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Existing animal models, such as streptozotocin (STZ)-induced models, suffer from high mortality and fail to replicate chronic metabolic dysregulation induced by high-fat diets (HFD), whereas HFD or HFD\/STZ-combined rodent models require high maintenance costs. This study aimed to establish a zebrafish HFD-DCM model to facilitate mechanistic exploration and drug discovery. Methods: Eighty wild-type female zebrafish were divided into normal diet (N, 6% fat) and HFD (H, 24% fat) groups and fed the diet for 8 weeks. Metabolic phenotypes were evaluated using intraperitoneal glucose tolerance tests and insulin level analysis. Cardiac function was assessed by using echocardiography (ejection fraction, E peak). Structural, metabolic, and oxidative stress alterations were analyzed by histopathology (H&amp;E, Masson, and Oil Red O staining), molecular assays (RT-qPCR, Western blotting), and mitochondrial structure\/function evaluations (respiratory chain activity, transmission electron microscopy, and DHE staining). Results: HFD-fed zebrafish developed obesity, insulin resistance, and impaired glucose tolerance. Echocardiography revealed cardiac hypertrophy, reduced ejection fraction, and diastolic dysfunction. Excessive lipid accumulation, upregulated fibrosis\/inflammatory markers, impaired mitochondrial respiration, elevated reactive oxygen species levels, and a disrupted redox balance were observed. Conclusions: We established a female zebrafish HFD model that recapitulates human DCM features, including hypertrophy, metabolic dysregulation, fibrosis, inflammation, and mitochondrial dysfunction. This model offers novel insights into DCM pathogenesis and serves as a valuable platform for mechanistic studies and targeted drug screening.<\/jats:p>","DOI":"10.3390\/nu17132209","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T04:35:52Z","timestamp":1751517352000},"page":"2209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["High-Fat Diet-Induced Diabetic Cardiomyopathy in Female Zebrafish: Cardiac Pathology and Functional Decline Mediated by Type 2 Diabetes"],"prefix":"10.3390","volume":"17","author":[{"given":"Shuaiwang","family":"Huang","sequence":"first","affiliation":[{"name":"College of Physical Education, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0724-6989","authenticated-orcid":false,"given":"Zhanglin","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoming","family":"Li","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3737-0198","authenticated-orcid":false,"given":"Yunyi","family":"Zou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bihan","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan Center for Public Sports Service Research, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuoqiong","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Physical Education, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1307-9785","authenticated-orcid":false,"given":"Xiyang","family":"Peng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Physical Fitness and Exercise Rehabilitation of Hunan Province, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfa","family":"Tang","sequence":"additional","affiliation":[{"name":"Hunan Center for Public Sports Service Research, Hunan Normal University, Changsha 410012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1002\/ehf2.14224","article-title":"Diabetic cardiomyopathy: A brief summary on lipid toxicity","volume":"10","author":"Ke","year":"2023","journal-title":"ESC Heart Fail."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00125-017-4390-4","article-title":"Diabetic cardiomyopathy: A hyperglycaemia- and insulin-resistance-induced heart disease","volume":"61","author":"Jia","year":"2018","journal-title":"Diabetologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1007\/s00125-005-1755-x","article-title":"Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats","volume":"48","author":"Ouwens","year":"2005","journal-title":"Diabetologia"},{"key":"ref_4","first-page":"151","article-title":"Predictors and prevention of diabetic cardiomyopathy","volume":"6","author":"Chavali","year":"2013","journal-title":"Diabetes Metab. 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