Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPAR α-dependent and -independent pathways

Goto T, Kim YI, Funakoshi K, Teraminami A, Uemura T, Hirai S, Lee JY, Makishima M, Nakata R, Inoue H, Senju H, Matsunaga M, Horio F, Takahashi N, Kawada T. Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPAR alpha-dependent and -independent pathways. Am J Physiol Endocrinol Metab 301: E1022-E1032, 2011. First published August 23, 2011; doi:10.1152/ajpendo.00061.2011.-Peroxisome proliferator-activated receptors (PPARs) control energy homeostasis. In this study, we showed that farnesol, a naturally occurring ligand of PPARs, could ameliorate metabolic diseases. Obese KK-Ay mice fed a high-fat diet (HFD) containing 0.5% farnesol showed significantly decreased serum glucose level, glucosuria incidence, and hepatic triglyceride contents. Farnesol-containing HFD upregulated the mRNA expressions of PPAR alpha target genes involved in fatty acid oxidation in the liver. On the other hand, farnesol was not effective in upregulating the mRNA expressions of PPAR gamma target genes in white adipose tissues. Experiments using PPAR alpha-deficient [(-/-)] mice revealed that the upregulation of fatty acid oxidation-related genes required PPAR alpha function, but the suppression of hepatic triglyceride accumulation was partially PPAR alpha dependent. In hepatocytes isolated from the wild-type and PPAR alpha (-/-) mice, farnesol suppressed triglyceride synthesis. In luciferase assay, farnesol activated both PPAR alpha and the farnesoid X receptor (FXR) at similar concentrations. Moreover, farnesol increased the mRNA expression level of a small heterodimer partner known as one of the FXR target genes and decreased those of sterol regulatory element-binding protein-1c and fatty acid synthase in both the wildtype and PPAR alpha (-/-) hepatocytes. These findings suggest that farnesol could improve metabolic abnormalities in mice via both PPAR alpha-dependent and -independent pathways and that the activation of FXR by farnesol might contribute partially to the PPAR alpha-independent hepatic triglyceride content-lowering effect. To our knowledge, this is the first study on the effect of the dual activators of PPAR alpha and FXR on obesity-induced metabolic disorders.