Arcuate nucleus (revision 7)

The arcuate nucleus is a region of the mediobasal hypothalamus containing two functionally opposed neuronal populations that regulate food intake: neurons expressing pro-opiomelanocortin (POMC), which suppress intake, and neurons expressing agouti-related peptide (AgRP) and neuropeptide Y, which promote it.^[1]

Its position adjacent to the median eminence, where the capillaries are fenestrated, gives it unusual access to circulating signals. Hormones that cannot cross an intact blood-brain barrier can nonetheless influence arcuate neurons, which is why the nucleus is a principal target for peripherally administered peptides including GLP-1 receptor agonists.^[1]

POMC and AgRP neurons project to the paraventricular nucleus and other second-order sites, where POMC-derived α-melanocyte-stimulating hormone acts at melanocortin-4 receptors and AgRP acts as an inverse agonist at the same receptors. This shared endpoint is what makes the two populations genuinely opposed rather than merely parallel.^[2]

POMC neurons synthesise a precursor that is cleaved to α-melanocyte-stimulating hormone and other products. Released α-MSH acts at melanocortin-3 and melanocortin-4 receptors on downstream neurons to suppress food intake. These neurons are activated by leptin, insulin and GLP-1 receptor signalling.^[2][3]

AgRP/NPY neurons are activated by fasting and by ghrelin, and inhibited by leptin. AgRP is an inverse agonist at melanocortin-4 receptors — it does not merely block α-MSH but reduces constitutive receptor signalling below baseline — and NPY acts at its own receptors to promote feeding. The two populations also inhibit each other directly.

The melanocortin-4 receptor is the convergence point, and loss-of-function mutations in it are the commonest known monogenic cause of severe early-onset obesity. Melanocortin agonists developed for other indications act on this same axis; see Melanotan II and Bremelanotide.^[2]