Vitamin D Receptor affects male mouse fertility via regulation of lipid metabolism and testosterone biosynthesis in testis

Vitamin D and vitamin D receptor (VD/VDR) plays a vital role in the development of spermatozoa, which is largely determined by the testosterone level in serum. Testosterone biosynthesis is closely related to lipid metabolism in gonadal adipose around testes. VDR could regulate lipid metabolism in adipocytes as well. However, it still remains unknown how VDR regulates lipid metabolism to impact testosterone biosynthesis in testis. Hereby, various parameters of male fertility were compared between wildtype (WT) and Vdr knockout (Vdr-KO) male mouse. For Vdr-KO mice, the size of testis and gonadal adipose was smaller than that of WT, and the sperm quality and testosterone level were lower than WT. Subsequently, testis proteome data between Vdr-KO and WT mice indicated that dysregulation of lipid metabolism was closely associated with decreased testosterone biosynthesis in Vdr-deficient mouse. And further evaluation of VDR functions in Leydig cells verified that VDR impacted lipid metabolism and regulated the expression of a range of genes involved in testosterone biosynthesis. Knockdown VDR could significantly decrease testosterone synthesis and secretion in Leydig cells. Meanwhile, expression of genes involved in androgen synthesis was decreased but genes related to lipolysis were up-regulated. Collectively, the present study unveiled the relationship between lipid metabolism and testosterone biosynthesis mediated by VDR in mouse testis and its effect on male fertility. These findings will greatly enhance our current understanding of VDR intermediate in lipid metabolism and androgen synthesis.