression of the individual genes, however, hardly overlapped between the tissues.
