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

Mol Metab. 2017 Apr 5;6(6):471-481. doi: 10.1016/j.molmet.2017.04.001. eCollection 2017 Jun.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Acetyl-CoA Carboxylase / metabolism*
  • Adipocytes / metabolism
  • Animals
  • Fibroblast Growth Factors / pharmacology*
  • Glucose / metabolism*
  • Homeostasis
  • Lipid Metabolism / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*

Substances

  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • Protein Kinases
  • AMP-Activated Protein Kinase Kinases
  • Acetyl-CoA Carboxylase
  • Glucose