In the past few years, much progress has been made in the understanding of how people maintain body weight and how homeostasis is affected.19–22
In 1999, ghrelin was discovered in the stomach as an appetite stimulatory signal from the periphery with structural resemblance to motilin.1,4,5,23
Previous studies have shown that acylated ghrelin produces stimulatory effects on food intake via activation of NPY, AGRP, and orexin in the hypothalamus, and on gastric emptying.4,5,23–25
However, very little is known about the physiological role of desacyl ghrelin. We found that administration of desacyl ghrelin produced inhibitory effects on feeding. Notably, the anorexigenic effect of desacyl ghrelin was inversely proportioned to that of the orexigenic effect of acylated ghrelin. Considerable evidence cumulatively indicates that rapid gastric emptying is closely related to overeating and obesity, as delayed gastric emptying is to anorexia and cachexia.26–28
We previously reported that acylated ghrelin stimulates feeding behaviour with its mechanism of action involving the increase of gastric emptying.23
In the present study, administered desacyl ghrelin decreased the gastric emptying rate. Recently, in vitro desacyl ghrelin has been shown to inhibit cell proliferation in breast cancer cells and cell death in cardiomyocytes and endothelial cells through binding to an unknown receptor that is distinct from GHS-R.29
In addition, desacyl ghrelin influences contractility of the papillary muscle.30
These observations indicate that desacyl ghrelin is not devoid of any activities and may have an anorexigenic activity that is contrary to the orexigenic activity of acylated ghrelin.
Neuropeptides in the hypothalamus play a pivotal role in physiological mechanisms regulating food intake and body weight.19–22
Neuropeptides that stimulate feeding comprise NPY, AGRP, orexin, MCH, and beacon, whereas those that inhibit comprise CART, POMC, NMU, CRH, and urocortin. Previous studies have shown that acylated ghrelin and GHS-R antagonists influence feeding behaviour and gut motility.4–6,31,32
GHS-R is present in various regions including the hypothalamus and intestine.1,4,5
In the hypothalamus, GHS-R is located in the ARC, where two orexigenic peptides, NPY and AGRP, are synthesised in the neuron. Up to now, acylated ghrelin has been reported to stimulate feeding behaviour with its mechanism of action involving activation of hypothalamic neurons.4,5,23–25
In the present study (unpublished data) and in previous reports,33
c-Fos expression in the ARC and the PVN was increased by administered acylated ghrelin. On the other hand, peripheral administration of desacyl ghrelin also showed an increase in c-Fos expression in the ARC and in the PVN. Gene expression of anorexigenic CART and urocortin in the hypothalamus was increased by administration of desacyl ghrelin. Both CART expressing neurons and urocortin expressing neurons are present in several brain regions that include the hypothalamus.34,35
Several studies have shown that CART and urocortin are endogenous satiety factors in the central nervous system.19–22
Date et al
recently reported that GHS-R is synthesised in vagal afferent neurons in the nodose ganglion and transported to their afferent terminals in the stomach.36
It has been demonstrated that desacyl ghrelin has no effects on vagal nerve activities, even though acylated ghrelin acts as an orexigenic signal from periphery to the hypothalamus through the vagal nerve.23,36
We also found that peripherally administered desacyl ghrelin showed no significant effects on c-Fos expression in the NTS of the brainstem. Banks et al
recently reported that desacyl ghrelin can cross the blood-brain barrier in the blood to brain direction, although acylated ghrelin enters the brain to a far lesser degree.37
Taken together, these observations indicate that desacyl ghrelin can act, on hypothalamic sites that are accessible to peripheral hormones, as a feeding suppressor through the endocrine pathway. On the other hand, the receptor for desacyl ghrelin has not been identified. However, our results indicate that desacyl ghrelin decreases food intake with its mechanism of action involving the hypothalamus and stomach. In addition, the inhibitory effect of desacyl ghrelin administered intraperitoneally on feeding was faster than that of desacyl ghrelin administered intracerebroventricularly, suggesting an involvement of peripheral mechanism(s) that are yet to be examined.
To explore the effects of long term overexpression of desacyl ghrelin, we created Tg mice that overexpress desacyl ghrelin. As expected, the Tg mice gained less weight with reduced fat mass compared with non-Tg littermates. The linear growth showed a tendency to decrease in Tg mice. Consistent with the observation that administration of desacyl ghrelin decreased food intake and gastric emptying, these were reduced in Tg mice. There was no significant difference between Tg mice and non-Tg littermates in body temperature and oxygen consumption. Therefore, this thin phenotype of the Tg mice may be due, at least in part, to a decrease in food intake.
These findings indicate that desacyl ghrelin induces a state of negative energy balance and body weight decrease by inhibiting food intake in an inverse manner to acylated ghrelin. The effect of ghrelin on adipogenesis still remains to be determined. In bone marrow, Thompson et al
recently reported that acylated ghrelin and desacyl ghrelin stimulate tibial bone marrow adipogenesis via a receptor other than GHS-R.38
On the other hand, Zhang et al
reported that ghrelin inhibits adipogenesis in 3T3-L1 cell line by stimulation of preadipocyte cell proliferation via a novel ghrelin receptor subtype.39
The present study shows that effects of administered desacyl ghrelin on food intake and gastric emptying were contrary to those of acylated ghrelin. Moreover, desacyl ghrelin overexpressing mice showed thin phenotype with decreased food intake and gastric emptying rate. Therefore, the distinction between acylated ghrelin and desacyl ghrelin may be needed to investigate physiological and pathological functions of ghrelin. Previous studies have shown that plasma ghrelin concentration is increased by fasting and decreased by feeding.4,5,17
Recently, Ariyasu et al
reported that 70% food restriction decreases the ratio of desacyl ghrelin to acylated ghrelin in food restricted mice compared with ad libitum fed mice.18
Thus, the stomach may regulate energy balance via acylated ghrelin and desacyl ghrelin as an endocrine organ. Eating abnormalities are associated with various diseases including obesity, diabetes, anorexia nervosa, and cachexia. Better understanding of the role of ghrelin peptides may provide an entirely new therapeutic approach for treatment of these various diseases, which have become increasingly prevalent throughout the world.