Regulation of Food Intake, Body Weight, and Metabolism

The actions of leptin and ghrelin appear to involve neurons in the arcuate nucleus, a part of the hypothalamus that is just above the pituitary stalk. These hormones can enter the brain through the hypophysial portal vessels, which lack a blood-brain barrier. Here they encounter neurons that have receptors for the hormones and form a key circuit in controlling eating. Neurons in the arcuate nucleus that contain the peptide neurotransmitters neuropeptide Y (NPY) and agouti-related protein (AgRP) form a positive part of the circuit. They contact cells in the paraventricular, ventromedial, and dorsomedial nuclei of the hypothalamus, as well as the lateral hypothalamic area and parabrachial nucleus, and drive feeding responses. By contrast, a different set of arcuate neurons contains the peptides derived from the pro-opiomelanocortin (POMC) precursor, including melanocyte–stimulating hormone (α-MSH), β-endorphin, and others. These POMC neurons contact many of the same targets as the NPY/AgRP neurons but use α-MSH and the melanocortin 3 and 4 receptors to inhibit the pathways that promote feeding. NPY neurons also contain γ-aminobutyric acid (GABA), and appear to inhibit the POMC neurons directly as well, while AgRP blocks melanocortin 3 and 4 receptors.

The feeding system also receives other central nervous system (CNS) inputs. For example, there is a strong circadian input to feeding, which is mediated by the pathway from the suprachiasmatic nucleus to the subparaventricular zone and then the dorsomedial nucleus. Dorsomedial hypothalamic neurons, in turn, send outputs to the lateral hypothalamic area and the paraventricular, ventromedial, and arcuate nuclei, which may drive circadian cycles of feeding.

The mechanisms by which hypothalamic neurons promote feeding are not well understood. There do not appear to be any “master neurons” that form a feeding center. Rather, different populations of neurons activate autonomic and behavioral responses that promote feeding. Some of the lateral hypothalamic neurons that are activated during starvation contain the peptide neurotransmitter orexin, and these neurons appear to cause arousal and to drive active exploration of the environment, which is necessary for most animals to acquire food. Other descending pathways may potentiate motor responses, such as sniffing, licking, chewing, and swallowing, which are a part of the ingestive behavior. Other descending pathways that control the autonomic nervous system may increase gastric motility and acid production, which may be perceived by the individual as “hunger pangs.”

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