Food Intake Inhibition

Food intake is considered a reliable indicator for the anxiolytic properties of drugs. Rodents usually are reluctant to eat unknown food (Boissier et al. 1976 Soubrie et al. 1975). When both famiUar and unknown food are presented, rodents will typically show a longer latency to the first intake of imknown food compared to the intake of famihar food. Anxiolytic drugs not only reverse this food intake inhibition (Fletcher and Davies 1990 Hodges et al. 1981) but also result in an increased consiunption of food (Britton and Britton 1981). 

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Neuropeptide Y (NPY) causes hypertension, increased food intake, inhibits sexual function, inhibits growth and causes sedation, amongst several other actions. The mythical NPY-blocked man would be thin, tall, vivacious and very interested in sex. Certainly a profitable image. 

It has been observed that lower food intake inhibits the developmental phases of eaneer eells (Williams and WeisbergCT, in Amdur et al., 1991, p. 151), whieh is corroborated by medieal folklore. 

CART (cocaine- and amphetamine-regulated transcript) is a hypothalamic peptide that inhibits both normal and starvation-induced feeding when injected into cerebral ventricles of rats. CART is co-localized with the anorexigenic peptide a-melanocyte-stimulating hormone in neurons of the arcuate nucleus. Secretion of CART is stimulated by leptin and CART may be an endogenous inhibitor of food intake. 

As to be expected from a peptide that has been highly conserved during evolution, NPY has many effects, e.g. in the central and peripheral nervous system, in the cardiovascular, metabolic and reproductive system. Central effects include a potent stimulation of food intake and appetite control [2], anxiolytic effects, anti-seizure activity and various forms of neuroendocrine modulation. In the central and peripheral nervous system NPY receptors (mostly Y2 subtype) mediate prejunctional inhibition of neurotransmitter release. In the periphery NPY is a potent direct vasoconstrictor, and it potentiates vasoconstriction by other agents (mostly via Yi receptors) despite reductions of renal blood flow, NPY enhances diuresis and natriuresis. NPY can inhibit pancreatic insulin release and inhibit lipolysis in adipocytes. It also can regulate gut motility and gastrointestinal and renal epithelial secretion. 

Obviously, regulation of food intake depends on many neurotransmitters and hormones but this final section will outline the role played by central 5-HT transmission in this process. It had been the belief for some time that increased 5-HT transmission in the brain reduces food intake (Blundell 1977) and this certainly explains the satiety in rats that follows infusion of 5-HT into the paraventricular nucleus (PVN) of the hypothalamus. However, recent studies using microdialysis have found that 5-HT efflux in the lateral hypothalamus is itself increased by food intake, suggesting the existence of a feedback control system. In fact, because the increase in 5-HT efflux is greater in genetically obese rats than in their lean counterparts, it has been proposed that there is a deficiency in the 5-HT inhibition of food intake in obesity. 

Pharmacological studies primarily have contributed to the idea that 5-HT has an inhibitory effect on feeding behavior. Drugs that either directly or indirectly activate postsynaptic 5-HT receptors decrease food consumption whereas agents that inhibit serotonergic transmission increase food intake. Precisely how this occurs is controversial, with claims that 5-HT governs the selection of macronutrients in the diet, or influences responses to the taste qualities of food, or modulates gastric activity to... 

Leptin is a homeostatic hormone. It inhibits food intake and promotes energy expenditnre. Therefore, in the face of a loss in body fat, the levels of leptin decrease and food intake is stimnlated. In contrast, if body fat stores increase, the levels of leptin increase as well and food intake is decreased and energy expenditure increased. Therefore, leptin tends to maintain body weight within fairly close limits. Since ob/ob mice are genetically deficient in leptin, it follows that administration of leptin shonld tend to restore normal body weight. That is exactly what happens. Injection of leptin into ob/ob mice reduces their food intake dramatically and they tend toward the body weights of their normal littermates. In these mice at least, leptin is a powerful force for treatment of obesity. 

Serotonin mediates many central and peripheral physiological functions, including contraction of smooth muscle, vasoconstriction, food intake, sleep, pain perception, and memory, a consequence of it acting on several distinct receptor types. Although 5-HT may be metabolized by monoamine oxidase, platelets and neurons possess a high-affinity mechanism for reuptake of 5-HT. This mechanism may be inhibited by the widely prescribed antidepressant drugs termed selective serotonin re-uptake inhibitors (SSRl), e.g. fluoxetine (Prozac ), thereby increasing levels of 5-HT in the central nervous system. 

All antipsychotics except clozapine and perhaps olanzapine produce hyperprolactinemia by removing the inhibitory actions of dopamine on prolactin secretion. This results in amenorrhea, galactorrhea, and infertility in women and in loss of libido and impotence in men. Inhibition of the release of follicle-stimulating and luteinizing hormones may also play a role. In addition, weight gain is common, and food intake must be monitored. 

Although the mechanism of action of SSRIs in treating alcohol dependence remains unclear, Gorelick and Paredes ( 432) postulate that it is not due to motor inhibition or general sedation. Rather, they believe it may be related to decreased appetite and food intake or a conditioned taste aversion mediated by increased brain serotonin activity. Other competing theories have been summarized by Thomas ( 433) ... 

Adenosine deaminase (ADA) is a ubiquitous enzyme that is essential for the breakdown of the purine base adenosine, from both food intake and the turnover of nucleic acids. ADA hydrolyzes adenosine and deoxyadenosine into inosine and deoxyinosine, respectively, via the removal of an amino group. Deficiency of the ADA enzyme results in the build-up of deoxyadenosine and deoxyATP (adenosine triphosphate), both of which inhibit the normal maturation and survival of lymphocytes. Most importantly, these metabolites affect the ability of T-cells to differentiate into mature T-cells [656430], [666686]. ADA deficiency results in a form of severe combined immunodeficiency (SCID), known as ADA-SCID [467343]. 

When the mass of adipose tissue increases, released leptin inhibits feeding and fat synthesis and stimulates oxidation of fatty acids. When the mass of adipose tissue decreases, a lowered leptin production favors a greater food intake and less fatty acid oxidation. 

FIGURE 23-35 A possible mechanism for cross-talk between receptors for insulin and leptin. The insulin receptor has intrinsic Tyr kinase activity (see Fig. 12-6), and the leptin receptor, when occupied by its ligand, is phosphorylated by a soluble Tyr kinase (JAK). One possible explanation for the observed interaction between leptin and insulin is that both may phosphorylate the same substrate—in the case shown here, insulin receptor substrate-2 (IRS-2). When phosphorylated, IRS-2 activates PI-3K, which has downstream consequences that include inhibition of food intake. IRS-2 serves here as an integrator of the input from two receptors. 

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