Orexigenic Gut Peptides Ghrelin

Ghrelin, the endogenous ligand for the growth hormone secretagog receptor (GHS-R), was discovered in 1999 (96,97). It is produced from preproghrelin peptide in the oxyntic gland in the fundus of the stomach, but not in the pylorus (97). Ghrelin is also produced, though to a lower extent, in the small and large intestine (96). Various ghrelin variants are produced from alternative splicing, but the mature molecule is a 28-amino-acid peptide with an octanoyl acyl group on its third amino acid residue. This is acquired after post-translational modification and is essential for its action on appetite (98). There is evidence for ghrelin expression in other tissues, including the hypothalamus, pancreas, lungs, ovaries, and testes. In the hypothalamus ghrelin expression is shown in the ARC adjacent to the orexigenic neurons; NPY and AgRP, PVN, DMN, and VMN; however, its physiological role needs to be established (99,100). Circulating levels change throughout the day in relations to meals, increasing during fasting, peaking just before food intake, and decreasing postprandially (101-104). Ghrelin reaches trough levels 60 to 120 min after food intake. As with other peptides, levels are subject to diurnal variations, being high at night and declining in the early hours of the morning along with leptin levels. The postprandial decline of ghrelin is proportional to calorie intake and nutrient sensing but not stomach volume load. In keeping with this, glucose, but not water/saline, infusion into the stomach caused suppression of ghrelin (105). However, no changes in ghrelin level were observed without normal gastric emptying, which suggests a requirement for a postgastric factor. The effect of glucose on ghrelin is independent of insulin actions. Further studies in humans showed that carbohydrate, and to a lesser extent fat, reduces, whereas protein appears to stimulate, ghrelin levels in normal (106) and type 1 diabetic patients (107). However, the micronutrient content and calorie load can not wholly explain the postprandial suppression of ghrelin; other factors might be involved. Whereas leptin, GHRH, testosterone, thyroid hormone, and para-sympathetic activity upregulate ghrelin, insulin, somatostatin, growth hormone, and PYY3-36 result in its downregulation.

Ghrelin Action

Ghrelin has a number of known effects, including release of growth hormone (GH), ACTH, and prolactin, increasing gastric motility, acid secretion in the cephalic phase response of food intake (108), and promoting cell proliferation. Since its discovery, accumulating evidence supports its orexigenic effects and its role in the regulation of body weight. In both animal and human studies ghrelin has been shown to contribute in signaling the preprandial hunger and meal initiation (97,109). In animals, acute administration of ghrelin increases food intake (110,111), whereas chronic administration results in hyperphagia and obesity (112). It is worth noting that the effects of ghrelin on food intake and adiposity are independent of its effect on GH. Central administration of ghrelin, by direct injection into the ICV or ARC, stimulates food intake and can be inhibited by pretreatment with ghrelin antagonists/antibodies. This suggests that ghrelin is an endogenous regulator of food intake. Ghrelin shows similar effects in humans; following intravenous ghrelin administration, appetite and food intake increase by 28% in normal volunteers, though this effect is short-lived (113). However, satiety is not changed postprandially following ghrelin administration (113).

Mechanism of Action

Evidence supports ghrelin exerting its effects mainly via the orexigenic peptides NPY/AgRP in the hypothalamus. ICV injection of ghrelin increases NPY/AgRP gene expression and blocks the anorexic actions of leptin. NPY/AgRP antibodies or NPY Y1 receptor antagonists abolish ghrelin-induced feeding, but ghrelin antibodies do not inhibit NPY-induced feeding. Electrophysiological studies have shown that ghrelin activates NPY neurons and inhibits POMC, with the former being postsynaptic and the latter a presynaptic effect. Peripheral administration of ghrelin also results, though reduced, in c-fos expression primarily at the ARC site. This suggests that ghrelin might reach the ARC through the incomplete blood-brain barrier at the base of the hypothalamus. In keeping with this, animals with damaged ARC show GH response, though reduced, but no feeding effects after ghrelin administration.

Ghrelin neurons are expressed elsewhere in the brain. An increase in c-fos activation following central ghrelin administration has been shown in the ARC, PVN, DMN, the lateral hypothalamus, and the area postrema and NTS in the brainstem (114,115). The central ghrelin neurons also terminate on orexin-containing neurons within the lateral hypothalamus (LH) (116), which have been shown to be stimulated following ICV ghrelin injection.

Despite the above evidence supporting its orexigenic effect, ghrelin appears not to be the only factor in meal initiation and food intake. Recently, ghrelin infusions in six men and one woman with previous complete truncal vagotomy had no effect on food intake (117). This suggests that an intact vagal nerve is required for ghrelin's stimulatory effect.

Ghrelin in Physiology and Disease

In addition to calorie intake and meal composition, ghrelin levels appear to be influenced by the nutritional status of the individual. The basal level is shown to be reduced in chronic obesity with an attenuated postprandial response (118-120). The latter may explain persistent eating habits in obese patients. Paradoxically, the level is increased during fasting, cachexia (121), in states of malnutrition, and in patients with anorexia nervosa (122). Interestingly, and contrary to these findings, ghrelin levels are reduced after a Roux-en-Y gastric bypass, but not other forms of antiobesity surgery, despite massive weight loss (33). One explanation might be that the surgery involves the removal of the ghrelin-secreting part of the stomach (33,123), although the real mechanism is still unknown. However, in addition to the mechanical restriction owing to reduced stomach size and hence reduced meal portions, it has been hypothesized that the decreased ghrelin level in these patients might be the reason for maintaining their weight loss.

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