Ghrelin, produced by the stomach, is a powerful appetite stimulant.

Ghrelin: An Orexigen

Ghrelin is as effective an orexigen as is NPY. Increased circulating levels readily stimulate feeding, and sustained high levels promote hyperphagia and adiposity. Ghrelin, produced in the stomach and in a discrete subpopulation of neurons located in the sub-PVN zone, is a putative physiological signal for generating hunger. Ultradian secretion of ghrelin from the stomach is accelerated during the pre-meal interval and by fasting. Unlike multiple leptin targets, central ghrelin targets are the ghrelin R expressing ARC NPY neurons only. Increasing ghrelin levels accelerate rhythmic NPY discharge in the PVN to stimulate appetite.

The orexigenic effects of ghrelin are regulated by leptin in two ways. Centrally, leptin restrains ghrelin-induced NPY release, and peripherally, it inhibits ghrelin secretion. Consequently, ghrelin hypersecretion during the pre-meal interval and fasting is due, in part, to attenuated leptin restraint on ghrelin secretion, and the postprandial rise in leptin secretion restores inhibition of ghrelin secretion peripherally and ghrelin-induced appetite centrally. It is highly likely that this dual action of leptin is crucial for suppression of ingestive behavior during the inter-meal interval.

NPY and Feeding Behavior

It seems that we can no longer think of NPY as only a potent orexigenic agent that acts to increase food intake in all circumstances. There is a more complex role of NPY in organizing feeding behavior than is apparent when only the total amount of food consumed is measured.33 Both NPY microinjections and injections of Y1 receptor agonist in the third ventricle of Siberian hamster markedly increase foraging and food hoarding to a greater extent than food intake.7 Conversely, Y5 receptor agonists stimulate food intake to a greater degree than foraging or hoarding.6 Accordingly with these results, NPY microinjections into the PVN and perifornical area (PFA) of the hypothalamus can alter the ingestive behavior of foraging and food hoarding in starving rats. Specifically, NPY injected into the PVN or PFA increases food hoarding to a greater extent than foraging or food intake. Moreover, the NPY Y1 receptor seems to play a role in controlling food hoarding through the PVN and PFA on the basis of the ability of an Y1 receptor antagonist to inhibit increases in food hoarding in refed rats.6,22 Therefore, understanding the NPY-mediated control of human foraging and food storing (hoarding) could provide an additional target for pharmaceutical or behavioral manipulations in the treatment or prevention of obesity7

Pharmacological Management of Undernutrition

Older patients with a poor response to treatment of underlying causes and nutritional supplementation may benefit from orexigenic agents (Table 5). Megestrol acetate is a synthetic progestogen approved for use by the Food and Drug Administration (FDA) as an orexigenic agent in patients with Acquired Immune Deficiency Syndrome (AIDS) and cancer-related anorexia and cachexia. Recent evidence indicates that megesterol acetate is also an effective orexigenic agent in geriatric patients. Thromboembolic disease and adrenal suppression are rare complications, but patients should be monitored closely for these events.

Table 5. Orexigenic agents

Megesterol acetateMirtazapineDronabinol (delta-9-tetrahydrocannabinol)CorticosteroidsLoxiglumide (cholecystokinin antagonist)OxoglutarateAnabolic agents (testosterone, anadrol)OxandrinGrowth hormoneCyproheptadine

Dronabinol (delta-9-tetrahydrocannabinol), the active ingredient of Cannabis sativa, is another FDA-approved orexigenic agent for use in patients with AIDS. Dronabinol is also an effective orexigenic and antiemetic in patients receiving cancer chemotherapy. Additional evidence indicates that dronabinol induces weight gain in persons with dementia, although research has yet to determine whether weight gain in such patients is due to increased energy intake or reduced agitation with improved behavior and consequently decreased energy expenditure. Side effects of dronabinol in older adults include delirium, euphoria, and increased somnolence. The latter two qualities may favor the use of dronabinol as an orexigenic agent in palliative care.

