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

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          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.

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          Most cited references 20

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          Diabetes

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            Obesity and the regulation of energy balance.

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              Molecular mediators of hepatic steatosis and liver injury.

              Obesity and its associated comorbidities are among the most prevalent and challenging conditions confronting the medical profession in the 21st century. A major metabolic consequence of obesity is insulin resistance, which is strongly associated with the deposition of triglycerides in the liver. Hepatic steatosis can either be a benign, noninflammatory condition that appears to have no adverse sequelae or can be associated with steatohepatitis: a condition that can result in end-stage liver disease, accounting for up to 14% of liver transplants in the US. Here we highlight recent advances in our understanding of the molecular events contributing to hepatic steatosis and nonalcoholic steatohepatitis.
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                Author and article information

                Journal
                Diabetes
                diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                January 2009
                : 58
                : 1
                : 250-259
                Affiliations
                [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
                Author notes

                Corresponding author: Jing Xu, jingx@ 123456amgen.com

                Article
                581250
                10.2337/db08-0392
                2606881
                18840786
                Copyright © 2009, American Diabetes Association

                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.

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                Categories
                Pharmacology & Therapeutics

                Endocrinology & Diabetes

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