The regulation of energy balance involves the exquisite coordination of food intake and energy expenditure. Experiments in the 1940s and 1950s showed that lesions of the lateral hypothalamus reduced food intake; hence, the normal role of this brain area is to stimulate feeding and decrease energy utilization. In contrast, lesions of the medial hypothalamus, especially the ventromedial nucleus (VMH) but also the PVN and dorsomedial nucleus (DMH), increased food intake; hence, the normal role of these regions is to suppress feeding and increase energy utilization. Yet discovery of the complex networks of neuropeptides 10–3 and other neurotransmitters acting within the hypothalamus and other brain regions to regulate food intake and energy expenditure began in earnest in 1994 with the cloning of the leptin (ob, for obesity) gene. Indeed, there is now explosive interest in basic feeding mechanisms given the epidemic proportions of obesity in our society, and the increased toll of the eating disorders, anorexia nervosa and bulimia. Unfortunately, despite dramatic advances in the basic neurobiology of feeding, our understanding of the etiology of these conditions and our ability to intervene clinically remain limited.
10–3Examples of Peptides That Regulate Feeding ||Download (.pdf) 10–3 Examples of Peptides That Regulate Feeding
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Parabiosis studies, in which the circulation of two animals is joined, suggested that humoral factors are involved in energy balance. Rats with a medial hypothalamic lesion become obese; when a rat with a VMH lesion had its circulation joined with an unlesioned rat, the normal surgically joined circulatory partner ate less and lost weight. It was hypothesized that fat mass, which represents energy stores, releases a humoral “lipostatic” factor that inhibits feeding.
Obese (ob/ob) and diabetic (db/db) mice are two strains homozygous for different recessive mutations. Both strains are diabetic and typically weigh more than three times those of wild-type mice even when fed an identical diet. When their circulations were joined, it could be concluded that the ob/ob mice lacked a circulating “lipostatic” factor and that the db/db mice were insensitive to it. The missing factor in the ob/ob mouse proved to be leptin, while the db/db mouse lacks the leptin receptor.
Leptin is produced primarily by adipocytes. Plasma levels of leptin correlate with adipose tissue mass; in both humans and rodents, such levels increase with increased adipose tissue and decrease with weight loss 10–11.
Neurobiologic mechanisms controlling feeding and energy expenditure. A. Shows the complex interplay between peripheral and central factors in controlling feeding and energy metabolism. Peripheral factors include short-term or satiety factors, such as CCK, as well as signals that act over longer time periods, such as leptin. B. Shows how leptin influences the arcuate nucleus to stimulate POMC/CART neurons and inhibit NPY/AgRP neurons (left). These arcuate neurons innervate the medial and lateral hypothalamus to regulate secondary orexigenic factors (MCH, orexin) and anorexigenic factors (CRF, TRH). PVN, paraventricular nucleus; LH, lateral hypothalamus; ARC, arcuate nucleus; POMC, proopiomelanocortin; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; CCK, cholecystokinin; AgRP, agouti-related peptide; CART, cocaine- and amphetamine-regulated transcript; CRF, corticotropin-releasing factor; TRH, thyrotropin-releasing hormone. (Adapted with permission from Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–671.)
Administration of leptin over time results in a dose-dependent decrease in body weight. Leptin levels do not change abruptly with meals; this finding distinguishes alterations in leptin from short-term satiety signals such as levels of glucose, amino acids, or cholecystokinin (CCK) 10–5. Mutations in leptin or in the leptin receptor in humans, which are very rare, produce morbid obesity and failure to undergo puberty.
The leptin receptor is most densely concentrated in the medial hypothalamus, the region known from lesion studies to be involved in suppression of feeding. Moreover, these nuclei are near the median eminence, a region of the brain with fenestrated capillaries that allows the entry of circulating leptin and other circulating peptides. The receptor is also highly expressed in the arcuate nucleus and more sparsely in other brain regions, including ventral tegmental area (VTA) dopamine neurons, which are important mediators of reward (Chapter 16). As will be seen later, activation of leptin receptors stimulates anorexigenic factors (antifeeding) and suppresses orexigenic factors (profeeding) to produce its powerful effects on feeding and energy utilization. The leptin receptor is a member of the GPI-linked receptor family, and leptin binding causes the activation of the JAK–STAT pathway.
