Elsevier

Molecular Metabolism

Volume 6, Issue 6, June 2017, Pages 471-481
Molecular Metabolism

Original Article
FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis

https://doi.org/10.1016/j.molmet.2017.04.001Get rights and content
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open access

Highlights

  • FGF21 reduces adiposity and improves insulin resistance in mice fed a high-fat diet.

  • FGF21 improves insulin sensitivity and hepatic steatosis independent of adipocyte AMPK.

  • FGF21 treatment does not elicit an increase in browning of BAT or WAT.

  • In contrast to metformin, FGF21's intracellular mechanism is not through AMPK/ACC.

  • Findings suggest that combination of FGF21 and AMPK activators could be of benefit.

Abstract

Objective

Fibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight and improves lipid profiles of participants in clinical studies; however, the intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor of the cell and a molecular target for anti-diabetic medications. This work examined the role of AMPK in mediating the glucose and lipid-lowering effects of FGF21.

Methods

Inducible adipocyte AMPK β1β2 knockout mice (iβ1β2AKO) and littermate controls were fed a high fat diet (HFD) and treated with native FGF21 or saline for two weeks. Additionally, HFD-fed mice with knock-in mutations on the AMPK phosphorylation sites of acetyl-CoA carboxylase (ACC)1 and ACC2 (DKI mice) along with wild-type (WT) controls received long-acting FGF21 for two weeks.

Results

Consistent with previous studies, FGF21 treatment significantly reduced body weight, adiposity, and liver lipids in HFD fed mice. To add, FGF21 improved circulating lipids, glycemic control, and insulin sensitivity. These effects were independent of adipocyte AMPK and were not associated with changes in browning of white (WAT) and brown adipose tissue (BAT). Lastly, we assessed whether FGF21 exerted its effects through the AMPK/ACC axis, which is critical in the therapeutic benefits of the anti-diabetic medication metformin. ACC DKI mice had improved glucose and insulin tolerance and a reduction in body weight, body fat and hepatic steatosis similar to WT mice in response to FGF21 administration.

Conclusions

These data illustrate that the metabolic improvements upon FGF21 administration are independent of adipocyte AMPK, and do not require the inhibitory action of AMPK on ACC. This is in contrast to the anti-diabetic medication metformin and suggests that the treatment of obesity and diabetes with the combination of FGF21 and AMPK activators merits consideration.

Keywords

FGF21
AMPK
ACC
Adipocyte
Brown fat
Obesity
Diabetes

Abbreviations

ACC
acetyl-CoA carboxylase
ACC DKI
ACC1-S79A and ACC2-S212A double knock-in
AKT
protein kinase B
AMPK
AMP-activated protein kinase
BAT
brown adipose tissue
COX
cytochrome c oxidase
CreERT2
Cre recombinase – estrogen receptor T2
CNS
central nervous system
DAG
diacylglycerol
FFA
free fatty acid
FGF21
fibroblast growth factor 21
FGFR1c
fibroblast growth factor receptor 1c
GTT
glucose tolerance test
gWAT
gonadal white adipose tissue
H&E
hematoxylin and eosin
HFD
high fat diet
iβ1β2AKO
inducible AMPK β1β2 adipocyte knockout
ITT
insulin tolerance test
iWAT
inguinal white adipose tissue
KLB
beta klotho
RER
respiratory exchange ratio
mTORC1
mammalian target of rapamycin
NAFLD
non-alcoholic fatty liver disease
TAG
triacylglycerol
UCP1
uncoupling protein 1
WAT
white adipose tissue
WT
wildtype

Cited by (0)

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Emilio P. Mottillo and Eric M. Desjardins contributed equally to this work.