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Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient-gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.

Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing properties. Because ghrelin is secreted mainly by the stomach, fasting levels fall after distal gastrectomy. The vagal nerve is responsible for periprandial changes. The presents study investigated the impact of preserving the celiac branch of the vagus nerve during laparoscopy-assisted distal gastrectomy on postoperative ghrelin secretion. Between May 2009 and July 2010, 42 consecutive patients who underwent LADG were divided into two groups, the first in which the celiac branch of the vagus was preserved (“Preserved,” n = 21) and the second in which it was not (“Not Preserved,” n = 21). Blood samples were collected for assays of several hormones, including ghrelin, leptin, and insulin; these were taken before and 2 h after breakfast on postoperative day 7. There were no significant differences in the background characteristics of the two groups. Plasma fasting ghrelin decreased significantly after LADG, by about 50 % of the baseline values in both groups. Postprandial plasma ghrelin levels in the Preserved group were significantly lower than those in the Not Preserved group (23 ± 8 vs 32 ± 9 fmol/ml; p = 0.0058). The ratio of the total ghrelin concentration after breakfast to that before was defined as the A/B ratio. The mean preoperative and postoperative A/B ratios were almost the same in the Preserved group (preoperative vs postoperative: 0.41 vs 0.44; p = 0.52). On the other hand, the mean A/B ratio in the Not Preserved group increased from 0.41 to 0.61 postoperatively (preoperative vs postoperative; p = 0.0003). Preservation of the celiac branch of the vagus nerve during LADG was related to the prandial ghrelin changes.

Background: Ghrelin is a gastric secreted hormone deeply implicated in meal initiation and body weight regulation. This peptide is a peripheral orexigenic hormone with a nutritional status-dependent regulation showing a pre-pandrial rise and post-prandial fall pattern. A wide variety of studies have tested the effect of meal different nutrient composition over stomach mucosa ghrelin content and plasmatic ghrelin levels; nevertheless, few and non-conclusive data exist about the direct action of macronutrients on the stomach in order to regulate ghrelin secretion. The recent identification of taste receptors or chemoreceptors in the stomach mucosa would reinforce this paradigm. Aims: To investigate the individual effect of different macronutrients (l-glutamine, lipids, and glucose) over gastric ghrelin secretion by using an in vitro gastric explants model. Results: L-glutamine and intralipid emulsion act locally in the stomach decreasing ghrelin secretion, while no effect was found after glucose exposure. Conclusions: These results show for the first time that macronutrients, and specially amino acids and lipids, act directly in the stomach in order to regulate gastric ghrelin release. Consequently, the chemosensory capacity of the stomach, until now restricted to the oral cavity or intestine, is demonstrated.

Ghrelin, produced mainly in abomasum of ruminants, is a peptide with roles in the regulation of feeding. The present study assessed the alterations of plasma ghrelin in sheep fed with all forage or high-grain rations and the probable effects of altered ghrelin secretion on feed intake in animals with acidic rumen. Eight Karakul male lambs were divided into the control (n = 4) and experiment groups (n = 4) and fed individually for 20 days. The control group was fed an all forage ration for the whole study period. For the experiment group, 40% of the ration was substituted with ground barley for 10 days. For the rest of the study, 62.5% of the ration was substituted with ground barley. Signs of negative alteration of digestive functions (e.g., reduced feed intake, loose manure with reduced dry matter) were observed in the experiment group after day 10 of the experiment when ground barley was increased to 62.5% of the ration. On days 8 and 10 of each step, blood samples were collected for measuring plasma ghrelin level from jugular vein 1 hour before, and 1 and 3 hours after feeding. In the control group, plasma ghrelin increased 1 hour post-feeding (p

Background: Data regarding the possible effects of estrogen on ghrelin secretion in humans are limited and contradictory. Aim: To investigate the effect of estradiol (E2) on ghrelin levels in normal pre- and post-menopausal women. Subjects and methods: A total of 21 women divided into 3 groups, i.e.13 normally cycling women (no.=7, group 1 and no.=6, group 2) and 8 post-menopausal women (group 3). Women of group 1 received increasing doses of E2 through skin patches from cycle days 3 to 5. Women of group 2, underwent total abdominal hysterectomy plus bilateral salpingooophorectomy (TAH+BSO) on cycle day 3. Women of group 3 received po increasing doses of E2 valerate for 15 days. Acylated ghrelin and E2 were measured in all blood samples. Results: In group 1, plasma ghrelin levels did not show any significant changes for the week following cycle day 3. In group 2, ghrelin levels were similar before and after TAH+BSO and remained stable during the first 7 post-operative days. In group 3, no significant changes in plasma ghrelin levels were seen during the 15 days of E2 administration. Conclusions: The present study demonstrates for the first time that ghrelin values were not affected either by exogenous short-term estrogen administration to pre- and post-menopausal women or following ovariectomy in pre-menopausal women. It is suggested that ovarian hormones are not involved in the regulation of ghrelin secretion in women.

