title: Insulin directly regulates steroidogenesis via induction of the orphan nuclear receptor DAX-1 in testicular Leydig cells.
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 phospho-insulin 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.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Seung Won
authors.initials: SW
authors.lastname: Ahn
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.forename: Ryun-Sup
authors.initials: RS
authors.lastname: Ahn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D002460:Cell Line; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis* / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D007985:Leydig Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004041:Dietary Fats; D012739:Gonadal Steroid Hormones; D007328:Insulin; C539966:Nr0b1 protein, mouse; D011972:Receptor, Insulin
keywords: DAX-1; Diabetes; Insulin; Insulin resistance; Nuclear receptors; Steroidogenesis