The polypeptide ghrelin was initially described and characterized as the endogenous ligand for the growth hormone secretagogue receptor in 1999 (92). The ghrelin molecule contains 28 amino acids and an acyl radical, the latter being essential for biological effect. Ghrelin is synthesized and secreted principally by the oxyntic cells of the stomach, reaches the anterior pituitary via the circulation, and stimulates growth-hormone secretion by the somatotrophs. The nutritional effects of ghrelin became evident when it was shown that central (i.c.v.) administration potently increased food intake in rodents (93). A similar effect on food intake was observed following peripheral (i.v.) injection of ghrelin in rats (93). In humans, intravenous administration of ghrelin stimulates food intake by ~30 percent (94). Interestingly, ghrelin is the only metabotrophic peptide thus far identified that stimulates food intake directly when administered peripherally.
Physiological studies have indicated that ghrelin serves as a peripheral signal for hunger and meal initiation: Blood levels increase during fasting, peak sharply just before feeding, and fall rapidly following food intake (95). Prolonged administration of ghrelin in rodents leads to chronic hyperphagia and weight gain, and obese persons typically have high plasma leptin and low ghrelin levels (96). There is a diurnal rhythm in ghrelin secretion, with peak levels in the morning and the nadir at night (95).
The mechanism of action of ghrelin involves stimulation of hypothalamic neurons (97) and inhibition of gastric vagal afferent signals (98). Based on the foregoing, it is plausible that ghrelin or its analogues could be candidates for future therapy for primary anorexia as well as the anorexia and cachexia often seen in patients with HIV/AIDS, systemic disorders, and malignant diseases. Conversely, ghrelin antagonism is an attractive idea for drug development for obesity and hyperphagic disorders.
The gut-derived peptideYY (PYY) is a member of a family of structurally related peptides that includes PP and NPY (7, 8, 91). PYY is synthesized by the mucosal endocrine L cells, which are located in the small intestine and large bowel. PYY3-36 is the major isoform secreted into the circulation (98). Feeding is a major stimulus for the release of PYY, which then serves as an anorectic/satiety signal from the intestinal cells. The potent, anorectic effect of PYY3-36 has been demonstrated in rodent studies involving direct administration of PYY3-36 into the arcuate nucleus. In human volunteers, peripheral administration of PYY3-36 inhibited food intake by 30 percent compared with placebo (99).
PYY3-36 appears to exert its anorectic effect through coordinate inhibition of orexigenic NPY neurons and stimulation of POMC neurons in the arcuate nucleus. These molecular changes are observed following peripheral administration of PYY3-36 (99). High-affinity hypothalamic Y receptors are the target of PYY3-36 action. Activation of the Y2 receptor subtype on NPY neurons triggers inhibitory presynaptic signals. Consonant with this mechanism, Y2 receptor knock-out mice lose their responsiveness to the anorectic effect of PYY3-36 (99). Notably, the NPY neurons in the arcuate nucleus are the central integrating sites for numerous peripheral signals (including leptin, insulin, PYY3-36, and ghrelin) that regulate food intake. Initial experience indicates that PYY3-36 is well tolerated and effective in suppressing appetite over the short term in human studies (100). Clearly, PYY or its analogues hold immense promise as candidates for obesity-drug development.
Glucagon-like peptide-1 (GLP-1) is derived from the precursor molecule prepro-glucagon. Site-specific cleavage of prepro-glucagon in the pancreas results in glu-cagon, whereas in the intestinal endocrine L cells the result is GLP-1. Both GLP-1 and PYY are cosecreted by the intestinal L cells in response to the arrival of nutrients in the gut. Like PYY, GLP-1 also appears to serve as a gut-derived satiety signal. Administration of GLP-1 into the cerebral ventricles results in marked inhibition of feeding in rodents (101). GLP-1 often is described as an incretin because of its effect in boosting postprandial insulin secretion. Additional glucoregulatory actions of GLP-1 include suppression of glucagon secretion and prolongation of gastric emptying (102). GLP-1 can induce modest weight loss probably through inhibition of food intake, induction of satiety, and delay in gastric emptying (103).
In clinical trials, subcutaneous injection of GLP-1 before each meal in patients with diabetes resulted in improvement in glycemic control without untoward effects (104). Exendin-4, a GLP-1 receptor agonist with longer biological action than GLP-1, also is showing promise in clinical trials (105). Endogenous GLP-1 abundance can be augmented by inhibition of dipeptidyl peptidase-4 (DPP4), the enzyme involved in GLP-1 breakdown. Such a strategy using a novel DPP-4 inhibitor (NVP DPP728) has been reported to improve glycemic control in subjects with diabetes (106). Thus, GLP-1 appears to be an intestinal satiety factor with diverse metabolic effects favorable for control of hyperglycemia. Not surprisingly, there are current efforts that are focused on developing novel antidiabetic agents based on GLP-1 augmentation, as reviewed elsewhere in the book.
Cholecystokinin (CCK) is best known for its role in food digestion, namely stimulation of pancreatic-enzyme secretion and gallbladder contraction. However, CCK has been recognized as a potent satiety factor for more than three decades (107). Peripheral and central mechanisms appear to mediate the anorectic/satiety effects of CCK. Peripherally, activation of CCKA receptors on vagal nerve endings and pyloric sphincter reduces food intake (108). Centrally, interactions between CCK and leptin pathways elicit synergistic anorectic effects; an additional mechanism of action of CCK might also involve activation of brain stem neurons that regulate portion size (8, 109). The effect of peripheral administration of CCK usually is transient and more consistent with a modulatory effect on satiety/meal termination rather than primary inhibition of meal initiation (108, 110). To induce durable inhibition of food intake, high doses and prolonged administration of CCK have been tried, but success has been limited by rapid development of tolerance (111).
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