Leptin in male reproduction: the testis paradigm

Abstract

Leptin, the adipocyte-derived hormone that plays a key role in body weight homeostasis, has recently emerged as a relevant neuroendocrine mediator in different systems, including the reproductive axis. Thus, compelling evidence points out a major role of leptin in the regulation of female pubertal development and fertility, both in humans and experimental animals. The contribution of leptin to the proper functioning of the male reproductive system has been less clear. However, data gathered in recent years, from independent groups and through a variety of experimental approaches, strongly suggest that leptin is able to act at different levels of the hypothalamic-pituitary-testicular axis. Herein, we review the biological effects and potential mechanisms of action of leptin upon rodent testis. Leptin appears to act as a direct inhibitory signal for testicular steroidogenesis, which may be relevant to explain the link between decreased testosterone secretion and hyperleptinaemia in obese men. Analysis of the molecular basis for leptin-induced inhibition of testosterone secretion revealed the potential involvement of decreased gene expression of several up-stream factors (e.g. SF-1, StAR and P450scc) in the steroidogenic pathway. In this context, testicular expression of leptin receptor (Ob-R) gene shows a complex pattern of alternative splicing with generation of multiple variants, including the functional leptin receptor type-b (Ob-Rb) and several short isoforms. Moreover, Ob-R mRNA expression in rat testis was regulated by homologous (leptin) as well as heterologous (gonadotropins) signals. Overall, the current data indicate that the testis is a direct target for leptin actions. Furthermore, the available evidence is suggestive of a tightly regulated, complex mode of action of leptin at different levels of the male gonadal axis that involves not only stimulatory but also inhibitory effects.