Agouti-Related Protein Stimulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis and Enhances the HPA Response to Interleukin-1 in the Primate

Abstract

alpha-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that alpha-MSH attenuates the stimulatory effect of IL-1 on the hypothalamic-pituitary-adrenal (HPA) axis and plays a physiological role in limiting the HPA response to IL-1. Recently an alpha-MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of alpha-MSH at specific melanocortin receptors. It is unknown whether AGRP can also modulate neuroendocrine responses to inflammatory cytokines. We have therefore examined the effects of AGRP on the HPA axis and on prolactin (PRL) at baseline and in response to stimulation by IL-1 beta in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (i.c.v) infusion of 20 microg (n = 6) and 50 micro g (n = 4) of human AGRP (83-132)-NH(2) were compared with icv saline infusion. There was a significant stimulatory effect of 20 microg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 microg AGRP vs. saline; the AUC for ACTH increased by 166% (P = 0.028); the AUC for PRL increased by 108% (P = 0.046). There was a significant stimulatory effect of 50 microg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 microg AGRP increased by 98%; the AUC for cortisol increased by 37%; the AUC for PRL increased by 161%. The effects of AGRP on ACTH, cortisol, and PRL release were prevented by alpha-MSH infusion. In the second study, animals received icv either 50 ng of human IL-1 beta or 20 microg of AGRP followed by 50 ng IL-1 beta. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1 beta. The peak ACTH response to IL-1 beta alone was 124 +/- 55 pg/ml vs. 430 +/- 198 pg/ml after IL-1 beta plus AGRP; the peak cortisol response was 70 +/- 8.2 microg/dl vs. 77 +/- 6.2 microg/dl, but this was not significantly different. In conclusion, AGRP stimulated ACTH, cortisol, and PRL release in the monkey and enhanced the ACTH response to IL-1 beta. These studies suggest that, in addition to its known orexigenic effects, AGRP may play a role in neuroendocrine regulation and specifically that AGRP may interact with alpha-MSH to modulate neuroendocrine responses to inflammation.

Alpha-Melanocyte-Stimulating Hormone through Melanocortin-4 Receptor Inhibits Nitric Oxide Synthase and Cyclooxygenase Expression in the Hypothalamus of Male Rats

“…Also, AgRP stimulates ACTH and cortisol in female monkeys [39]. Consistent with previous findings [40], we observed that central administration of α-MSH reduces the increase in serum corticosterone levels induced by LPS.…”

“…Regarding PRL secretion, α-MSH blocks IL-1-stimulated PRL release [24]whereas AgRP stimulates PRL release in the monkey [39]supporting the idea of a physiological role for endogenous α-MSH in PRL secretion. α-MSH has been shown to suppress, whereas an α-MSH antiserum has been shown to enhance, basal and stress-induced PRL secretion [42].…”

Melanocortin-3 receptor regulates the normal fasting response

“…We propose that the blunted fasting-induced CRH response results from a blunted NPY and AgRP response. Intracerebroventricular injection of either AgRP or NPY ICV has been shown to increase corticosterone (21,22). Surprisingly, the MC3/4-R agonist MTII also increases circulating corticosterone (53).…”

“…Because neuropeptide Y (NPY) and AgRP peptides play a role in the fasting-induced increase in CRH mRNA (21,22), and that the MC3-R −/− mouse displayed a defect in fasting-induced CRH mRNA expression, fasting-induced refeeding and fasting-induced changes in NPY and AgRP mRNA expression were characterized in the MC3-R −/− mouse. Fasting-induced 12-h refeeding was blunted in MC3-R −/− mice (Fig.…”

Comparative Analysis of a Putative Tuberculosis-Susceptibility Gene, <i>MC3R</i>, and Pseudogene Sequences in Cattle, African Buffalo, Hyena, Rhinoceros and Other African Bovids and Ruminants

“…All of the finely integrated key components and upstream regulators of the melanocortin system have widespread immunologic influence modulated via their downstream targets [Xiao et al, 2003;La Cava and Matarese, 2004;Matarese and La Cava, 2004;Taub, 2008;Savos et al, 2011] and some also act as neuroimmune cotransmitters [Bedoui et al, 2003]. Cytokines are the effector molecule links between immune response and the neuroendocrine system.…”