Central Infusion of Agouti-Related Peptide Suppresses Pulsatile Luteinizing Hormone Release in the Ovariectomized Rhesus Monkey

Abstract

Agouti-related peptide (AGRP), an endogenous melanocortin receptor antagonist, is a powerful orexigenic peptide when infused centrally. AGRP and neuropeptide Y (NPY), another orexigenic peptide, are colocated within the same neurons in the arcuate nucleus. Both NPY and AGRP mRNA expression increases during food restriction, a condition that is known to suppress the GnRH pulse generator and reproductive function. Although NPY has been shown previously to suppress LH secretion in the ovariectomized monkey, data on AGRP are lacking. In this study, we examined the effect of AGRP infusion into the third ventricle on pulsatile LH release in five adult monkeys. The 8-h protocol included a 3-h intraventricular saline infusion to establish baseline pulsatile LH release, followed by a 5-h infusion of AGRP (83-132) [5 microg/h (n=1) or 10 microg/h (n=4)]. In separate experiments, each animal received an 8-h saline treatment as a control. Blood samples were collected every 15 min for LH measurements. Cortisol levels were measured every 45 min. AGRP infusion significantly decreased LH pulse frequency (from a baseline of 0.74 +/- 0.07 pulse/h to 0.36 +/- 0.12 during AGRP infusion; P <0.01) and mean LH concentrations (to 41.1 +/- 7.5% of baseline by h 5 of AGRP infusion; P < 0.001). LH pulse amplitude was not modified by AGRP treatment. AGRP infusion also significantly increased cortisol release, as previously reported. The data demonstrate that central administration of AGRP inhibits pulsatile LH release in the monkey and suggest that AGRP, like NPY, may mediate the effect of a negative energy balance on the reproductive system by suppressing the GnRH pulse generator.

Peptides: Basic determinants of reproductive functions

“…Deficiency of either NPY or its receptors recovered fertility [92]. It has been reported that AgRP has an inhibitory effect on LH secretion in ovariectomized monkeys [161]. In this sense, ablation of AgRP expressing neurons in ob/ob mice recovered fertility [169].…”

Altered Gene Expression Profiles of the Hypothalamic Arcuate Nucleus of Male Mice Suggest Profound Developmental Changes in Peptidergic Signaling

“…The orexigenic peptides AGRP and NPY are both potent inhibitors of pulsatile LH secretion [61,62]. AGRP is an endogenous antagonist of Mc3/4r.…”

Neuroendocrine integration of nutritional signals on reproduction

“…As both NPY-knockout mice and AgRP-deficient mice were shown to exhibit improved reproductive phenotypes in response to nutritional stress (fasting and LepR deficiency, respectively), it appears that they are both independently involved in the suppression of GNRH. These data highlight both the powerful inhibitory tone NPY/AgRP-expressing neurons exert on reproductive function and also reveal that leptin signaling exclusively in NPY/AgRP neurons is sufficient to permit fertility (Vulliemoz et al 2005).…”

“…A subset of GABAergic neurons in the arcuate nucleus (ARC) of the hypothalamus co-express neuropeptide Y (NPY) and agouti-related peptide (AgRP), which are both orexigenic neuropeptides shown to have predominantly inhibitory effects on GNRH neurons (McShane et al 1992, Cone 2005, Vulliemoz et al 2005, Roa & Herbison 2012. NPY/AgRP neurons, in turn, are directly modulated by insulin (Konner et al 2007) and leptin (Elias et al 1999) and are also innervated by ghrelin-expressing neurons (Cowley et al 2003).…”