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-P₄), Δ₄-androstenedione (Δ₄A) and testosterone (T) secretions were significantly lower in MSG than in CTR cells. Exposure to murine leptin (mleptin, 10^–8M) significantly inhibited hCG-elicited T secretion by CTR cells after 180 min incubation. While mleptin significantly inhibited hCG-stimulated Δ₄A output and the Δ₄A:17-OH-P₄ ratio of secretion, conversely, it failed to modify the ratio T:Δ₄A 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-P₄, Δ₄A 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.

Semen parameters and hormonal profile in obese fertile and infertile males

“…Elevated serum leptin in hypogonadal men (33,34) and elderly men (35) was shown to decrease during T replacement therapy. Giovambattista et al (36) suggested that leptin could affect both Leydig and Sertoli cells in the testis, but its direct effect might be only through Leydig cells. Ishikawa et al (24) showed that the ratio of leptin-immunostained germ cells to total germ cells was inversely correlated with serum T, sperm concentration, and Johnsen's score.…”

Immunohistochemical and hybridocytochemical study on ghrelin signalling in the rat seminiferous epithelium.

“…In mice a lack of ghrelin does not affect fertility. While mice lacking ghrelin are fertile the mice lacking functional leptin (ob/ob) or with mutation of leptin receptor are obese, infertile, and exhibit impaired spermatogenesis [59][60][61][62][63]. In turn, experimental hyperghrelinemia in prepubertal male rats decreased serum LH and testosterone concentration and delayed timing of puberty [64].…”

Roles of Ghrelin and Leptin in the Control of Reproductive Function

“…This inhibitory action was independently confirmed using primary cultures of rat Leydig cells and the murine mLTC-1 clone from Leydig cell origin [53, 54]. The molecular basis for the inhibitory effects of leptin on testosterone secretion likely involves the decreased expression levels of the mRNAs encoding key steroidogenic factors, such as steroidogenic factor-1 (SF-1), steroid acute regulatory (StAR) protein, and P450 side-chain cleavage (P450scc) enzyme, but not of those of 17β-hydroxyl steroid dehydrogenase (17β-HSD) type III [55].…”