Leptin's Role in Reproduction

Nutrition and leptin

Food availability is considered the single most important environmental factor that influences mammalian reproduction. The first recognized role for leptin was to send a negative feedback signal to the brain when energy stores were adequate, resulting in decreased food intake and increased energy expenditure. However, studies of animals that are leptin deficient revealed that leptin also plays a dynamic role in reproduction. The findings point to adipocytes as the main, if not the only, source of circulating leptin and are consistent with the tight association between circulating leptin and adiposity.

Leptin interactions with hypothalamic-pituitary-gonadal target cells

Leptin target cells in the hypothalamus. Stimulation by leptin is mediated by neurons in the ventral premammillary nucleus (PMV), which send connections to kisspeptin neurons in the anteroventral periventricular and caudal arcuate nuclei and stimulate Kiss1 expression by glutamate, PACAP or nitric oxide. Also, leptin normally inhibits the orexigenic AgRP-NPY-GABAergic neurons in the arcuate. When leptin signals are reduced (by food deprivation, for example), these neurons signal kisspeptin neurons in the AVPV and caudal arcuate, inhibiting the expression of Kiss1 by AgRP or GABA. These actions ultimately stimulate or inhibit GnRH neurons and modulate pulsatile activity to effect gonadotropin secretion and the LH surge.

Fig 1. Pathways for leptin's permissive actions in the hypothalamus.
(Source: Endocrinology, 2021)

Pituitary gonadotropes as leptin target cells. Leptin receptors on gonadotropes and somatotropes receive rising serum leptin which peaks at midcycle. Leptin stimulates gonadotropes to produce GnRHR proteins and Fshb and activin mRNAs in partnership with pulsatile GnRH and estradiol positive feedback. Leptin also stimulates the translation of GH and GHRHR proteins to support the cogonadotropic function of somatotropes.

Leptin's actions on gonadotropes: a role for Musashi. Musashi functions to regulate differentiated gonadotropes by mediating their expression of GnRHR. The data support the hypothesis that leptin functions to stimulate hormone expression in the gonadotrope, through its up regulation of GnRHR, activin, and Fshb mRNA levels. We propose that when nutrition is optimal, the midcycle rise in serum leptin would be permissive for the translation of Gnrhr mRNA resulting in an activated gonadotrope population.

Biphasic actions of leptin on target cells in the ovary. All ovarian follicular cells have leptin receptors and physiological levels of leptin stimulate granulosa and theca cells and oocyte maturation. Physiological levels of leptin stimulates, in partnership with growth factors (IGF-1), GH, and FSH, to promote the development of follicles to the antral stage. Leptin also promotes ovulation and oocyte maturation in partnership with LH. Leptin levels rise in association with rising estradiol from the follicles (granulosa cells). Leptin also acts with LH and growth factors to promote oocyte meiosis and formation of the polar body.

Testicular Leptin target cells: a little leptin goes a long way in the male. In the male, leptin is stimulatory before puberty. However, in the earlier section on sex differences in serum leptin levels, it was reported that adult males have relatively low serum leptin, when compared with females. Leptin levels in normal adult males are presumably limited by androgens, which inhibit secretion of adipocyte leptin. Leptin inhibits testicular function if serum levels rise above a certain threshold. However, with obesity levels of leptin, there was a dose-dependent decrease in acetate production, suggesting that rising leptin levels impair Sertoli cell nutritional support for spermatocytes.