Orexigenic Neuropeptides

Eat Stop Eat

Best Weight Loss Programs That Work

Get Instant Access

Effects of Neuropeptide Y (NPY)

NPY is a 36 amino acid neuropeptide that is widely distributed in the brain. In the hypothalamus, it is synthesized in the arcuate nucleus and released in the paraventricular nucleus. It stimulates food intake by binding to Y1 and /or Y5 receptor subtypes (12-14). This increase in feeding can be observed upon infusing the peptide intracerebroventricularly (i.c.v.) in normal rats and is accompanied by a rapid, sustained and marked increase in body weight (15,16). Central NPY infusion also stimulates insulin secretion via an activation of the parasym-pathetic nervous system reaching the endocrine pancreas (17). Concomitantly, central NPY administration increases the activity of the hypothalamo-pituitary-adrenal axis, with resulting hypercorticos-teronemia and increased susceptibility to stressful situations (15,17). Finally, central NPY reduces the activity of the efferent sympathetic nerves reaching brown adipose tissue, with resulting decrease in energy dissipation as heat (18,19).

The metabolic consequences of the hormonal

International Textbook of Obesity. Edited by Per Bjorntorp. © 2001 John Wiley & Sons, Ltd.

Anorexigenic Neuropeptides

Figure 7.1 Diagram of food intake regulation by orexigenic and anorexigenic neuropeptides. Stimulators of food intake are depicted as increasing the diameter of a tube by exerting a pressure (+) from inside, with agouti-related peptide (AGRP) mainly exerting its action by inhibiting the melanocortin system (a-MSH and MC4 receptor), the effect of which is to reduce this diameter. Inhibitors of food intake are depicted as reducing ( — ) the diameter of the tube, with AGRP having little effect on the melanocortin system, allowing the latter to largely contribute to reducing this diameter. NPY, neuropeptide Y; MCH, melanin concentrating hormone; ORE, orexins; a-MSH, a-melanocyte-stimulating hormone and the melanocortin-4 (MC4-R) receptor; CRH, corticotropin-releasing hormone, CART, cocaine- and amphetamine-regulated transcript; NT, neurotensin. Not all neuropeptides are represented. Solid lines indicate marked effects, dotted ones weak effects

Figure 7.1 Diagram of food intake regulation by orexigenic and anorexigenic neuropeptides. Stimulators of food intake are depicted as increasing the diameter of a tube by exerting a pressure (+) from inside, with agouti-related peptide (AGRP) mainly exerting its action by inhibiting the melanocortin system (a-MSH and MC4 receptor), the effect of which is to reduce this diameter. Inhibitors of food intake are depicted as reducing ( — ) the diameter of the tube, with AGRP having little effect on the melanocortin system, allowing the latter to largely contribute to reducing this diameter. NPY, neuropeptide Y; MCH, melanin concentrating hormone; ORE, orexins; a-MSH, a-melanocyte-stimulating hormone and the melanocortin-4 (MC4-R) receptor; CRH, corticotropin-releasing hormone, CART, cocaine- and amphetamine-regulated transcript; NT, neurotensin. Not all neuropeptides are represented. Solid lines indicate marked effects, dotted ones weak effects changes produced by central NPY infusion (increased plasma insulin and corticosterone levels) are increased adipose tissue and liver lipogenic activity, changes mainly due to hyperinsulinemia (15,16), together with decreased insulin-stimulated glucose utilization by muscles (15,16). This muscle insulin resistance is likely to be due to the combined NPY-induced hyperinsulinemia/hypercorticostero-nemia(1).

It should be noted that the NPY-elicited effects are very marked when exogenous NPY is chronically infused i.c.v., resulting in high central concentrations of the neuropeptide. Physiologically, however, it is thought that these changes are modest, occurring via the spontaneous fluctuations of hy-pothalamic NPY levels, which transiently change nutrient partitioning toward fat accretion and decreased oxidation processes. This situation persists until leptin is secreted into the blood as a result of hormonal changes such as transient hyperin-sulinemia in response to meal taking. Secreted lep-tin reaches the brain and decreases hypothalamic NPY levels by exerting its negative feedback inhibition on the expression and amount of this neuropeptide (20-22). Experiments have shown, however, that in addition to NPY, other brain neuropeptidic systems play a role in the regulation of food intake. Thus, in transgenic mice made deficient in NPY, the expected decrease in both food intake and body weight fails to occur (23,24). Transgenic mice lacking the NPY-Y1 or Y5 receptor actually gain more weight, not less, than the controls. (25,26). This indicates that the regulation of food intake and body weight is redundant, i.e. that several pathways are implicated and that when one of them is knocked out, others take over to maintain a normal body weight homeostasis.

