title: The hepatokine FGF21 is crucial for peroxisome proliferator-activated receptor-α agonist-induced amelioration of metabolic disorders in obese mice.
abstract: Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-α (PPARα) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPARα activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPARα agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such asUcp1,Pgc1a, andCpt1bFenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-deficient mice. These findings indicate that FGF21 is crucial for the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan, tgoto@kais.kyoto-u.ac.jp.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501 Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Goto
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Hirata
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Yumeko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Iwase
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Haruya
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Minji
authors.initials: M
authors.lastname: Kim
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Yongjia
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.
authors.forename: Huei-Fen
authors.initials: HF
authors.lastname: Jheng
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501 Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501 Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, South Korea.
authors.forename: Chu-Sook
authors.initials: CS
authors.lastname: Kim
authors.affiliation: Department of Food Science and Nutrition, University of Ulsan, Ulsan 680-749, South Korea.
authors.forename: Rina
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Suita 565-0871, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Seno
authors.affiliation: Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Suita 565-0871, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto 606-8507, Japan, and.
authors.forename: Megumi
authors.initials: M
authors.lastname: Aizawa-Abe
authors.affiliation: Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto 606-8507, Japan, and.
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.affiliation: Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Itoh
authors.affiliation: From the Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011, Japan.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501 Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Kawada
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004734:Energy Metabolism / Q000235:genetics; D011345:Fenofibrate / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D047493:PPAR alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005947:Glucose; D011345:Fenofibrate
keywords: UCP1; adipocyte; beige cells; browning; fibrates; fibroblast growth factor (FGF); insulin resistance; obesity; peroxisome proliferator-activated receptor (PPAR)