Figure 5.

Pathways in the reproductive axis and the critical leptin targets that must be activated for reproductive competence. The pathway in green is proposed based on the evidence that leptin stimulates activin mRNA (Figure 2) and that activin mRNA is reduced in leptin receptor (LEPR)-null gonadotropes (33). It is also based on evidence that restoration of LEPR in LEPR-null gonadotropes results in elevated follicle-stimulating hormone (FSH) (101) as activin is important for FSH synthesis. We propose that this well-established FSH-driven pathway provides the stimulation to the follicle that results in a rise in estradiol needed early in the cycle to promote responses from GnRH neurons and gonadotropes. The red pathway is focused on the well-established circuitry in which leptin regulates LEPR-target neurons in the hypothalamus to stimulate GnRH neurons. It is based on evidence from key studies showing that restoration of LEPR in the PMV improves fertility (50, 82). The pathway shows that GnRH pulses are needed for transcription of Gnrhr mRNA as well as transcription and translation of LH and FSH. The blue pathway is based on our recent studies showing that mice lacking LEPR in gonadotropes are subfertile (33) or infertile (Figure 1; Table 1) and have significantly reduced gonadotropin releasing hormone receptor (GnRHR) proteins, but not mRNA levels (33). We hypothesize that leptin plays a direct post-transcriptional role in de-repressing mRNA translation by inhibiting miRNAs and/or MSI1, which then allows activation of Gnrhr mRNA translation.