Interplay between FGF21 and insulin action in the liver regulates metabolism
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
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
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 3

Effect of FGF21 on gluconeogenesis and glucose uptake in skeletal muscle and BAT.

Options: View larger image (or click on image) Download as PowerPoint
Effect of FGF21 on gluconeogenesis and glucose uptake in skeletal muscle...
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. (A) Pyruvate challenge test. Gray lines with squares represent control mice; black lines with triangles represent LIRKO mice; dashed lines represent saline-treated mice; solid lines represent FGF21-treated mice. (B) Gene expression in liver was assessed by real-time qPCR. P value was determined by nonparametric tests. 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. (C and D) In vivo glucose uptake was assessed by measuring [14C]DOG uptake in (C) skeletal muscle and (D) iBAT, with or without insulin stimulation, in animals on a CD. P value for D was determined by 3-way ANOVA. White bars represent saline treatment; black bars represent FGF21 treatment. Data represent the means ± SEM. #P < 0.05 between genotypes; *P < 0.05 with FGF21 treatment; §P < 0.05 upon insulin stimulation. n = 6–12 animals per group.