Endogenous ACTH, not only alpha-melanocyte-stimulating hormone, reduces food intake mediated by hypothalamic mechanisms

ACTH and alpha-melanocyte-stimulating hormone (alpha-MSH) are both consecutively processed from proopiomelanocortin (POMC), which is synthesized in hypothalamic arcuate neurons innervating the paraventricular nuclei (PVN). POMC secretion/synthesis is regulated by energy availability. ACTH and alpha-MSH bind with equal affinity to melanocortin-4 receptors and elicit similar effects on signal transduction in-vitro. Endogenous alpha-MSH thus far is believed to be the major physiological agonist and to act in an anorexigenic manner. Until now, it was fully unknown whether endogenous ACTH is also involved in the regulation of appetite and food intake. In this study in rats, we now show that icv ACTH as well as alpha-MSH possess anorexigenic effects in the PVN or areas in close proximity in vivo and that the effect of ACTH is direct and not mediated via alpha-MSH. We investigated the roles of endogenous ACTH and alpha-MSH by PVN application of the respective Antibodies under different physiological conditions. In satiated rats with high levels of ACTH and alpha-MSH in the PVN, antibody administration increased food intake and body weight gain; hungry Animals were unaffected. Finally, repeated injections of ACTH Antibodies into PVN resulted in persistently increased food intake during the LIGHT period. These data now provide robust evidence that endogenous ACTH without further processing acts in the PVN or areas in close proximity to reduce food intake under conditions of feeding-induced satiety.