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.
View: Text | PDF | Corrigendum
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

×

Figure 2

Glycemia, insulinemia, and insulin signaling in mice treated with FGF21.

Options: View larger image (or click on image) Download as PowerPoint
Glycemia, insulinemia, and insulin signaling in mice treated with FGF21....
Control and LIRKO mice on a CD or an HFD for 7 weeks were treated with saline or FGF21 (1 mg/kg/day) delivered s.c. by osmotic pump during the last 2 weeks of the diet. Metabolic parameters (A and B) and insulin signaling (C–E) were determined on day 14 after pump insertion. Data represent the means ± SEM. P values were determined by nonparametric statistical tests. #P < 0.05 between genotypes; *P < 0.05 with FGF21 treatment. 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. (A) Fed glucose was reduced by 40% with FGF21 treatment (223.5 ± 16.1 mg/dl to 133.7 ± 5.9 mg/dl) in LIRKO mice on a CD and by 44% (242.8 ± 22.0 mg/dl to 137.7 ± 5.3 mg/dl) in LIRKO mice on an HFD. (B) Administration of FGF21 to LIRKO mice reduced insulin levels from 21.8 ± 4.5 ng/ml to 3 ± 0.7 ng/ml in mice on a CD and from 35 ± 5.4 ng/ml to 3 ± 0.7 ng/ml in mice on an HFD. n = 10–20 animals per group. (C–E) Insulin signaling in vivo. Data shown are for 4 mice in each group of 5 to 7 animals. Total lysates obtained from liver (C), skeletal muscle (D), or s.c. adipose tissue (E) from control or LIRKO mice on a CD or an HFD and treated with saline or FGF21 before insulin injection were immunoblotted with various antibodies against insulin signaling molecules as indicated.