Normal Body Weight

Figure 7.2 Diagram of the central effects of leptin on food intake. Leptin is depicted as decreasing the diameter of a tube relative to a normal one (dotted lines), due to its dual effect of reducing (j) the expression or amount of neuropeptides that stimulate food intake (neuropeptide Y, NPY; melanin concentrating hormone, MCH; orexin, ORE; agouti-related protein, AGRP) and of increasing (|) the expression or amount of neuropeptides that inhibit food intake (cocaine- and amphetamine-regulated transcript, CART; corticotropin-releasing hormone, CRH; the melanocortin system with proopiomelanocortin, POMC, a-MSH and the melanocortin-4 receptor, MC4-R). The effect of leptin on food intake (FI) is accompanied by increased fat oxidation and energy (E) expendidure, the three parameters together producing leanness

Figure 7.2 Diagram of the central effects of leptin on food intake. Leptin is depicted as decreasing the diameter of a tube relative to a normal one (dotted lines), due to its dual effect of reducing (j) the expression or amount of neuropeptides that stimulate food intake (neuropeptide Y, NPY; melanin concentrating hormone, MCH; orexin, ORE; agouti-related protein, AGRP) and of increasing (|) the expression or amount of neuropeptides that inhibit food intake (cocaine- and amphetamine-regulated transcript, CART; corticotropin-releasing hormone, CRH; the melanocortin system with proopiomelanocortin, POMC, a-MSH and the melanocortin-4 receptor, MC4-R). The effect of leptin on food intake (FI) is accompanied by increased fat oxidation and energy (E) expendidure, the three parameters together producing leanness

NPY and Obesity

When considering the hormono-metabolic changes produced by central NPY, one realizes that experimentally produced increases in central levels of this neuropeptide reproduce most of the abnormalities observed in experimental or genetic obesity syndromes (15,16), as well as in human obesity. The pathological relevance of increased hypothalamic NPY levels in mimicking obesity syndromes is supported by the observation that NPY expression and levels are indeed increased in the ob/ob, db/db obese mice and in the fa/fa obese rat (1,20-22). Increased NPY levels in ob/ob mice are due to the lack of synthesis and secretion of leptin in adipose tissue, the ob (leptin) gene being mutated. As a result of this mutation, plasma leptin levels are nil, leptin fails to exert its negative feedback on hypothalamic NPY levels which remain continually elevated maintaining, probably with other neuropeptides that are influenced by leptin, the obesity syndrome (1,27). In the db/db and the fa/fa obese rodents, the ob gene of adipose tissue is normal, but the long form leptin receptor is mutated in its intracellular (db/db) (5) or extracellular (fa/fa) (28) domain. Even though leptin is overproduced by adipose tissue, bringing about a state of hyperleptinemia, it cannot act centrally and hypothalamic NPY levels remain high. The latter, probably in concert with other neuropeptides, maintain the obesity syndrome (29).

Effects of Melanin Concentrating Hormone (MCH)

MCH is a cyclic neuropeptide comprising 19 amino acids which is present in many areas of the brain, notably in the lateral hypothalamus (30). Its name derives from its ability to cause melanosome aggregation in fish skin, an action which is antagonized by a-MSH, the melanosome-dispersing factor. Recently, a role for MCH in the central regulation of food intake has been discovered, i.c.v. MCH

administration increasing food intake in normal rats (31,32). As for the melanosome aggregation/ dispersion system, the action of a-MSH is the opposite of that of MCH, resulting in decreased food intake (33). The antagonistic action of MCH and a-MSH extends to the regulation of the hy-pothalamo-pituitary-adrenal (HPA) axis, MCH decreasing plasma corticosterone and ACTH levels relative to controls, while a-MSH does the contrary, increasing plasma corticosterone and ACTH levels. (33).

I.c.v. administration of a single dose of MCH results in stimulation of food intake that is dose-dependent, lasts for about 6 hours (32,33), but is moderate in amplitude when compared to the effect of NPY (34). The feeding effect of central MCH administration is counteracted not only by a-MSH as just mentioned, but also by glucagon-like peptide (GLP-1) and neurotensin (34).

As is the case for NPY, central leptin administration decreases hypothalamic MCH expression and prevents MCH-induced increase in food intake (35,36). However, contrary to what is observed with NPY, long-term central MCH administration fails to produce sustained increases in food intake or in body weight gain, thus obesity (32). This is in contrast with the observation that, in the obese ob/ob mouse, hypothalamic MCH expression is increased and may participate in the final development of the obese phenotype (31).

To strengthen the physiological role of MCH in food intake regulation, mice carrying a targeted deletion of the MCH gene have been produced. When compared to controls, these mice are hy-pophagic, leaner, have decreased carcass lipids, and increased metabolic rate (37). Thus, MCH does represent an important hypothalamic pathway in the regulation of body weight homeostasis, a pathway further completed recently by the discovery of a 353 amino acid G-protein-coupled receptor, to which MCH specifically binds (38,39). Such a receptor is present in the hypothalamus and many other brain regions, in keeping with the several functions, beyond the feeding behavior, that are under the influence of MCH (38,39).