One-third of depressed older adults manifest with weight loss. Effective antidepressant therapy should result in weight gain in this subset of patients. Notably, the choice of antidepressant therapy may influence body weight reuptake. Selective serotonin (5-hydroxytryptamine, 5-HT) inhibitors, such as fluoxetine, can cause significant weight loss at the onset of therapy. Evidence in younger adults suggests that this is a transient phenomenon with baseline body weight being restored as treatment progresses. However, age-related changes in energy regulation and adaptation to chronic disease may delay or prevent return to baseline body weight in older patients. Mirtazapine has proved useful in the management of depressed patients with weight loss. Mirtazapine is a well-tolerated and effective antidepressant that inhibits presynaptic alpha2 adrenergic receptors and postsynaptic 5-HT2 and 5-HT3 receptors. Mirtazapine has been shown to induce an earlier increase in appetite and subsequent weight gain in older depressed persons with weight loss.

Several agents previously touted as effective orexigenic agents, such as human growth hormone, have fallen out of favor. The administration of human growth hormone to healthy older adults has been shown to increase muscle bulk. However, significant side effects such as carpal tunnel syndrome, gynecomastia, and hypoglycemia were noted; furthermore, the increase in muscle bulk failed to produce a parallel increase in muscle strength. Inadequate data regarding the safety and efficacy of growth hormone administration preclude routine clinical use. Similarly, the role of insulin-like growth factor (IGF-I) in the management of undernutrition is questionable. Although the data suggest that exogenously administered IGF-I may enhance nitrogen retention, gluconeogenesis, and maintenance of normal gastrointestinal function, evidence-based outcome studies are lacking.

Abundant data exist regarding the role of anabolic steroids in the management of undernutrition. However, current evidence supports the restriction of testosterone therapy as an orexigenic agent to hypogonadal undernourished men. As a general rule, pharmacological treatment should be considered second-line therapy and reserved for patients who have failed to respond to nonpharmacological measures.

Neuropeptide Mediators

It was soon established after neuropeptide Y (NPY) was discovered in 1982 that this 36–amino acid neuropeptide is a highly potent orexigen in the brain.153 The finding that a set of arcuate nucleus neurons express NPY led to focus on this region in appetite regulation (Figure 44.3). NPY neurons co-express agouti-related peptide (AgRP), another orexigen that is longer acting.154 Pro-opiomelanocortin (POMC) neurons are also clustered in the arcuate nuclei and release α-melanocyte stimulating hormone (α-MSH), an anorectic peptide derivative of POMC, which stimulates metabolism, via melanocortin-4 receptors (MC4), expressed in several brain regions, including the PVN, nucleus tractus solitarii (NTS), lateral hypothalamus, and VMN.155,156

AgRP is an antagonist at MC4 receptors, so it blocks α-MSH actions.157,158 POMC neurons also produce cocaine and amphetamine regulated transcript (CART) in the rat,159 but not in humans, in which CART is found only in a minority of NPY neurons and is absent in POMC neurons.160 Overall, CART has anorexigenic and thermogenic actions,159,161 but applied to the PVN CART is orexigenic.163

It is clear that the NPY/AgRP and POMC/CART arcuate nucleus neurons in the base of the hypothalamus, adjacent to the median eminence, where the blood–brain barrier is deficient, are the major first order hypothalamic neurons in the control of appetite and metabolism, positioned to respond to blood-borne metabolic signals.9 Hence, when stimulated, NPY/AgRP neurons alter activity of second-order neurons in the regulatory network that results in stimulated feeding, and reduced metabolism, in particular neurons in the PVN and dorsomedial hypothalamus (DMH)163 and, thence, melanin concentrating hormone (MCH) neurons and orexin neurons in the lateral hypothalamus (Figure 44.3).164,165 These lateral hypothalamic neurons increase feeding164,166 and affect peripheral metabolism and fat storage via autonomic (sympathetic) outflow.167 The actions of NPY/AgRP from arcuate neurons on MCH neurons are evidently indirect, via the PVN or DMH.163,168,169