Leptin influences other neuroendocrine functions. For example, ob mice exhibit many abnormalities characteristic of the starvation state, despite the animals’ obesity and hyperphagia. Such mice exhibit decreased body temperature, decreased energy expenditure, infertility, and decreased immune function. Because leptin replacement corrects all of these abnormalities in the ob mouse, it is believed that leptin may play a role in multiple neuroendocrine cascades.
Satiety signals act more rapidly than the leptin signal and are released in response to meals. Glucose and amino acids absorbed from meals can serve as satiety signals. Another satiety signal is the peptide, cholecystokinin (CCK). It is synthesized in the gut wall and released into the circulation in response to the presence of certain nutrients in the gut. It stimulates G protein–coupled receptors located on the vagus nerve, which in turn transmit information to the nucleus of the solitary tract in the brainstem and subsequently to the hypothalamus. Blockade of peripheral CCK receptors leads to increased food intake. CCK is also synthesized and released by certain neuronal cell types in the brain, where it functions as a peptide neurotransmitter. CCK is reported to exert diverse behavioral effects via actions on CCK1 and CCK2 receptors (see 7–4, Chapter 7). While there remains interest in the development of CCK receptor antagonists for the treatment of obesity and neuropsychiatric conditions, no clinical validation is yet available.
The discovery of leptin raised a great deal of excitement regarding its usefulness in the treatment of obesity. It turned out, however, that the vast majority of obese individuals already have appropriately high levels of leptin, which has turned the field’s attention to other feeding factors, many of which are leptin targets.
The peptide hormone ghrelin is produced by the cells that line the stomach. Ghrelin secretion increases hours after the end of a meal and stimulates appetite for the next meal. The ghrelin receptor, termed the growth hormone secretagogue receptor (GHSR), is G protein–linked. In addition to stimulating feeding, ghrelin helps maintain glucose during caloric restriction. Ghrelin stimulates feeding by activating NPY and agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (see below) and possibly by acting directly on VTA dopamine neurons in the brain’s reward circuit to increase the motivational value of food and related cues. Ghrelin also increases growth hormone release, that is, it is a growth hormone secretagogue. Ghrelin’s activity depends on its octanoylation by ghrelin O-acyltransferase (GOAT). Among many possible mechanisms, bariatric surgery, in which portions of the stomach are excised or constricted in the treatment of severe obesity, may reduce appetite in part by reducing ghrelin secretion. There is interest in the possible use of ghrelin receptor antagonists or GOAT antagonists, still in early stages of investigation, in the treatment of obesity and of ghrelin itself in the treatment of cachexia.
POMC, NPY, and the Arcuate Nucleus
The arcuate nucleus of the hypothalamus plays a central role in energy balance. It contains two groups of GABAergic neurons that produce opposite effects on feeding and energy balance 10–11B. One group expresses POMC and cocaine- and amphetamine-regulated transcript (CART) and exerts anorexigenic effects and increases energy utilization; these cells are potently stimulated by leptin. The other group expresses NPY and AgRP and exerts orexigenic effects and reduces energy expenditure; these cells are inhibited by leptin and are stimulated by ghrelin.
As described above in the discussion of the HPA axis, POMC is a large precursor that is cleaved to produce ACTH, α-, β-, and γ-MSH, and β-endorphin (see 7–4 in Chapter 7). α- and β-MSH reduce feeding and increase energy expenditure acting primarily via the melanocortin receptor 4 (MC4), which is Gs-linked), in the arcuate nucleus itself and also in the lateral hypothalamus, PVN, and DMH, those regions of the hypothalamus known to suppress feeding. MC4 receptors are also highly expressed in the nucleus accumbens, a component of the brain’s reward circuitry (Chapter 16), which may provide a mechanism by which α-MSH suppresses motivation for feeding in addition to suppressing food consumption and increasing energy utilization per se. Knockout of the MC4 receptor in animal models produces excessive feeding and obesity, and, likewise, very rare loss-of-function mutations in the MC4 gene cause morbid obesity in humans.
