Insulin-Like Peptide 3 in Leydig Cells

Abstract

Insulin-like peptide 3 (INSL3) is a novel member of the insulin-relaxin family of structurally related peptides, which has evolved by sequential duplication from a common ancestor. INSL3 is expressed in large amount by fetal and adult-type Leydig cells, once these have attained a mature phenotype. Experimental evidence suggests that the expression of INSL3 is not acutely regulated, but rather reflects the differentiation status of the Leydig cells. As such it is not regulated by the acute response of the hypothalamic-pituitary-gonadal axis, but only in a chronic context, where LH is promoting Leydig cell differentiation. INSL3 can be measured in the male circulation with values for the human ranging between 0.5 and 2.5 ng/mL, all of which appears to derive from the testis. INSL3 acts through a G protein-coupled receptor called RXFP2 (relaxin family peptide receptor 2; previously called LGR8), which appears to be expressed in multiple tissues, including germ cells, where INSL3 seems to act as a survival or antiapoptotic factor. However, the principal function for INSL3, is in the male fetus, during the first phase of testicular descent, where INSL3 from the fetal Leydig cells promotes the growth and expansion of the gubernaculum, retaining the embryonic testis in the inguinal region. New research implicates the involvement of INSL3 downregulation in xenobiotic-induced cryptorchidism, following exposure of the pregnant mother to environmental endocrine disruption. However, there is as yet little evidence for the involvement of INSL3 or its receptor in natural human cryptorchidism. Note: for convenience, all references to INSL3 or its receptor make use of the human gene nomenclature, even for rodents.