Effects of Orexins

Orexin A and B (from the Greek word for appetite) have been discovered recently and are also referred to as 'hypocretins' (due to their hypothalamic location and sequence analogy to secretin) (40,41). Orexin A (33 amino acids) and orexin B (28 amino acids) neurons are restricted to the lateral and posterior hypothalamus, whereas both orexin A and orexin B fibers project widely into different areas of the brain (42-45). The corresponding cloned receptors, OX1 and OX2, are found in the hypothalamus (ventromedial hypothalamic nucleus, paraventricu-lar nucleus) a distribution that is receptor-specific (41,46).

The stimulatory effect of central administration of orexin on food intake is much weaker than that of NPY, and is smaller than that elicited by MCH. Orexin A is more potent than orexin B in eliciting feeding, and its effect is consistent, whereas that of orexin B is not (47, 48). When given peripherally, orexin A rapidly enters the brain by simple diffusion as it is highly lipophilic, while orexin B with its low lipophilicity is degraded, thus failing to reach the brain adequately (49). The fact that orexin B is easily inactivated by endopeptidases could be one of the reasons for its relative inefficiency in regulating food intake. In a way similar to what has been observed with NPY, some of the centrally elicited effects of orexin A, e.g. the stimulation of gastric acid secretion, are mediated by an activation of the parasympathetic nervous system, favoring anabolic processes (50).

Leptin administration produces a diminution of orexin A levels in the lateral hypothalamus (51), a finding that is in keeping with the observation of the presence of numerous leptin receptors on orexin-immunoreactive neurons in the lateral hypothalamus (52). Additional data must be gathered for the physiological role of the orexin system in food intake regulation to be better understood.

Effects of Opioids

The endogenous opioid system has long been known to play a role in the regulation of ingestive behavior. The opioid peptides exert their action via a complex receptor subtype system implicating kappa, mu and delta receptors for, respectively, dynor-phin, ^-endorphin and the enkephalins (53). The specific modulation of taste and food intake can be partly understood by the use of selective receptor subtype agonists and antagonists (54,55). Typically, the central administration of opioid agonists stimulates food intake, decreases the latency to feed, increases the number of interactions with the food, favors fat as well as sucrose ingestion, and increases body weight gain (54,56-60). In contrast, the central administration of opioid antagonists does the reverse, decreasing food intake and body weight (55,60-62).

The three major types of opioid receptors, mu, kappa, delta, have been cloned and belong to the G-protein-coupled family. Recently, another receptor highly homologous to the opioid receptors, but one that does not bind any opioid peptide with high affinity, has been cloned (63). This opioid receptorlike (ORL-1) is widely distributed within the central nervous system (CNS), the hypothalamus, hippocampus, and the amygdala, in particular (64). The endogenous ligand for this opioid-like orphan receptor has now been isolated (63). It is called nociceptin (as it increases pain responsiveness), or orphanin FQ. It is an 18 amino acid peptide which resembles dynorphin A and has a marked affinity for ORL-1 (63-65). Nociceptin and ORL-1 thus constitute a new peptidergic system within the CNS, a system of potential interest as it is present not only in rodents, but also in humans (64,65). When given centrally, nociceptin stimulates food intake in satiated rats, an effect that is blocked by an opioid antagonist, naloxone. As naloxone does not act at the level of ORL-1, this indicates that stimulation of food intake by nociceptin involves, at some ill-defined steps, the function of the 'classical' opioid system (65). Microinjection of nociceptin into two brain areas implicated in food intake (the ven-tromedial hypothalamic nucleus and the nucleus accumbens) also results in increased in food intake (64). The physiopathological implications of these findings will soon be unraveled.

Opioids and Obesity

The susceptibility to diet-induced obesity in the rat is strain dependent. For example, some strains of rats (e.g. Osborne-Mendel) overeat and become obese when fed a diet rich in fat. Other strains (e.g. S5B/P1) are resistant to high fat diet-induced obesity (66). In this context, it is interesting that central administration of a kappa opioid receptor antagonist decreases the intake of a high fat diet in the obesity-prone rats, while it does not do so in the obesity-resistant ones. In contrast, the central ad ministration of a kappa opioid receptor agonist increases the intake of a high fat diet in obesity-prone rats, while it increases the intake of any type of diet in obesity-resistant animals (66). It is thus conceivable that the sensitivity to opioids differs from strain to strain, possibly from species to species. It is also possible that, within the brain areas constituting the opioid system, the distribution of the opioids, that of their receptors, may vary from strain to strain. This may lead to a strain-specific opioid dependency of the food intake process and evolution to obesity (66).

The likely importance of the opioid system in obesity is illustrated by the observation that the peripheral administration of compounds with potent opioid antagonistic activity to obese rats results in rapid, marked and sustained decreases in food intake and body weight gain (67,68).

Was this article helpful?

0 0
Natural Weight Loss

Natural Weight Loss

I already know two things about you. You are an intelligent person who has a weighty problem. I know that you are intelligent because you are seeking help to solve your problem and that is always the second step to solving a problem. The first one is acknowledging that there is, in fact, a problem that needs to be solved.

Get My Free Ebook


Post a comment