Sleeve gastrectomy (SG) and modified duodenal jejunal bypass (MDJB) were compared as procedures for glucose control. We aim to form the initial conclusions with respect to the possibility of (1) whether gastric fundus exclusion is essential for the control of diabetes and (2) application as a low morbidity procedure. SG and MDJB were performed on 10- to 12-week-old Goto–Kakizaki rats that spontaneously develop type 2 diabetes. Rats were observed for 36 weeks after surgery, and glucose, insulin, glucagons-like peptide-1 (GLP-1), glucose tolerate, insulin sensitivity, cholesterol, triglycerides, and free fatty acid levels were measured. Apart from distinct weight loss of SG and MDJB after 1 month compared with sham-operated rats (P

This proof-of-concept study was performed in order to establish the pharmacokinetics and pharmacodynamics of increasing oral doses of the satiety peptides glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY3-36). Six healthy male subjects were given oral doses of either a placebo or GLP-1 in a dose-escalating schedule (doses of 0.5, 1.0, 2.0, and 4.0 mg). Next, another group of six healthy male subjects were given oral doses of either a placebo or PYY3-36 in the same pattern of escalating doses (doses of 0.25, 0.5, 1.0, 2.0, and 4.0 mg). In healthy male volunteers, (i) oral administration of either of the peptides induced a rapid and dose-dependent increase in plasma drug concentrations; (ii) oral administration of GLP-1 induced a potent effect on insulin release; and (iii) both peptides suppressed ghrelin secretion. In conclusion, this study showed, for the first time, that satiety peptides such as GLP-1 and PYY3-36 can be orally delivered safely and effectively in humans.

Roux-en-Y gastric bypass (RYGBP) effectively produces massive weight reduction, improving health in morbidly obese patients. The mechanisms for the weight loss, and the fate of the excluded gastric mucosa, are not fully clarified. To what extent the appetite-stimulating gastric peptide ghrelin is affected remains controversial. Circulating concentrations of ghrelin, pancreatic polypeptide (PP), pepsinogen I (PGI) and gastrin were examined in 15 morbidly obese patients (median BMI 45 kg/m2) preoperatively, and on days 1, 2, 4, 6 and at months 1, 6 and 12 after RYGBP. Ghrelin levels fell on postoperative day 1 and increased after 1 month to preoperative levels, and rose further at 6 and 12 months. PP concentrations decreased on day 1 and subsequently returned to preoperative levels. PGI levels peaked transiently the first days after surgery and subsequently declined to lower than preoperative levels. Gastrin levels were gradually reduced postoperatively. Ghrelin and PP fall transiently after surgery, possibly due to vagal dysfunction, and ultimately, as weight loss ensues, ghrelin secretion increases to higher than preoperative levels. The RYBGP procedure affects the gastric mucosa, as reflected by a transient increase in circulating PGI, and subsequently, the mucosa in the excluded stomach is at rest, as shown by low levels of PGI and gastrin.

BACKGROUND: Little is known about the pathophysiology of ghrelin secretion in growth hormone-deficient adults treated with growth hormone, and the relationship between plasma ghrelin and hyperinsulinemia induced by an oral glucose load has not been investigated in these patients. OBJECTIVE: In the present study we examined the relationship between plasma ghrelin, insulin, C-peptide and leptin after an oral glucose load in growth hormone-deficient adults receiving treatment with growth hormone. METHODS: Plasma ghrelin, leptin, insulin, C-peptide and blood glucose were measured before and then at 30, 60, 90 and 120 min after the ingestion of glucose (75 g orally) in 20 growth hormone-deficient adults (12 women and 8 men), who had been treated with growth hormone for 7.2 ± 1.3 years (mean ± SE). Plasma ghrelin was also determined before and after the glucose load in 10 age-and weight-matched healthy persons (5 women and 5 men). RESULTS: The oral glucose load induced a similar percent suppression of plasma ghrelin in the growth hormone-deficient patients and in the healthy persons. In both groups plasma ghrelin decreased significantly 30 min after the glucose load and remained suppressed throughout the test period. In the patients plasma insulin (baseline, 15.9 ± 3.9 µIU/ml) and C-peptide (baseline, 2.5 ± 0.3 ng/ml) showed opposite changes with peak responses at 30 min (insulin, 109.5 ± 15.6 µIU/ml) or 60 min (C-peptide, 10.3 ± 1.1 ng/ml). In these patients, post-glucose, but not baseline plasma ghrelin levels correlated negatively with plasma insulin, C-peptide and blood glucose levels, whereas baseline plasma ghrelin correlated inversely with baseline plasma leptin. CONCLUSIONS: The similar suppression of plasma ghrelin in growth hormone-deficient patients treated with growth hormone and in healthy persons after an oral glucose load argues against disturbed regulation of ghrelin secretion in these patients. The correlations between post-glucose plasma ghrelin, insulin and blood glucose support the existence of a previously proposed link between hyperinsulinemia (or increased blood glucose) and suppression of ghrelin levels.

