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.
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.



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.



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.



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.
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
P
P
Tanajak
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
P
P
Sa-Nguanmoo
School of Pharmaceutical Sciences, Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, China.
X
X
Wang
School of Pharmaceutical Sciences, Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, China.
G
G
Liang
School of Pharmaceutical Sciences, Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, China.
X
X
Li
School of Pharmaceutical Sciences, Wenzhou Medical University, University-Town, Wenzhou, Zhejiang, China.
C
C
Jiang
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.|Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
S C
SC
Chattipakorn
Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.|Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand.
N
N
Chattipakorn
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000627:therapeutic use*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D011236:Prediabetic State / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology
D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D005227:Fatty Acids; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
FGF21 resistance; cardiac function; fatty acid β-oxidation; fibroblast growth factor 21 (FGF21); mitochondria; obesity-insulin resistance