Fibroblast growth factor 21 (FGF21) therapy attenuates left ventricular dysfunction and metabolic disturbance by improving FGF21 sensitivity, cardiac mitochondrial redox homoeostasis and structural changes in pre-diabetic rats

Acta Physiol (Oxf). 2016 Aug;217(4):287-99. doi: 10.1111/apha.12698. Epub 2016 May 20.

Abstract

Aims: Fibroblast growth factor 21 (FGF21) acts as a metabolic regulator and exerts cardioprotective effects. However, the effects of long-term FGF21 administration on the heart under the FGF21-resistant condition in obese, insulin-resistant rats have not been investigated. We hypothesized that long-term FGF21 administration reduces FGF21 resistance and insulin resistance and attenuates cardiac dysfunction in obese, insulin-resistant rats.

Methods: Eighteen rats were fed on either a normal diet (n = 6) or a high-fat diet (HFD; n = 12) for 12 weeks. Then, rats in the HFD group were divided into two subgroups (n = 6 per subgroup) and received either the vehicle (HFV) or recombinant human FGF21 (rhFGF21, 0.1 mg kg(-1) day(-1) ; HFF) injected intraperitoneally for 28 days. The metabolic parameters, inflammation, malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, cardiac mitochondrial redox homoeostasis, cardiac mitochondrial fatty acid β-oxidation (FAO) and anti-apoptotic signalling pathways were determined.

Results: HFV rats had increased dyslipidaemia, insulin resistance, plasma FGF21 levels, TNF-α, adiponectin and MDA, depressed HRV, and impaired LV and mitochondrial function. HFV rats also had decreased cardiac Bcl-2, cardiac PGC-1α and CPT-1 protein expression. However, FGF21 restored metabolic parameters, decreased TNF-α and MDA, increased serum adiponectin, and improved HRV, cardiac mitochondrial and LV function in HFF rats. Moreover, HFF rats had increased cardiac Bcl-2, cardiac PGC-1α and CPT-1 protein expression.

Conclusion: Long-term FGF21 therapy attenuates FGF21 resistance and insulin resistance and exerts cardioprotection by improving cardiometabolic regulation via activating anti-apoptotic and cardiac mitochondrial FAO signalling pathways in obese, insulin-resistant rats.

Keywords: FGF21 resistance; cardiac function; fatty acid β-oxidation; fibroblast growth factor 21 (FGF21); mitochondria; obesity-insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cytokines / blood
  • Diet, High-Fat / adverse effects
  • Echocardiography
  • Fatty Acids / metabolism
  • Fibroblast Growth Factors / therapeutic use*
  • Homeostasis / drug effects
  • Humans
  • Insulin Resistance
  • Male
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism*
  • Oxidation-Reduction
  • Prediabetic State / drug therapy*
  • Prediabetic State / metabolism
  • Prediabetic State / physiopathology
  • Rats
  • Rats, Wistar
  • Recombinant Proteins
  • Ventricular Dysfunction, Left / diagnostic imaging
  • Ventricular Dysfunction, Left / drug therapy*
  • Ventricular Dysfunction, Left / physiopathology

Substances

  • Apoptosis Regulatory Proteins
  • Cytokines
  • Fatty Acids
  • Recombinant Proteins
  • fibroblast growth factor 21
  • Fibroblast Growth Factors