Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart

Abstract

Our previous studies showed that both exogenous and endogenous FGF21 inhibited cardiac apoptosis at the early stage of type 1 diabetes. Whether FGF21 induces preventive effect on type 2 diabetes-induced cardiomyopathy was investigated in the present study. High-fat-diet/streptozotocin-induced type 2 diabetes was established in both wild-type (WT) and FGF21-knockout (FGF21-KO) mice followed by treating with FGF21 for 4 months. Diabetic cardiomyopathy (DCM) was diagnosed by significant cardiac dysfunction, remodeling, and cardiac lipid accumulation associated with increased apoptosis, inflammation, and oxidative stress, which was aggravated in FGF21-KO mice. However, the cardiac damage above was prevented by administration of FGF21. Further studies demonstrated that the metabolic regulating effect of FGF21 is not enough, contributing to FGF21-induced significant cardiac protection under diabetic conditions. Therefore, other protective mechanisms must exist. The in vivo cardiac damage was mimicked in primary neonatal or adult mouse cardiomyocytes treated with HG/Pal, which was inhibited by FGF21 treatment. Knockdown of AMPKα1/2, AKT2, or NRF2 with their siRNAs revealed that FGF21 protected cardiomyocytes from HG/Pal partially via upregulating AMPK–AKT2–NRF2-mediated antioxidative pathway. Additionally, knockdown of AMPK suppressed fatty acid β-oxidation via inhibition of ACC–CPT-1 pathway. And, inhibition of fatty acid β-oxidation partially blocked FGF21-induced protection in cardiomyocytes. Further, in vitro and in vivo studies indicated that FGF21-induced cardiac protection against type 2 diabetes was mainly attributed to lipotoxicity rather than glucose toxicity. These results demonstrate that FGF21 functions physiologically and pharmacologically to prevent type 2 diabetic lipotoxicity-induced cardiomyopathy through activation of both AMPK–AKT2–NRF2-mediated antioxidative pathway and AMPK–ACC–CPT-1-mediated lipid-lowering effect in the heart.

Fibroblast growth factor 21 in chronic kidney disease

“…As a cardiomyokine, FGF21 is expressed and released by cardiomyocytes under stressful conditions, and protects against isoproterenol, ischemia and doxorubicin-induced myocardial damage, reducing inflammation, apoptosis and remodeling [81–84]. FGF21 is also protective against diabetic cardiomyopathy; FGF21 −/− diabetic mice show earlier and more severe cardiac dysfunction, remodeling and oxidative stress, as well as greater increase in cardiac lipid accumulation, which can be prevented by rFGF21 treatment [85–87]. Additionally, fenofibrate (a PPARα agonist) increased cardiac expression of FGF21 and prevented diabetes-induced cardiac dysfunction, inflammation and remodeling in wild-type diabetic mice, but not in FGF21 −/− mice, indicating that FGF21 might mediate fenofibrate cardio-protective effects [88].…”

“…Additionally, fenofibrate (a PPARα agonist) increased cardiac expression of FGF21 and prevented diabetes-induced cardiac dysfunction, inflammation and remodeling in wild-type diabetic mice, but not in FGF21 −/− mice, indicating that FGF21 might mediate fenofibrate cardio-protective effects [88]. In vitro studies showed that FGF21 protects cardiomyocytes by increasing antioxidant, autophagy and mitochondrial biogenesis and oxidative capacities, reducing ER stress and suppressing inflammatory and apoptosis pathways [85, 87–90]. …”

Heparin‐poloxamer hydrogel‐encapsulated rhFGF21 enhances wound healing in diabetic mice

“…However, to the best of our knowledge, no research has shown that FGF21 can repair skin wounds. Because FGF21 has anti-inflammatory abilities, regulates metabolism, and promotes the repair of some injuries (20,21), we hypothesized that FGF21 may enhance skin wound healing in diabetic mice. However, growth factors rapidly degrade in vivo, and therefore, we needed a suitable delivery vehicle to maintain the biologic activity and bioavailability of growth factors, transport them safely to the wound, and control their release.…”

“…FGF21 has been reported to improve photoreceptor function by reducing photoreceptor oxidative stress and inflammation through metabolism regulation (20). Moreover, FGF21 can improve cardiac function in T2DMinduced cardiomyopathy (21) by regulating metabolic disruption. The skin wound healing process requires cell proliferation and cell stroma formation.…”

The FGF metabolic axis

“…In addition to the liver, pancreas, and adipose tissues, cardiac muscle produces FGF21 in response to cardiac stress, cardio exercise, and endurance training [126,127], which then speeds up glucose uptake, lipid catabolism, and energy metabolism, and protects against cardiovascular stress damage, apoptosis, and heart dysfunctions, such as cardiac hypertrophy, myopathy, steatosis, ischemic infarction, and atherosclerosis [128][129][130][131][132]. Through a multiorgan crosstalk, hepatic FGF21 drives the expression of angiotensin-converting enzyme 2 in adipocytes and renal cells, which hydrolyzes angiotensin II to active vasodilator angiotensin-(1-7) in the renin-angiotensin system, thereby alleviating angiotensin II-associated hypertension and reversing vascular damage [133].…”