成纤维细胞生长因子21（FGF21）疗法通过改善糖尿病前期大鼠的FGF21敏感性、心脏线粒体氧化还原稳态和结构变化，减轻左心室功能障碍和代谢紊乱。
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.
作者信息
Tanajak P, Sa-Nguanmoo P, Wang X, Liang G, Li X, Jiang C, Chattipakorn S C, Chattipakorn N
机构信息
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.
出版信息
Acta Physiol (Oxf). 2016 Aug;217(4):287-99. doi: 10.1111/apha.12698. Epub 2016 May 20.
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.
目的
成纤维细胞生长因子21（FGF21）作为一种代谢调节因子，具有心脏保护作用。然而，在肥胖、胰岛素抵抗大鼠的FGF21抵抗状态下，长期给予FGF21对心脏的影响尚未得到研究。我们假设，长期给予FGF21可降低肥胖、胰岛素抵抗大鼠的FGF21抵抗和胰岛素抵抗，并减轻心脏功能障碍。
方法
18只大鼠分别给予正常饮食（n = 6）或高脂饮食（HFD；n = 12）12周。然后，将HFD组大鼠分为两个亚组（每组n = 6），分别腹腔注射溶媒（HFV）或重组人FGF21（rhFGF21，0.1 mg kg-1 天-1；HFF），持续28天。测定代谢参数、炎症、丙二醛（MDA）、心率变异性（HRV）、左心室（LV）功能、心脏线粒体氧化还原稳态、心脏线粒体脂肪酸β-氧化（FAO）和抗凋亡信号通路。
结果
HFV大鼠出现血脂异常、胰岛素抵抗、血浆FGF21水平、TNF-α、脂联素和MDA升高，HRV降低，LV和线粒体功能受损。HFV大鼠心脏Bcl-2、心脏PGC-1α和CPT-1蛋白表达也降低。然而，FGF21恢复了HFF大鼠的代谢参数，降低了TNF-α和MDA，增加了血清脂联素，并改善了HRV、心脏线粒体和LV功能。此外，HFF大鼠心脏Bcl-2、心脏PGC-1α和CPT-1蛋白表达增加。
结论
长期FGF21治疗可减轻肥胖、胰岛素抵抗大鼠的FGF21抵抗和胰岛素抵抗，并通过激活抗凋亡和心脏线粒体FAO信号通路改善心脏代谢调节，从而发挥心脏保护作用。
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