AgRP to Kiss1 neuron signaling links nutritional state and fertility

Significance

Women suffering from malnutrition and athletes with low body fat become infertile as a result of low gonadotropin secretion. Gonadotropin release is determined by a neural endocrine circuit; however, the metabolic cues that are responsible for attenuating this axis during starvation remain unclear. Here, we find that starvation-activated agouti-related peptide (AgRP) neurons can inhibit the reproductive neuroendocrine circuit. Furthermore, artificial activation of genetically defined AgRP neurons is sufficient to delay estrous cycle length and parturition in female mice. This work demonstrates a mechanism by which AgRP neurons can relay metabolic information to the fertility axis during starvation.

Abstract

Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1 ^AVPV, and arcuate hypothalamus, Kiss1 ^ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1 ^ARH and Kiss1 ^AVPV neurons. In agreement with this finding, Kiss1 ^ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.