Background: Restrictive bariatric surgery causes weight loss through substantial decline of appetite with satiety after meals. Reduction of plasma ghrelin levels after Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding could contribute to these effects, although contradictory results have been reported. The only restrictive operation still not yet investigated is vertical banded gastroplasty (VBG). We studied the effects of VBG on basal plasma ghrelin levels and meal-mediated inhibition. Methods: 12 morbidly obese patients, 11 female and 1 male, were studied before and after VBG, when the BMI fell by 20%. The control group consisted of 6 lean volunteers. Active ghrelin was determined by RIA after overnight fasting and after the administration of a liquid meal. Results: Obese patients preoperatively had significantly lower basal plasma ghrelin levels than lean volunteers, and the meal did not inhibit ghrelin secretion. After VBG and 20% BMI loss, basal plasma ghrelin levels increased and the reduction caused by a meal recovered. Conclusions: Weight loss caused by VBG is associated with higher plasma ghrelin levels in obese patients. The operation restores the normal adaptation of the A- cells of the stomach to a meal.

BACKGROUND: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is known to increase food intake in lean humans and rodents. In addition, ghrelin levels are increased by fasting in lean rodents and are elevated before meals in humans, suggesting an important role for ghrelin in meal initiation. However, in obese human, circulating ghrelin levels were found to be significantly reduced as compared to lean individuals. OBJECTIVES: To evaluate whether circulating ghrelin levels, as well as ghrelin sensitivity, are decreased in obese individuals in order to limit its effect on food intake. DESIGN: Lean C57BL/6J mice fed a chow, a low- (LFD) or a high-fat diet (HFD) were used to determine ghrelin regulation and secretion as well as ghrelin sensitivity. MEASUREMENTS: Plasma ghrelin levels were measured in low- and high-fat fed mice. Ghrelin-induced food intake was measured in chow, low- and high-fat fed mice. RESULTS: We measured ghrelin levels in lean and diet-induced obese mice, fed on an LFD or an HFD, respectively. We observed that not only ghrelin secretion was reduced in obese mice but its diurnal regulation was also lost. In addition, we failed to observe any change in ghrelin secretion upon fasting and refeeding. Moreover, we observed that the sensitivity to the orexigenic effects of exogenous ghrelin was reduced in obese mice when compared to lean mice fed a chow or a LFD. The insensitivity of obese mice to ghrelin was improved upon weigh loss. CONCLUSION: Altogether, these results indicate that ghrelin secretion and regulation is impaired in dietary-induced obesity in mice and suggest that ghrelin inhibition could prevent weight regain after weight loss.

Ghrelin, the endogenous ligand of GH-secretagogue receptors, has been implicated in the regulation of feeding behavior and energy balance. Aim of the study was to investigate ghrelin levels in fasting conditions and after a standard meal test in obese subjects before and after a 3-week integrated body weight reduction (BWR) program (consisting of energy-restricted diet, exercise training, psychological counselling and nutritional education). Weight, height, fat mass, fat free mass (by impedentiometry), circulating ghrelin, insulin and leptin levels were evaluated in 10 obese subjects (3 male, 7 female; mean age: 35 +/- 9.3 yr; body mass index BMI: 45.2 +/- 10.6 kg/m2) before and after weight reduction. At baseline, obese subjects showed significantly lower ghrelin levels than controls, which were negatively correlated with BMI, weight, insulin and leptin levels. Fasting ghrelin levels were not modified by standard meal test in obese subjects (from 110.8 +/- 69.7 to 91.8 +/- 70.2 pmol/l p=ns), while a significant reduction was observed in controls (from 352.4 +/- 176.7 to 199.0 +/- 105.2 pmol/l; p0.01). After a 3-week integrated BWR program obese subjects significantly reduced weight, BMI and leptin levels, while no significant changes were found both in fasting ghrelin and in ghrelin response after the meal. In conclusion, 5% weight loss obtained after a short-term period of integrated BWR program is not sufficient to normalize fasting ghrelin levels nor to restore the normal ghrelin suppression after a meal in severely obese subjects.

