As stated previously, certain brainstem, hypothalamic, and other limbic sites appear critical in the regulation of food intake and feeding behavior. Within these sites numerous neurochemicals (first neurotransmitters and then neuropeptides) have been identified as potent inhibitors and stimulators of feeding behavior. 5-HT has been implicated as a critical CNS satiety factor in the short-term regulation of food intake. Specifically, the 5-HT system appears to be sensitive to meal-generated satiety factors such as CCK, enterostatin, and ingested macronutrients. Moreover, 5-HT drugs appear to enhance satiety, suppress CNS NPY release, and inhibit hunger. 5-HT appears to mediate the effects of episodic meal-generated satiety on appetite. The second CNS system to be involved is that of the melanocortins, which appear integral in the action of circulating leptin on intake and (like 5-HT) its agonists also inhibit NPY functioning. Thus, the melanocortins may mediate the effects of tonic energy status on appetite.
Of all the monoamines, 5-HT has been most closely linked with the episodic process of satiation and the state of satiety. Moreover, it has been known for a long time that serotoninergic drugs reliably reduce food intake and body weight, both in animals and humans. A number of researchers have identified the critical role of 5-HT1B and 5-HT2C in mediating the satiety effect of 5-HT. Direct agonists of 5-HT1B and 5-HT2C have been shown to reduce intake and to produce changes in feeding behavior consistent with the operation of satiety. Studies with selective 5-HT1B and 5-HT2C agonists in humans confirm their satiety-enhancing properties. Hypothalamic areas, including the PVN, have been implicated in 5-HT hypophagia. 5-HT activation suppresses the levels of the appetite stimulatory peptide NPY within the PVN. Conversely, blocking 5-HT synthesis or antagonizing 5-HT receptors increases NPY functioning in the PVN. This interaction between 5-HT and NPY may be one of the critical mechanisms in short-term (episodic) appetite, determining the generation of either hunger or satiety. As mentioned previously, 5-HT function has been linked to peripheral signals triggered by fat ingestion, such as CCK and enterostatin. Moreover, CNS levels of the 5-HT precursor tryptophan are directly affected by dietary carbohydrate, through its action on the tryptophan/large neutral amino acid competition to cross the blood-brain barrier. Thus, CNS 5-HT is sensitive to both fat and carbohydrate ingestion.
The melanocortins are one of the inhibitory systems through which the tonic adiposity signal leptin inhibits food intake. Like leptin, the role of CNS melanocortins was revealed through the investigation of a genetic mouse model of obesity (agouti (A y/a)) syndrome. These animals were obese, displayed marked hyper-phagia, and produced excessive amounts of agouti, an endogenous antagonist of melanocortin receptors. The hyperphagia was linked specifically to blockade of the melanocortin MC4R receptor. Children who are unable to synthesize endogenous melanocortin receptor agonists also display abnormal eating patterns and obesity. It soon became apparent that the melanocor-tin receptor MC4R, and a number of its endogenous agonists (such as aMSH), and antagonists (such as AgRP) were part of the endogenous body weight regulation system. MC4R receptors are expressed widely throughout the CNS and in the hypothalamus and these systems appear to mediate the effects of a number of factors such as leptin and insulin. For instance, CNS administration of MC4R receptor agonists inhibits NPY-induced hyperphagia.
Even if tonic signals such as leptin are generated independently from episodic signals they must feedback to reduce intake by altering subjective experiences of hunger and satiety. Increases and decreases in endogenous circulating leptin do have an effect on the modulation of subjective experiences of hunger. Moreover, endogenous leptin levels may fluctuate across the day, in part as a consequence of meal consumption and the effects this has on metabolism. Individuals with an inability to produce leptin experience constant hunger and without the tonic leptin signal the constant drive for energy is unleashed and leads to continuous and voracious food-seeking behavior. Similarly, specific deficits in a system that responds to circulating leptin, in this case the absence of functional melanocortin MC4R receptors, produces similar effects on appetite and intake. These extreme examples demonstrate the inability of short-term meal-generated episodic signals alone to block the override demand for energy (expressed as continuous hunger) generated by tonic basal metabolism.
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