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Title 

Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular leydig cells

Authors 

S W AhnGil Tae GangY D KimR S AhnR A HarrisChul Ho LeeH S Choi

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

2013

Citation 

Journal of Biological Chemistry, vol. 288, no. 22, pp. 15937-15946

Keywords 

Critical regionDiet-induced obesityInsulin receptorsInsulin resistanceLuteinizing hormonesNuclear receptorsRegulatory mechanismType-2 diabetes

Abstract 

Testosterone level is low in insulin-resistant type 2 diabetes. Whether this is due to negative effects of high level of insulin on the testes caused by insulin resistance has not been studied in detail. In this study, we found that insulin directly binds to insulin receptors in Leydig cell membranes and activates phosphoinsulin receptor-β (phospho-IR-β), phospho-IRS1, and phospho-AKT, leading to up-regulation of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene expression in the MA-10 mouse Leydig cell line. Insulin also inhibits cAMP-induced and liver receptor homolog-1 (LRH-1)-induced steroidogenic enzyme gene expression and steroidogenesis. In contrast, knockdown of DAX-1 reversed insulin-mediated inhibition of steroidogenesis. Whether insulin directly represses steroidogenesis through regulation of steroidogenic enzyme gene expression was assessed in insulin-injected mouse models and high fat diet-induced obesity. In insulin-injected mouse models, insulin receptor signal pathway was activated and subsequently inhibited steroidogenesis via induction of DAX-1 without significant change of luteinizing hormone or FSH levels. Likewise, the levels of steroidogenic enzyme gene expression and steroidogenesis were low, but interestingly, the level of DAX-1 was high in the testes of high fat diet-fed mice. These results represent a novel regulatory mechanism of steroidogenesis in Leydig cells. Insulin-mediated induction of DAX-1 in Leydig cells of testis may be a key regulatory step of serum sex hormone level in insulin-resistant states.

ISSN 

0021-9258

Link 

http://dx.doi.org/10.1074/jbc.M113.451773

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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