Arcuate nucleus (revision 11)
Old revision·18:12, 1 Feb 2025·ProglucagonPia
| Arcuate nucleusHypothalamic region | |
|---|---|
| Location | Mediobasal hypothalamus, adjacent to the median eminence |
| Anorexigenic population | POMC and CART neurons |
| Orexigenic population | AgRP and NPY neurons |
| Topic infobox · conventions | |
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]
Neuronal populations
[edit]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]
Access to circulating signals
[edit]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.[1]
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.
See also
References
- ^ a b c 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.
- ^ a b c Cone RD. "Anatomy and regulation of the central melanocortin system." Nature Neuroscience 8(5):571–578 (2005). DOI:10.1038/nn1455. PMID 15856065.
- ^ Woods SC. "The control of food intake: behavioral versus molecular perspectives." Cell Metabolism 9(6):489–498 (2009). PMID 19490904.