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

By Jing Xu, D. Lloyd, C. Hale, Shanaka Stanislaus, Michelle M. Chen, Glenn Sivits, S. Vonderfecht, R. Hecht, Yue-sheng Li, R. Lindberg and 6 more. Diabetes, 2009

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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.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/3900019a35fa424f182a2e913cc3c121832f721a

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Citations in the corpus

FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. (2012, background): “The beneficial affects of FGF21 on glucose metabolism and body weight have evoked a substantial interest in FGF21 as a potential treatment for diseases such as obesity and diabetes (Coskun et al. 2008; Berglund et al. 2009; Xu et al. 2009).”
FGF/FGFR signaling in health and disease (2020, background): “FGF21 can cause weight loss, decrease plasma glucose and triglycerides level, and improve insulin sensitivity in obese and diabetic animal models without affecting total caloric intake.(553,554) Mice with overexpressed FGF21 resist to DIO.”
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. (2013, background): “Themetabolic effects of native FGF21 or its derivatives and mimetics have also been replicated by other investigators in rodents and nonhuman primates (Foltz et al., 2012; Hecht et al., 2012; Mu et al., 2012; Smith et al., 2013; Véniant et al., 2012; Xu et al., 2009).”
Non-Alcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases (2017, positive): “Rodent studies have shown that exogenous FGF21 protects high-fat-fed mice from insulin resistance by increasing cellular energy expenditure independently of brown adipose tissue activation (Camporez et al., 2013; Xu et al., 2009).”