Recent evidence indicates that POMC neurons express the serotonin 5HT2C receptor, which, when activated, stimulates melanocortin release. This might explain the mechanism by which serotonin-promoting drugs (eg, fenfluramine or fenfluramine–phentermine combinations; Chapter 6) cause weight loss, while many second-generation antipsychotic drugs with 5HT2C antagonism properties cause severe weight gain. Lorcaserin, a selective 5HT2C agonist, has recently been approved by the US Food and Drug Administration for the treatment of obesity. Meanwhile, phentermine, in combination with the anticonvulsant drug topiramate (Chapter 19), is also approved for the treatment of obesity, but the mechanism involved remains unknown.
In contrast to melanocortins, NPY is a potent activator of feeding and suppressor of energy expenditure acting at its Y1 and Y5 receptors, which are linked to Gi/o. The NPY neurons of the arcuate nucleus also express AgRP that acts as an inverse agonist at the MC3 and MC4 receptors. AgRP not only blocks α- and β-MSH binding but also serves as an inverse agonist: it independently inhibits MC3 and MC4 function and thereby stimulates feeding and inhibits energy expenditure. In addition to being inhibited by leptin, NPY/AgRP cells are stimulated by ghrelin.
Based on this evolving model of feeding regulation, one would predict that melanocortin agonists or NPY antagonists would be useful in the treatment of obesity. Numerous agents are in development but have not yet been tested extensively in the clinic.
These complex peptidergic networks provide many potential molecular targets for the treatment of obesity, but to date potential treatments have been difficult to develop likely because of compensation within the hypothalamus and brainstem and rapid development of homeostatic adaptations.
Both the POMC and the NPY neurons of the arcuate nucleus project to the lateral hypothalamus. As mentioned earlier, this brain area is the site of potent orexigenic factors. One of the most important is melanin-concentrating hormone (MCH), which stimulates appetite and suppresses energy utilization. MCH receptors, which are Gi/o linked, are enriched in the hypothalamus as well as in the nucleus accumbens. MCH antagonists, beyond serving as potential antiobesity treatments, are being evaluated for their possible antidepressant use, based on a growing number of studies in animal models.
More recently, the lateral hypothalamus was also found to play a central role in arousal. Neurons in this region contain cell bodies that produce the orexin (also called hypocretin) peptides (see also Chapter 6, 6–25). These neurons project widely throughout the brain and are involved in sleep, arousal, feeding, reward, aspects of emotion, and learning. In fact, orexin is thought to promote feeding primarily by promoting arousal. Mutations in orexin receptors are responsible for narcolepsy in a canine model, knockout of the orexin gene produces narcolepsy in mice, and humans with narcolepsy have low or absent levels of orexin peptides in cerebrospinal fluid (Chapter 13).
Lateral hypothalamus neurons have reciprocal connections with neurons that produce monoamine neurotransmitters (Chapter 6). It should not be surprising that arousal and feeding are jointly regulated since feeding is absolutely central to survival, and the wake period for free-living organisms must be associated with the ability to find and consume food.
Dopaminergic Reward Circuits
Reward circuits, which are described in detail in Chapter 16, play a key role in feeding behavior. New, palatable foods cause dopamine release from VTA neurons of the midbrain that project to the nucleus accumbens, prefrontal cortex, and other limbic structures that regulate emotion. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with rewards (such as food). It acts in the orbital prefrontal cortex to set a value on rewards, and dopamine released from the substantia nigra acts in the dorsal striatum to consolidate efficient motor programs to obtain rewards. It is very interesting then, as mentioned above, that orexin, leptin, and ghrelin receptors are expressed in the VTA, and MC4 and MCH receptors are enriched in the nucleus accumbens. There is increasing evidence that some of the actions of these feeding peptides are mediated at the level of the VTA–NAc circuit: recent studies, for example, have shown that injection of leptin into the VTA suppresses feeding behavior, while RNA interference (RNAi; Chapter 4)–mediated knockdown of leptin receptors in the VTA increases food intake, sensitivity to highly palatable foods, and locomotor activity.