Volume 6, Issue 6, June 2017, Pages 471–481

Open Access
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

  • 1 Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8N 3Z5, Canada
  • 2 Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8N 3Z5, Canada
  • 3 Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark
  • 4 Wayne State University School of Medicine, Detroit, MI, 48201, USA
  • 5 Liver Disease Research, Takeda Pharmaceuticals, 35 Landsdowne Street, Cambridge, MA, 02139, USA
  • 6 Cardiovascular & Metabolic Diseases, Novartis Institute of Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA
  • 7 Cardiometabolic Diseases, Merck Research Laboratories South San Francisco LLC, 630 Gateway Boulevard, South San Francisco, CA, 94080, USA

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