Source of Arcuate nucleus

{{Infobox concept | name = Arcuate nucleus | subtitle = Hypothalamic region | Location = Mediobasal hypothalamus, adjacent to the median eminence | Anorexigenic population = POMC and CART neurons | Orexigenic population = AgRP and NPY neurons }} 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.{{r|schwartz2000}} 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 agonist|GLP-1 receptor agonists]].{{r|schwartz2000}} 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.{{r|cone2005}} == Neuronal populations == 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 [[Glucagon-like peptide-1|GLP-1]] receptor signalling.{{r|cone2005,woods2009}} 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]].{{r|cone2005}} == Access to circulating signals == The median eminence is a circumventricular organ with fenestrated capillaries, and tanycytes lining the third ventricle provide a regulated route by which circulating molecules reach arcuate neurons. Access is not free — the tanycyte barrier is selective and its permeability changes with nutritional state — but it is far greater than across an intact blood-brain barrier.{{r|schwartz2000}} This is the mechanistic basis for the central action of peripherally injected peptides that are far too large to cross the barrier elsewhere. It also explains why the area postrema, another circumventricular organ, is the site of the nausea produced by the same agents. Whether a given peptide agonist acts principally at the arcuate, at the brainstem, or through vagal afferents differs between molecules and doses, and the relative contributions in humans are inferred from animal work rather than measured directly.{{r|drucker2018}} == Relevance to incretin pharmacology == [[GLP-1 receptor|GLP-1 receptors]] are expressed in the arcuate and in downstream hypothalamic sites. Agonist administration activates POMC neurons and inhibits AgRP/NPY neurons in animal models, which is the expected signature of an anorexigenic drug.{{r|drucker2018}} The clinically interesting question is whether sustained agonism produces adaptation in these circuits. Weight regain after discontinuation is rapid and largely complete, which is consistent with the circuits returning to their prior set point rather than being reset by the period of treatment; see [[Weight regain after discontinuation]]. Melanocortin-pathway agonists and incretin agonists therefore act on the same axis at different points, and combining them has been proposed but not established as beneficial. Nothing in this article is medical advice.{{r|cone2005}} == References == {{reflist}} <ref name="schwartz2000">Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG. "Central nervous system control of food intake." ''Nature'' 404(6778):661–671 (2000). PMID 10766253.</ref> <ref name="cone2005">Cone RD. "Anatomy and regulation of the central melanocortin system." ''Nature Neuroscience'' 8(5):571–578 (2005). DOI:10.1038/nn1455. PMID 15856065.</ref> <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> <ref name="woods2009">Woods SC. "The control of food intake: behavioral versus molecular perspectives." ''Cell Metabolism'' 9(6):489–498 (2009). PMID 19490904.</ref> == See also == * [[Satiety signalling]] * [[GLP-1 receptor]] * [[Melanotan II]] * [[Bremelanotide]] * [[Weight regain after discontinuation]] {{DEFAULTSORT:Arcuate nucleus}} [[Category:Appetite regulation]] [[Category:Incretin biology]] [[Category:Receptor pharmacology]]