Stimulated arcuate nucleus NPY/AgRP neurons release GABA, which inhibits nearby POMC/CART neurons.170 Conversely, when POMC/CART neurons are stimulated they inhibit feeding, partly through releasing α-MSH to act on MC4 receptors in the PVN to stimulate oxytocin and CRH neurons,171 and by also inhibiting MCH and orexin neurons they increase metabolism. Actions of α-MSH on MCH neurons are indirect as they do not express MC4 receptors.169,172

Fine details of the relative importance of the different components of these networks are being clarified by application of optogenetics (channelrhodopsin-assisted circuit mapping), which involves viral transfection of neurons expressing a specific peptide with the channelrhodopsin gene, which then allows excitation of the cell bodies or axons of these neurons by light pulses from a laser source via an implanted optical fiber. This approach is combined with recording of electrophysiological responses of identified neurons to test whether they are targets for the light-stimulated neurons, and with recording eating behavioral responses.173 With this combination, it has been shown that stimulation of AgRP neurons (also producing NPY and GABA) in the arcuate nucleus inhibits POMC neurons, but that this connection is not important for acute feeding responses;173 however, stimulating AgRP inputs to the PVN is important in evoking feeding, and this is mediated by inhibition (via GABA) of oxytocin neurons in the PVN, hence indicating a key role for these neurons in appetite regulation,173 with implications for the explanation of increased appetite in pregnancy, as discussed following.

3.2.3.3 Ghrelin

In contrast to the aging-related increase (or no change) of gut peripheral anorexigens (CCK, PYY, GLP-1), data on the plasma levels of the only one peripheral orexigen, ghrelin, are not consistent. Although some authors reported a decline in serum ghrelin levels in old humans (Rigamonti et al., 2002; Sturm et al., 2003), a recent study did not confirm these findings (Bauer et al., 2010). The plasma concentration of ghrelin in a group of centenarian women was lower by 33% and in a group of elderly (mean age 66 years) by 25% than in young subjects (Baranowska et al., 2006). However, the number of investigated subjects was in all studies too small to allow for definite conclusions. Ghrelin secretion depends also on the composition of the diet (Ferrini et al., 2009), which was different in the studied populations. The low secretion of ghrelin in the elderly may result from impaired sensitivity of ghrelin-secreting cells since after a carbohydrate-rich test meal their serum ghrelin level did not change postprandially, whereas the decline was substantial in middle-aged individuals (Ariyasu et al., 2008).

It was found that GH responses to ghrelin administration in the elderly were lower than those seen in young people (Broglio et al., 2003). If the orexigenic response of the NPY/AgRP neurons to ghrelin decreases similarly in the elderly, it may be concluded that decreased serum ghrelin levels and an inadequate orexigenic response to ghrelin (Akimoto-Takano et al., 2005) may contribute to the age-related impairment of food intake and anorexia of aging.

Ghrelin administration to old patients with heart failure or chronic obstructive pulmonary disease improved food intake, BW, functional capacities, and attenuated muscle wasting (Depoortere, 2009; Nagaya et al., 2005, 2004). Moreover, it was also useful in elderly patients when applied prior to hip replacement (Akamizu et al., 2008).

The presented data that demonstrated the effects of aging on the secretion or efficacy of the anorexigenic enteric peptides involved in the control of food intake have to be regarded with caution since the results were subjected to several biases. The obvious ones were gender, the small number of participating old subjects, and the different body mass and health status of the elderly (“healthy,” “frail,” or “undernourished”). In some of the studies, the basic blood levels of hormones were measured after an overnight fast (Leidy et al., 2010), whereas other authors performed measurements before and after a test meal not reporting on the time elapsed since the previous meal. In all studies, the sensation of hunger, fullness, and satiation were measured by similar methods; however, the types of test meals were different in respect to their caloric content, proportions of fat and carbohydrates, food form, and portion size. For example, Leidy et al. (2010) showed in a study of 25 elderly persons that postprandial hunger and ghrelin concentration were greater following a beverage versus a solid meal, whereas no effects were observed for CCK or GLP-1 (Leidy et al., 2010). Fatty meals (40% vs. 20% fat) increased the serum concentration of GLP-1 and lowered the level of active ghrelin more in the elderly than in young subjects (Di Francesco et al., 2010). Thus, the consumption of fat-rich meals in the elderly increases the satiety signal from the gut, and this condition may lead to a reduction in calorie intake.

