Hepatic insulin resistance and increased hepatic glucose production in mice lacking Fgf21

    1. François R Jornayvaz1,3
    1. 1Department of Internal Medicine
      2Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536, USA
      3Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne CHUV, Switzerland
    1. Correspondence should be addressed to F R Jornayvaz; Email: francois.jornayvaz{at}chuv.ch


    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.

    • Received in final form 26 June 2015
    • Accepted 21 July 2015
    • Made available online as an Accepted Preprint 22 July 2015
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