Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 1; pp. 250 - 259
• Main Authors: Xu, Jing, Lloyd, David J, Hale, Clarence, Stanislaus, Shanaka, Chen, Michelle, Sivits, Glenn, Vonderfecht, Steven, Hecht, Randy, Li, Yue-Sheng, Lindberg, Richard A, Chen, Jin-Long, Jung, Dae Young, Zhang, Zhiyou, Ko, Hwi-Jin, Kim, Jason K, Véniant, Murielle M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2009
• Subjects: Adipocytes; Adiposity - drug effects; Animals; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Western; Body fat; Body Weight - drug effects; Calorimetry; Care and treatment; Cholesterol; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats - administration & dosage; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy Metabolism - drug effects; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty liver; Fatty Liver - metabolism; Fatty Liver - physiopathology; Fatty Liver - prevention & control; Fibroblast growth factors; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblast Growth Factors - pharmacology; Fibroblasts; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Glucagon; Glucokinase - genetics; Glucokinase - metabolism; Glucose; Glucose Clamp Technique; Growth factors; Health aspects; Insulin - blood; Insulin resistance; Insulin Resistance - physiology; Kinases; Lipids; Lipids - blood; Liver; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Metabolic diseases; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Obesity; Obesity - drug therapy; Obesity - etiology; Obesity - physiopathology; Other diseases. Semiology; Pharmacology & Therapeutics; Proteins; Pyruvate Kinase - genetics; Pyruvate Kinase - metabolism; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Research design; Reverse Transcriptase Polymerase Chain Reaction; Sterols; United States; Endocrinopathy; Fibroblast growth factor; Obesity; Pancreatic hormone; Diabetes mellitus; Rodentia; Nutrition disorder; Hepatic disease; Insulin; Feeding; Vertebrata; Sensitivity; Mammalia; Fatty liver; Diet; Mouse; Animal; Digestive diseases; Nutritional status
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db08-0392

Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice Jing Xu 1 , David J. Lloyd 1 , Clarence Hale 1 , Shanaka Stanislaus 1 , Michelle Chen 1 , Glenn Sivits 1 , Steven Vonderfecht 2 , Randy Hecht 3 , Yue-Sheng Li 3 , Richard A. Lindberg 1 , Jin-Long Chen 1 , Dae Young Jung 4 , Zhiyou Zhang 4 , Hwi-Jin Ko 4 , Jason K. Kim 4 and Murielle M. Véniant 1 1 Department of Metabolic Disorders, Amgen, Thousand Oaks, California 2 Department of Pathology, Amgen, Thousand Oaks, California 3 Department of Protein Sciences, Amgen, Thousand Oaks, California 4 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Corresponding author: Jing Xu, jingx{at}amgen.com Abstract OBJECTIVE— Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model. RESEARCH DESIGN AND METHODS— DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS— FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity. CONCLUSIONS— FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 7 October 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted September 29, 2008. Received March 19, 2008. DIABETES