Physiological Control of Ghrelin Secretion

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Circulating ghrelin levels, mostly represented by its acylated form, are rapidly reduced by 80% after total gastrectomy but gradually recover thereafter, indicating that the stomach is the major source of circulating ghrelin but that other tissues can compensate for the loss of ghrelin production after gastrectomy [13].

Ghrelin is secreted in a pulsatile manner [14]. Notably, there is no strict correlation between ghrelin and GH levels, while ghrelin pulses are correlated with food intake episodes and sleep cycles [14].

Specifically, ghrelin secretion in humans has been shown to follow a circadian rhythm with superimposed increases before meals and decreases after food intake [15]. Such a secretory profile suggested that food intake may be triggered by ghrelin increases [15] and, on the other hand, revealed that ghrelin secretion mainly undergoes a metabolic control [16]. In fact, ghre-lin secretion is markedly inhibited by food intake but not by simple gastric distension [17,18].

Among nutrients, glucose, after either oral or intravenous administration, has been shown to exert the most potent inhibitory effect on ghrelin secretion, while the role of free fatty acids and arginine load has not yet been fully established [18-20].

Evidence of a clear negative association between ghrelin and insulin secretion [15] suggested an inhibitory influence of insulin on ghrelin secretion in agreement with data showing a direct modulation of gastric ghrelin expression by insulin itself [21]. Indeed, during both euglycaemic and hypoglycaemic clamp, the steady-state increase in insulin levels is associated with a clear reduction in circulating ghrelin levels [22, 23]. Recently, it has been shown that post-prandial hyperinsulinaemia is a decisive signal for meal-related ghrelin suppression [16]. In insulin-resistant states there is a lower decrement in post-prandial circulating ghrelin concentrations suggesting a negative cycle that augments nutrient intake in obese and type 2 diabetic subjects [16].

Moreover, further confirming the major role of metabolic and nutritional factors in the regulation of ghrelin secretion, several other factors involved in the regulation of food intake and metabolic balance have also been reported as being able to inhibit ghrelin secretion, such as glucagon-like peptide 1 [24], gastrin [24], urocortin-1 [25], PYY [26] and oxyntomodulin [27], or to increase it, such as gastrin [24].

Notably, although playing a functional complementary role in the regulation of appetite at the hypothalamic level, leptin has been shown to be devoid of any modulatory effect on ghrelin secretion [28].

However, the most remarkable inhibitory input on ghrelin secretion reported so far is represented by the activation of somatostatin receptors by somatostatin as well as by its natural analogue cortistatin [29].

Overall, evidence that insulin and somatostatin exert a critical inhibitory action on ghrelin secretion indicates that the latter is under major control from the endocrine pancreas, which, in turn, is under the influence of ghrelin. In fact, in humans, acute intravenous ghrelin administration has been reported to increase circulating somato-statin levels [30] and to induce a transient inhibi tion of insulin secretion that is coupled, although mediated by independent mechanisms, with an increase of circulating glucose levels [30,31].

In agreement with the major influence of nutrition on ghrelin secretion, circulating ghrelin levels are inversely related to body mass index (BMI), i.e. increased in anorexia and cachexia while reduced in obesity and overfeeding, a notable exception being patients with Prader-Willi syndrome (PWS) [3, 32, 33]. In particular, ghrelin hypersecretion has been suggested to be responsible for the hyperphagia and weight excess commonly present in this syndrome [32,33].

In both anorexia and obesity, ghrelin secretion is normalised by recovery of ideal body weight [18,34,35]. These changes are opposite to those of leptin, suggesting that both ghrelin and leptin are hormones signalling the metabolic balance and managing the neuroendocrine and metabolic response to starvation [3,35,36].

In humans, ghrelin secretion has been reported to occur throughout the lifespan, with some age-related variations. In particular, ghrelin secretion significantly increases after birth, peaking during the first two years of life, then decreases until the end of puberty [37]. Moreover, a further decrease of ghrelin levels in elderly subjects has also been reported recently [38].

Gender-dependent differences have been found by some authors [39] but not by others [40].

This general picture of the control of ghrelin secretion generally comes from evaluating total circulating ghrelin levels. As endocrine actions are displayed by acylated ghrelin only, more appropriate information about the control of ghrelin secretion and its functional significance could come from distinguishing plasma variations in acylated and unacylated ghrelin.

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