Interplay between FGF21 and insulin action in the liver regulates metabolism
Brice Emanuelli, … , Alexei Kharitonenkov, C. Ronald Kahn
Brice Emanuelli, … , Alexei Kharitonenkov, C. Ronald Kahn
Published January 9, 2014
Citation Information: J Clin Invest. 2014;124(2):515-527. https://doi.org/10.1172/JCI67353.
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Research Article

Interplay between FGF21 and insulin action in the liver regulates metabolism

Abstract

The hormone FGF21 regulates carbohydrate and lipid homeostasis as well as body weight, and increasing FGF21 improves metabolic abnormalities associated with obesity and diabetes. FGF21 is thought to act on its target tissues, including liver and adipose tissue, to improve insulin sensitivity and reduce adiposity. Here, we used mice with selective hepatic inactivation of the IR (LIRKO) to determine whether insulin sensitization in liver mediates FGF21 metabolic actions. Remarkably, hyperglycemia was completely normalized following FGF21 treatment in LIRKO mice, even though FGF21 did not reduce gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects on reducing glucose levels, the effects of FGF21 on reducing circulating cholesterol and hepatic triglycerides and regulating the expression of key genes involved in cholesterol and lipid metabolism in liver were disrupted in LIRKO mice. Thus, FGF21 corrects hyperglycemia in diabetic mice independently of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism.

Authors

Brice Emanuelli, Sara G. Vienberg, Graham Smyth, Christine Cheng, Kristin I. Stanford, Manimozhiyan Arumugam, Mervyn D. Michael, Andrew C. Adams, Alexei Kharitonenkov, C. Ronald Kahn

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Figure 1

Effects of FGF21 on body and tissue weights.

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Effects of FGF21 on body and tissue weights. Control and LIRKO mice were...
Control and LIRKO mice were fed either a CD or an HFD for 7 weeks and were treated with saline or FGF21 (1 mg/kg/day) delivered s.c. by osmotic pump during the last 2 weeks of the diet. Body weight was measured once a week, and tissue weights were determined on day 14 after insertion of the pump. (A and B) Body weight gain of animals on a CD (A) or an HFD (B). Gray lines with squares represent control mice, black lines with triangles represent LIRKO mice, dashed lines represent saline-treated mice, and solid lines represent FGF21-treated mice. (C) Liver weight. White bars represent saline-treated mice on a CD, black bars represent FGF21-treated mice on a CD, light gray bars represent saline-treated mice on an HFD, and dark gray bars represent FGF21-treated mice on an HFD. (D and E) Lean mass (D) and fat mass (E) from DXA analysis. Light gray bars represent saline-treated mice on an HFD, and dark gray bars represent FGF21-treated mice on an HFD. Data represent the means ± SEM. P values were calculated using 2- or 3-way ANOVA. #P < 0.05 between genotypes; §P < 0.05 between diets; *P < 0.05 with FGF21 treatment. n = 5–12 animals per group.