title: Modulatory effects of leptin on leydig cell function of normal and hyperleptinemic rats.
abstract: Neonatal L-monosodium glutamate (MSG) administration in rats induces several neuroendocrine and metabolic disruptions. Leptin, the adipocyte product, modulates several neuroendocrine systems including the hypothalamic-pituitary-gonadal (HPG) axis in mammals. The aim of the present study was to determine whether MSG-induced chronic hyperleptinemia could play any relevant role in the hypogonadism developed by male rats when examined in adulthood. We found that 120-day-old MSG male rats displayed significant hyperleptinemia, hypogonadism, and undisturbed basic testis structure and spermatogenesis. In vitro studies in purified Leydig cells from normal (CTR) and MSG-damaged rats revealed that basal and human chorionic gonadotropin (hCG)-stimulated 17-hydroxy-progesterone (17-HO-P(4)), Delta(4)-androstenedione (Delta(4)A) and testosterone (T) secretions were significantly lower in MSG than in CTR cells. Exposure to murine leptin (Mleptin, 10(-8)M) significantly inhibited hCG-elicited T secretion by CTR cells after 180 min incubation. While Mleptin significantly inhibited hCG-stimulated Delta(4)A output and the Delta(4)A:17-OH-P(4) ratio of secretion, conversely, it failed to modify the ratio T:Delta(4)A release by CTR Leydig cells. Interestingly, the effects of Mleptin found on CTR Leydig cells were absent in MSG Leydig cells. Finally, endogenous hyperleptinemia was associated with a significant decrease in Leydig cell expression of Ob-Rb mRNA in MSG rats. In summary, this study demonstrates that: (1) Mleptin inhibited testicular steroidogenesis in CTR rats; (2) MSG-treated rats showed lower in vitro 17-OH-P(4), Delta(4)A and T production under basal and post-hCG stimulation conditions; (3) purified Leydig cells from MSG-treated rats displayed resistance to the inhibitory action of Mleptin on T release, and (4) endogenous leptin exerts a modulatory effect on Leydig cell Ob-Rb mRNA expression. The inhibitory effect of leptin on testicular function is thus abrogated in MSG-damaged rats. The testicular leptin-resistance developed by MSG rats seems to be due to early chronic exposure of Leydig cells to high leptin circulating levels, which in turn down-regulate testicular Ob-Rb expression. It remains to be determined whether the testicular dysfunction of MSG rats can be reversed after correction of hyperleptinemia or whether it is an irreversible effect of the hypothalamic lesion.
authors.affiliation: Instituto Multidisciplinario de Biología Celular, La Plata, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Giovambattista
authors.forename: María O
authors.initials: MO
authors.lastname: Suescun
authors.forename: Claudio C D L
authors.initials: CC
authors.lastname: Nessralla
authors.forename: Luiz R
authors.initials: LR
authors.lastname: França
authors.forename: Eduardo
authors.initials: E
authors.lastname: Spinedi
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Calandra
mesh_terms: D000704:Analysis of Variance; D000737:Androstenols / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D001835:Body Weight; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005640:Follicle Stimulating Hormone / Q000032:analysis; D007006:Hypogonadism / Q000139:chemically induced / Q000503:physiopathology; D020738:Leptin / Q000097:blood* / Q000502:physiology; D007985:Leydig Cells / Q000473:pathology / Q000502:physiology*; D007986:Luteinizing Hormone / Q000032:analysis; D008297:Male; D051379:Mice; D009929:Organ Size; D012333:RNA, Messenger / Q000096:biosynthesis; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012970:Sodium Glutamate; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000032:analysis; D013974:Thyroxine / Q000097:blood
chemical_list: D000737:Androstenols; C515448:LEPR protein, human; D020738:Leptin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; C000152:androsta-5,16-dien-3 beta-ol; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013974:Thyroxine; D012970:Sodium Glutamate