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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 AMPK\u03b11\/2, AKT2, or NRF2 with their siRNAs revealed that FGF21 protected cardiomyocytes from HG\/Pal partially via upregulating AMPK\u2013AKT2\u2013NRF2-mediated antioxidative pathway. Additionally, knockdown of AMPK suppressed fatty acid \u03b2-oxidation via inhibition of ACC\u2013CPT-1 pathway. And, inhibition of fatty acid \u03b2-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\u2013AKT2\u2013NRF2-mediated antioxidative pathway and AMPK\u2013ACC\u2013CPT-1-mediated lipid-lowering effect in the heart.<\/jats:p>","DOI":"10.1038\/s41419-018-0307-5","type":"journal-article","created":{"date-parts":[[2018,2,14]],"date-time":"2018-02-14T07:01:09Z","timestamp":1518591669000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart"],"prefix":"10.1038","volume":"9","author":[{"given":"Hong","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyun","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sundong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lechu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemian","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,2,14]]},"reference":[{"key":"307_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s11154-010-9131-7","volume":"11","author":"S Boudina","year":"2010","unstructured":"Boudina, S. & Abel, E. 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