title: Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARα-dependent and -independent pathways.
abstract: 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 PPARα target genes involved in fatty acid oxidation in the liver. On the other hand, farnesol was not effective in upregulating the mRNA expressions of PPARγ target genes in white adipose tissues. Experiments using PPARα-deficient [(-/-)] mice revealed that the upregulation of fatty acid oxidation-related genes required PPARα function, but the suppression of hepatic triglyceride accumulation was partially PPARα-dependent. In hepatocytes isolated from the wild-type and PPARα (-/-) mice, farnesol suppressed triglyceride synthesis. In luciferase assay, farnesol activated both PPARα 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 wild-type and PPARα (-/-) hepatocytes. These findings suggest that farnesol could improve metabolic abnormalities in mice via both PPARα-dependent and -independent pathways and that the activation of FXR by farnesol might contribute partially to the PPARα-independent hepatic triglyceride content-lowering effect. To our knowledge, this is the first study on the effect of the dual activators of PPARα and FXR on obesity-induced metabolic disorders.
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Goto
authors.forename: Young-Il
authors.initials: YI
authors.lastname: Kim
authors.forename: Kozue
authors.initials: K
authors.lastname: Funakoshi
authors.forename: Aki
authors.initials: A
authors.lastname: Teraminami
authors.forename: Taku
authors.initials: T
authors.lastname: Uemura
authors.forename: Shizuka
authors.initials: S
authors.lastname: Hirai
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Rieko
authors.initials: R
authors.lastname: Nakata
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Senju
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Matsunaga
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Horio
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Teruo
authors.initials: T
authors.lastname: Kawada
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D059305:Diet, High-Fat; D005204:Farnesol / Q000494:pharmacology* / Q000627:therapeutic use*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008297:Male; D008659:Metabolic Diseases / Q000188:drug therapy* / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013729:Terpenes / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D005204:Farnesol; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D013729:Terpenes; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated