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Alteration in iron efflux affects male sex hormone testosterone biosynthesis in a diet-induced obese rat model
- KurniawanThese authors contributed equally to this work., Adi Lukas, Lee, Yu-Chieh, Shih, Chun-Kuang, Hsieh, Rong-Hong, Chen, Seu-Hwa, Chang, Jung-Su
- Food & function 2019 v.10 no.7 pp. 4113-4123
- Western blotting, adults, animal disease models, apoptosis, biogenesis, biosynthesis, diet, germ cells, hepcidin, iron, iron overload, laboratory animals, lipid content, males, men, mitochondria, obesity, proteins, rats, staining, testes, testosterone, therapeutics
- This study was motivated by clinical observations that dysmetabolic iron overload syndrome (DIOS) and an androgen deficiency are common features observed in obese adult men; however, the molecular mechanism underlying the effects of DIOS on androgen deficiency remains to be elucidated. We established a DIOS animal model by feeding Sprague-Dawley rats an iron/fat-enriched diet (50% fat plus 0.25, 1, or 2 g ferric iron per kg diet) for 12 weeks to induce iron dysfunction (indicated by decreased tissue iron efflux) in obese rats. Obese rats fed an iron/fat-enriched diet showed decreased levels of testicular total Testosterone (T) and iron exporter ferroportin but increased levels of testicular iron and hepcidin, and these effects were more evident with a >1 g ferric iron per kg diet. A western blot analysis showed that an iron/fat-enriched diet triggered testicular endoplasmic reticular (ER) stress but decreased mitochondrion biogenesis proteins (PGC1α and TFAM) and T-converting proteins (StAR, CYP11A, and 17β-HSD). TUNEL staining showed that >1 g ferric iron induced apoptosis mainly in germ cells and Leydig's cells. Uncontrolled testicular iron efflux may cause mitochondrial-ER dysfunction and affect T biosynthesis. Future study targeting the testicular hepcidin–ferroportin axis may offer a therapeutic tool to alleviate testicular iron retention and mitochondrial-ER stress in Leydig's cells.