Original ResearchFull Report: Basic and Translational—LiverFibroblast Growth Factor 21 Limits Lipotoxicity by Promoting Hepatic Fatty Acid Activation in Mice on Methionine and Choline-Deficient Diets
Section snippets
Mouse Maintenance and Experiments
All procedures were approved by the Beth Israel Deaconess Medical Center Institutional Animal Care and Use Committee. Mice were housed in groups of 2–4 mice at 24°C under a 12-hour light-dark cycle (6:00 am to 6:00 pm), with ad libitum access to food and water. Mice were fed either an MCD diet (TD.90262; Harlan Teklad, Indianapolis, IN), the matched control diet (TD.94149; Harlan Teklad), or a high-fat diet (D12451; Research Diets, New Brunswick, NJ) for either 4, 8, or 16 weeks. Mice were
Hepatic FGF21 Expression Is Increased During MCD-Induced Steatohepatitis
FGF21-KO mice fed a high-fat diet for 16 weeks showed evidence of exacerbated fibrosis and inflammation (Supplementary Figure 1), however, the phenotype was mild in both the WT and FGF21-KO mice. Because we were interested in the role of FGF21 in attenuating the more severe pathologies associated with NASH such as lipotoxicity and inflammation, we fed mice an MCD diet (Figure 1). Consumption of the MCD diet led to the development of fatty liver independent of obesity and was associated with a
Conclusions
FGF21 is a novel metabolic regulator that has potent effects on glucose and lipid homeostasis. Administration of FGF21 reduces circulating triglyceride levels, non-esterified fatty acids, and glucose levels, and leads to weight loss in obese animals. This occurs through enhanced insulin sensitivity and increased adipose tissue energy expenditure22 caused, in part, by increased white adipose tissue thermogenesis.23 In human beings, an FGF21 analog was found to improve serum lipid profiles and
Acknowledgments
The authors are grateful for the help from Gary Cline at the Yale Mouse Metabolic Phenotyping Core and the technical assistance of Patrick Antonellis, Deanna Sverdlov, and Anisha Sharma.
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Cited by (0)
Conflicts of interest These authors disclose the following: Alexei Kharitonenkov is an employee of Eli Lilly and Co, and Eleftheria Maratos-Flier has been a consultant for Novo/Nordisk and Novartis regarding fibroblast growth factor 21. The remaining authors disclose no conflicts.
Funding Supported by grants R01 DK069983 and R37 DK28082 (J.S.F. and E.M.F.) and 5 T32 DK007760-12 (P.C.C.) from the National Institutes of Health.
Author names in bold designate shared co-first authors.
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Authors share co-first authorship.