title: Leptin-mediated decrease of cyclin A2 and increase of cyclin D1 expression: relevance for the control of prepubertal rat Leydig cell division and differentiation.
abstract: The number of adult Leydig cells is one of the factors controlling testosterone secretion by sexually mature testis, and it depends on the proliferative capacity of prepubertal Leydig cells. We investigated here whether this capacity is controlled by leptin because this hormone regulates proliferation in other cell types and has a crucial role in male fertility. Our data show that prebupertal Leydig cells express the Ob/Rb form of leptin receptor and are thus direct targets of this hormone. The analysis of G1/S-phase cyclins by quantitative (real-time) RT-PCR and Western blot points to the leptin-induced decrease in cyclin A2 and subsequent increase in cyclin D1 expression that precedes a leptin-triggered decrease in the number of prepubertal Leydig cells. Quantitative assessments of DNA synthesis by bromodeoxyuridine incorporation and of cycling cell population by Ki67 immunocytochemistry indicate that leptin decreases the cell number by inhibiting cell division and increases mRNA levels of Leydig cell differentiation markers such as relaxin-like factor. Immunohistochemistry of cyclin D1 and relaxin-like factor pointed to the parallel increase of their expression coinciding with the onset of Leydig cell differentiation. Moreover, leptin-treated Leydig cells display increased expression of another differentiation marker (3beta-hydroxysteroid dehydrogenase) that is abolished by knocking down cyclin D1 with small interference RNA. Altogether, our data show that leptin inhibits division of prepubertal Leydig cells via a cyclin D-independent mechanism and suggest that cyclin D1 might be involved in leptin-induced differentiation of Leydig cells.
authors.affiliation: Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité 29, Parc Scientifique de Luminy-BP13, F-13273 Marseille, Cedex 09, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Fombonne
authors.forename: Céline
authors.initials: C
authors.lastname: Charrier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Goddard
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Moyse
authors.forename: Slavica
authors.initials: S
authors.lastname: Krantic
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000367:Age Factors; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019925:Cyclin A / Q000235:genetics*; D056751:Cyclin A2; D056741:Cyclin D; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000235:genetics; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D007985:Leydig Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011506:Proteins / Q000235:genetics; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D012741:Sexual Maturation
chemical_list: C503722:Ccna2 protein, rat; C486197:Ccnd2 protein, rat; C534698:Ccnd3 protein, rat; D019925:Cyclin A; D056751:Cyclin A2; D056741:Cyclin D; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D007328:Insulin; D020738:Leptin; C084797:Leydig insulin-like protein; D011506:Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D015096:3-Hydroxysteroid Dehydrogenases