The intimate contact of mainly chemical, but also physical, stimuli with receptors in the mucosa of the nose and mouth set up orosensory effects of food stimuli. This is in turn transmitted to the brain by afferent fibers of primary olfactory, gustatory, and somatosensory neurons of cranial nerves 1, 5, 7, 9, and 10. These peripheral inputs appear to make contact with dopamine and opioid neurotrans-mitters in the brain. The cephalic phase of appetite control refers to physiological responses engendered by the sight or smell of food, which are anticipatory and serve to prepare the system for the imminent ingestion of food. Cephalic phase responses occur in the mouth (anticipatory secretion of saliva), stomach, and small intestine and represent preprandial changes that are precursors for the onset of a meal.
In addition it has been proposed that changes in blood glucose may serve as a signal for meal initiation. Recent evidence provides some support for a role for 'transient declines' in blood glucose in humans leading to increased expression of hunger and the initiation of eating. Potent feeding responses can also be obtained by microinjection of peptides to the brain of animals. A number of peptides, including ^-endorphin, dynorphin, neuropeptide Y (NPY), orexins (OX-A and OX-B), galanin, agouti-related peptide (AgRP), and melanin-concentrating hormone (MCH) increase food intake.
Neuropeptide Y (NPY) is probably the most studied appetite stimulatory peptide. NPY is found throughout the CNS and in particular abundance in the PVN of the hypothalamus. Hypothalamic NPY neurons that are implicated in appetite regulation project from the ARC to the PVN. Infusing NPY directly into the CNS or increasing release of NPY within the PVN promotes meal initiation and produces an immediate and marked increase in food intake, delaying the onset of satiety. The hyperpha-gic effects of NPY appear to be mediated by both NPY Y1 and Y5 receptors. Endogenous NPY is sensitive to a variety of peripherally generated signals. It is stimulated by the gut factor ghrelin, but inhibited by the pancreatic hormone amylin, the adiposity signal leptin, and the satiety neurotrans-mitter serotonin (5-HT). Like NPY, galanin-induced hyperphagia has been well documented. Early studies demonstrated that direct infusion of galanin into the hypothalamus of rodents stimulated feeding behavior. Moreover, high concentrations of galanin and its receptors are found in the hypothalamus in areas associated with appetite regulation.
A more recently discovered CNS stimulatory system is that of the orexins. The endogenous orexin system is integrated with other critical hypothalamic energy regulatory systems. The system consists of two peptides, termed orexin-A and orexin-B, along with two orexin receptors, orexin-1 (OX1) and orexin-2 (OX2). The strongest and most reliable effect on food intake is produced by orexin-A. The endogenous orexin system responds to insulin-induced hypoglycemia and food restriction. Moreover, leptin reduces orexin-A concentration in the hypothalamus, and partially blocks orexin-A induced changes in feeding behavior.
Not all stimulatory peptide systems are within the brain. Ghrelin is a peripherally secreted hormone responsive to nutritional status. Human plasma ghre-lin increases during fasting and decreases after food intake. Unlike the other gut-derived factors detailed in this review, ghrelin stimulates rather than inhibits feeding behavior. Both peripheral and central infusions of ghrelin have been shown to stimulate food intake in rats and mice, an effect in part mediated by central NPY. In lean humans, endogenous plasma ghrelin levels rise markedly before a meal and are suppressed by food intake. In lean healthy volunteers, ghrelin infusions increase food intake, premeal hunger, and prospective consumption.
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