Profound Modification of Fatty Acid Profile and Endocannabinoid-Related Mediators in PPARα Agonist Fenofibrate-Treated Mice

Fenofibrate (FBR), an oral medication used to treat dyslipidemia, is a ligand of the peroxisome proliferator-activated receptor alpha (PPAR alpha), a nuclear receptor that regulates the expression of metabolic genes able to control lipid metabolism and food intake. PPAR alpha natural ligands include fatty acids (FA) and FA derivatives such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), known to have anti-inflammatory and anorexigenic activities, respectively. We investigated changes in the FA profile and FA derivatives by HPLC and LC-MS in male C57BL/6J mice fed a standard diet with or without 0.2% fenofibrate (0.2% FBR) for 21 days. Induction of PPAR alpha by 0.2% FBR reduced weight gain, food intake, feed efficiency, and liver lipids and induced a profound change in FA metabolism mediated by parallel enhanced mitochondrial and peroxisomal beta-oxidation. The former effects led to a steep reduction of essential FA, particularly 18:3n3, with a consequent decrease of the n3-highly unsaturated fatty acids (HUFA) score; the latter effect led to an increase of 16:1n7 and 18:1n9, suggesting enhanced hepatic de novo lipogenesis with increased levels of hepatic PEA and OEA, which may activate a positive feedback and further sustain reductions of body weight, hepatic lipids and feed efficiency.

Automated summary

The oral medication Fenofibrate (FBR) can reduce body weight, food intake, and liver lipids, and increase hepatic de novo lipogenesis through inducing changes in fatty acid metabolism. This may be achieved by activating the reactions of fatty acid derivatives such as PEA and OEA.