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However, it remains unclear whether IF can alleviate metabolic disorder-induced male infertility. The aim of this study was to investigate the potential of IF to improve fertility outcomes in obese mice. Methods: Eight-week-old C57BL\/6J mice were fed a high-fat diet (HFD) for 24 weeks to induce obesity, followed by alternate-day fasting for 6 weeks. We assessed obesity-related metabolic changes and fertility issues postintervention. Comprehensive metabolomic and transcriptomic analyses of serum and testicular samples were used to identify significant metabolic pathway modifications attributable to IF. Results: IF effectively alleviated obesity-induced male infertility, demonstrating significant attenuation of body weight gain and restoration of testicular morphology. IF normalized hypogonadism-associated testosterone depletion and improved sperm parameters. Testis multi-omics integration revealed IF-mediated reprogramming of testicular purine metabolism, coupled with coordinated regulation of glycolipid metabolism and inflammatory-immune homeostasis. Reproductive competence was enhanced as evidenced by statistically elevated successful mating rates and embryonic developmental progression. Serum metabolomics further identified metabolites involved in amino acid metabolism, glycolipid metabolism, and inflammation (e.g., methionine, BCAA, glutathione, and spermidine) may serve as potential targets for treating obesity-related metabolic disorders. Additionally, multidimensional analysis highlighted the crucial role of allantoin in alleviating obesity and related reproductive dysfunction. Conclusions: IF not only resolves obesity-induced metabolic issues but also alleviates male infertility by regulating bioactive metabolites and gene expression linked to glycolipid metabolism, energy homeostasis, and immune responses in the testis. Our study provides a theoretical basis for IF as a clinical treatment for obesity-induced male infertility.<\/jats:p>","DOI":"10.3390\/nu17061029","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:07:51Z","timestamp":1741957671000},"page":"1029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Integrated Multiomics Analyses Reveal Molecular Insights into How Intermittent Fasting Ameliorates Obesity and Increases Fertility in Male Mice"],"prefix":"10.3390","volume":"17","author":[{"given":"Shuyu","family":"Zhang","sequence":"first","affiliation":[{"name":"The International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory of Embryo Original Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China"},{"name":"Shanghai Key Laboratory of Reproduction and Development, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics, Ministry of Education, Department of Reproductive Endocrinology, Women\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Bao","sequence":"additional","affiliation":[{"name":"Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junsen","family":"She","sequence":"additional","affiliation":[{"name":"International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Reproductive Genetics, Ministry of Education, Department of Reproductive Endocrinology, Women\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxue","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Department of Psychiatry of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aibing","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Department of Psychiatry of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Reproduction and Development, Shanghai 200030, China"},{"name":"Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200030, China"},{"name":"Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hefeng","family":"Huang","sequence":"additional","affiliation":[{"name":"The International Peace Maternity and Child Health Hospital, Shanghai Key Laboratory of Embryo Original Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China"},{"name":"Shanghai Key Laboratory of Reproduction and Development, Shanghai 200030, China"},{"name":"Key Laboratory of Reproductive Genetics, Ministry of Education, Department of Reproductive Endocrinology, Women\u2019s Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China"},{"name":"International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, China"},{"name":"Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai 200030, China"},{"name":"Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155217","DOI":"10.1016\/j.metabol.2022.155217","article-title":"A 2022 update on the epidemiology of obesity and a call to action: As its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on","volume":"133","author":"Boutari","year":"2022","journal-title":"Metabolism"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1111\/dom.15238","article-title":"Meinian Investigator Group: Prevalence of obesity and associated complications in China: A cross-sectional, real-world study in 15.8 million adults","volume":"25","author":"Chen","year":"2023","journal-title":"Diabetes Obes. 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