Much of the activity related to appetite perception and intake regulation has been located to the arcuate nucleus of the hypothalamus near the third ventricle, the nearby ventromedial nucleus and lateral areas of the hypothalamus, increased expression of the oncogene c-fos in some of these brain regions correlates with appetite perception. NPY melanoeortin neurons: Two types of neurons, w hich arc located mainly in the arcuate nucleus, constitute a significant portion of the appetite perception circuitry (Schwartz and Morton, 2002). One type is characterized by its production of neuropeptide Y iNPY J and agouti-related protein (AgRP). Production of melanoeortin characterizes the second type of neurons. The action of NPY AgRP neurons on other neurons nearby stimulates the perception of appetite. The binding of melanoeortin to melanoeortin receptor 4 (Mc4r) on hypothalamic neurons inhibits appetite. AgRP specifically blocks the binding of melanoeortin to Mc4r and other melanoeortin receptors (Mc I rand Mc3r).
The (appetite-promoting) NPY AgRP neurons are stimulated by ghrcltn (signaling an empty stomach) and inhibited by leptin (signaling fat-lilled adipose tissue), insulin (signaling plentiful carbohydrate supplies), and PYYi (signaling a filled distal intestine). They arc also inhibited by their own activ ity and by melanoeortin neuron input. The PYY; J(( action is mediated by a type of NPY receptor, Y2R that responds to both intact NPY and fragments such as PYY; 1(l.
The (appetite-decreasing) melanoeortin neurons are inhibited by leptin and insulin, and by input from NPY' AgRP neurons. Melanoeortin is produced by post-translational processing (Pritchard et a!., 2002) of the much larger peptide proopiomelanocortin (POMC). which is also the precursor of alpha, beta. gamma-MSH (melanocyte stimulating hormone) and ACTH (adreno-cortieotrophic hormone). Neurotransmitters: Several types of neurons that are intimately involved in the regulation of appetite (and also in thirst regulation) use serotonin (5-hydroxytryptamin las a neurotransmitter. Food intake stimulates the release of serotonin by such neurons and thereby induces a reeling of satiation. Various drugs (e.g. dexfenfluramine) that increase the availability of serotonin induce weight loss, and also serious side-effects like pulmonary hypertension and heart valve damage (Michelakis and Weir. 2001).
Two distinct receptors respond to dopamine binding. The DI receptors in the hypothalamus promote food intake, while the D2 receptors inhibit it. Some peripheral mediators of food intake regulation, such as amylin. act on dopamine receptors.
Catecholamine- and histamine-producing neurons also contribute to appetite suppression. Beta-adrenergic agonists (e.g. sibutramine) are used to induce weight loss. Other central mediators: Galanin, opioid peptides, growth hormone releasing hormone, and other hormones increase food intake as part of their broad activity profiles.
Galanin in brain stimulates appetite, especially for fat. Specialized neuroendocrine cells in the hypothalamus, other brain regions, and the gastrointestinal tract secrete this peptide together with prolactin. Three gal an in receptors in brain and many other tissues respond to galanin.
Melanin-concentrating hormone (MCH) is a cyclic small neuropeptide from the lateral hypothalamic area and arcuate nucleus that promotes food intake. It acts on target neurons by activating the G-protem-linked MCH receptor i (Marsh el a/., 2002), and possibly also on the NPY Y1 receptor (Chaffer and Morris. 2002).
Neurons of the lateral, dorsomedial and perifornical areas of the hypothalamus near the base of the stalk of the pituitarv produce the appetite-promoting peptides orcxin A (hypocretin 1) and orcxin B (hypocrctm 2) from the same precursor. The orcxin-producing neurons respond directly to low glucose availability, Orexins stimulate appetite by activating opioid receptors (Clegg et a!„ 2002). These peptides arc also involved in the regulation of wakefulness and other behaviors (Shirasaka et ul., 2002).
Further food-intake-inhibitmg central mediators include CART (cocaine and amphetamine-regulated transcript) peptide (a regulator of pituitary function) and corticotrophin-releasing factor (CRF).
Cannabinoids: The G-protein-coupled cannabinoid receptors CB1 (mainly in brain) and CB2 (mainly in immune cells) respond to both endocannabinoids and several of the phytochcmicals from the cannabis plant (Onaivi et til., 2002). Putative endogenous ligands for these receptors include 2-arachidoylglycerol. 2-arachidonyl glyceryl ether, and anandamide. An important function of this signaling mechanism may be the inhibition of neurotransmitter release by target neurons. Cannabis-derived compounds. including tetrahydrocannabinol, cannabidiol (non-psychotroptc). and delta-y-tetrahydrocannabinol promote appetite. A distinct mechanism, for instance of delta-9-tetrahydrocannabinol, is the suppression of nausea and vomiting (in cancer and AIDS patients) and thereby an improvement of intake desire (Mechouiam and Hanu, 2001).
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