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

Seung Won Ahn, Gil Tae Gang, Yong Deuk Kim, Ryun Sup Ahn, Robert Harris, Chul Ho Lee, Hueng Sik Choi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)15937-15946
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number22
DOIs
StatePublished - May 31 2013

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DAX-1 Orphan Nuclear Receptor
Leydig Cells
Insulin
Gene expression
Gene Expression
Testis
Insulin Receptor
High Fat Diet
Nutrition
Enzymes
Fats
X-Linked Genes
Gonadal Steroid Hormones
Luteinizing Hormone

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells. / Ahn, Seung Won; Gang, Gil Tae; Kim, Yong Deuk; Ahn, Ryun Sup; Harris, Robert; Lee, Chul Ho; Choi, Hueng Sik.

In: Journal of Biological Chemistry, Vol. 288, No. 22, 31.05.2013, p. 15937-15946.

Research output: Contribution to journalArticle

Ahn, Seung Won ; Gang, Gil Tae ; Kim, Yong Deuk ; Ahn, Ryun Sup ; Harris, Robert ; Lee, Chul Ho ; Choi, Hueng Sik. / Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 22. pp. 15937-15946.
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