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

Departments of Medicine and Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians & Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: sw22{at}columbia.edu.

-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that -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 -MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of -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-1ß in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (icv) infusion of 20 µg (n = 6) and 50 µg (n = 4) of human AGRP (83–132)-NH₂ were compared with icv saline infusion. There was a significant stimulatory effect of 20 µg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 µg 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 µg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 µg 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 -MSH infusion. In the second study, animals received icv either 50 ng of human IL-1ß or 20 µg of AGRP followed by 50 ng IL-1ß. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1ß. The peak ACTH response to IL-1ß alone was 124 ± 55 pg/ml vs. 430 ± 198 pg/ml after IL-1ß plus AGRP; the peak cortisol response was 70 ± 8.2 µg/dl vs. 77 ± 6.2 µg/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-1ß. 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 -MSH to modulate neuroendocrine responses to inflammation.

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