title: Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21.
abstract: Fibroblast growth factor 21 (FGF21) is an important regulator of hepatic glucose and lipid metabolism and represents a potential pharmacological agent for the treatment of type 2 diabetes and obesity. Mice fed a ketogenic diet (KD) develop hepatic insulin resistance in association with high levels of FGF21, suggesting a state of FGF21 resistance. To address the role of FGF21 in hepatic insulin resistance, we assessed insulin action in FGF21 whole-body knock-out (FGF21 KO) male mice and their littermate WT controls fed a KD. Here, we report that FGF21 KO mice have hepatic insulin resistance and increased hepatic glucose production associated with an increase in plasma glucagon levels. FGF21 KO mice are also hypometabolic and display increased fat mass compared with their WT littermates. Taken together, these findings support a major role of FGF21 in regulating energy expenditure and hepatic glucose and lipid metabolism, and its potential role as a candidate in the treatment of diseases associated with insulin resistance.
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland.
authors.forename: João Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Asrih
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Kahn
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland.
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.affiliation: Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland Department of Internal MedicineHoward Hughes Medical InstituteYale University School of Medicine, New Haven, Connecticut 06536, USAService of EndocrinologyDiabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland francois.jornayvaz@chuv.ch.
authors.forename: François R
authors.initials: FR
authors.lastname: Jornayvaz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000096:biosynthesis*; D006003:Glycogen / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001786:Blood Glucose; D008055:Lipids; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D006003:Glycogen; D005934:Glucagon; D005947:Glucose
keywords: FGF21; NAFLD; energy expenditure; insulin resistance; obesity