Ghrelin And Obesity

In contrast to earlier models that expected the endogenous ligand of the growth hormone secretagogue receptor to exclusively govern growth hormone secretion, ghrelin is believed to play its main physiological role in the regulation of energy balance. As the only peripherally circulating orexigenic agent known, ghrelin triggers appetite and nutrient intake. Ghrelin might even represent the first known “meal initiation factor.” However, conclusive evidence that meal-related circadian changes in plasma ghrelin concentrations are responsible for the initiation of nutrient intake rather than representing an epiphenomenon of trained meal patterns is still missing. Based on clinical investigations of meal-related changes in plasma ghrelin levels and data generated by insulin- and glucose-clamp studies, plasma insulin and blood glucose levels are very likely to be involved in the general regulation of ghrelin secretion. Although hyperinsulinemic–euglycemic clamps have been repeatedly shown to decrease circulating ghrelin levels, it remains unclear whether experimental conditions during clamp studies are comparable with the lower maximum peaks and the shorter duration of postprandial insulin levels. The possibility cannot be excluded that additional blood-derived factors may be responsible for meal-related changes in ghrelin concentrations or that gastrointestinal nutrient sensors may modulate ghrelin expression and secretion rates.

Although counterintuitive, the finding that circulating ghrelin concentrations are low in obesity not only mirrors earlier observations of hyperleptinemia in obesity, but may be explained by compensatory mechanisms aiming to communicate to the central regulatory centers that energy stores are full. Though it is unclear which signal communicates increased adipocyte size to ghrelin-secreting cells (leptin, interleukin-6, and adiponectin would be candidates), other phenomena and symptoms that commonly occur during obesity (such as a frequently filled stomach or insulin resistance) should be carefully investigated to determine their contribution to hypoghrelinemia. Ghrelin gene polymorphisms have been described by several groups; linkage analysis studies, however, failed to prove a solid association between ghrelin and obesity. Although diet-induced human obesity and polygenic (e.g., Pima Indians) or monogenic (e.g., MC4-R defect) causes of human obesity all present with low plasma ghrelin levels, there is one group of severely obese patients in whom markedly increased plasma ghrelin concentrations have been observed. Prader-Willi syndrome, an impressive hunger syndrome in which patients exhibit morbid obesity and numerous other symptoms, is caused by a defect in the short arm of chromosome 15 and is accompanied by circulating ghrelin levels that are three- to fivefold higher than in healthy controls. Although the overlap between symptoms of Prader-Willi syndrome and the effects of ghrelin administration is impressive, only treatment with a potent, but safe ghrelin antagonist compound will reveal whether ghrelin is part of the pathogenesis in Prader-Willi syndrome. Discussion is ongoing as to whether increased plasma ghrelin is only a consequence of the severe caloric restrictions that are a central part of the treatment strategies for patients with Prader-Willi syndrome in an attempt to control their energy balance. The only other population in which comparably high ghrelin levels have been reported are patients with cachexia or anorexia nervosa, in whom high ghrelin levels are believed to reflect a physiological compensation effort in response to either a chronically empty stomach or a markedly decreased fat mass. Though circulating ghrelin levels are significantly lower in obese individuals, these levels are still very substantial when compared to nearly undetectable ghrelin concentrations in patients after gastric bypass surgery. The superior effectiveness of this bariatric procedure is considered to be partially due to a “knock-down” of endogenous ghrelin secretion caused by the lack of stimulation of gastric cells by incoming nutrients. On the other hand, an increase in endogenous ghrelin in response to diet-induced weight loss could contribute to the very high likelihood of recurrence of obesity. Carefully conducted clinical studies are imperative to discover the answer to this important question.

Which of the following stimulates hunger?

Which of the following is known as a hunger hormone quizlet?

Which of the following is the major role of leptin in the body?

What is the major role of leptin quizlet?