The pulsatile release of growth hormone (GH) from anterior pituitary gland is regulated by the interplay of at least two hypothalamic hormones, GH-releasing hormone (GHRH) and somatostatin, via their engagement with specific cell surface receptors on the anterior pituitary somatotroph. Furthermore, release of GH in vivo may also be controlled by a third type of receptor, the growth hormone secretagogue receptor, a G-protein-coupled receptor, called GHS receptor type 1a (GHSR1a), which was identified in the pituitary and the hypothalamus in humans using a nonpeptidyl growth hormone secretagogue (MK-0677). Ghrelin, the endogenous ligand for the GHS-R1a, is a 28-amino-acid peptide isolated from human stomach that is modified by a straight chain octanoyl group covalently linked to Ser3, which is essential for its endocrine activity. This hormone, predominantly expressed and secreted by the stomach, has a dual action on GH secretion and food intake, showing interdependency between these actions. The finding that fasting and food intake, respectively, increase and decrease the secretion of ghrelin suggests that this hormone may be the bridge connecting somatic growth and body composition with energy metabolism, and appears to play a role in the alteration of energy homeostasis and body weight in pathophysiological states such as hypothyroidism and hyperthyroidism. Despite this, little is known about the intracellular signaling through which ghrelin exerts its regulatory actions. Activation of intracellular calcium mobilization is one of the earliest known cellular signals elicited by ghrelin. In HEK- 293 cells expressing the GHS-R1a, ghrelin induces a biphasic cytosolic calcium elevation characterized by a spike phase of the response, which reflects Ins(1,4,5)P3- dependent calcium mobilization of intracellular stores, and a sustained phase of the response, which is due to calcium influx across the plasma membrane triggered by aperture of capacitative calcium channels (store-operated calcium channels). Upon repeated administration, ghrelin showed a marked suppression of ghrelin-mediated elevations of intracellular calcium. This homologous desensitization represents an important physiological mechanism that modulates receptor responsiveness and acts as an information filter for intracellular signaling system. The discovery of ghrelin adds a new component to the complex machinery responsible for regulation of GH secretion in connection with the regulation of appetite and energy homeostasis.

The therapeutic potential of molecular hydrogen (H₂) is emerging in a number of human diseases and in their animal models, including in particular Parkinson's disease (PD). H₂ supplementation of drinking water has been shown to exert disease-modifying effects in PD patients and neuroprotective effects in experimental PD model mice. However, H₂ supplementation does not result in detectable changes in striatal H₂ levels, indicating an indirect effect. Here we show that H₂ supplementation increases gastric expression of mRNA encoding ghrelin, a growth hormone secretagogue, and ghrelin secretion, which are antagonized by the β1-adrenoceptor blocker, atenolol. Strikingly, the neuroprotective effect of H₂ water was abolished by either administration of the ghrelin receptor-antagonist, D-Lys(3) GHRP-6, or atenolol. Thus, the neuroprotective effect of H₂ in PD is mediated by enhanced production of ghrelin. Our findings point to potential, novel strategies for ameliorating pathophysiology in which a protective effect of H₂ supplementation has been demonstrated.

The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons and in the brainstem. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.

Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from the pituitary. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide 'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow'). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.

Ghrelin stimulates appetite, promotes adiposity, and worsens glucose metabolism. Ghrelin levels vary according to both chronic and acute nutritional status, but the regulation of ghrelin secretion is not well understood. The primary site of production of ghrelin is the stomach; however, evidence suggests that there is post-gastric regulation of ghrelin secretion. A reduction in fasting and postprandial ghrelin levels is implicated in the efficacy of RYGB to produce metabolic improvements in the immediate postoperative period. In this study, we determined if the enhanced postprandial ghrelin suppression observed after RYGB could be attributed to more rapid intestinal nutrient stimulation. We studied 9, Class III obese, non-diabetic but insulin resistant subjects on two occasions, where we simulated pre- and post-RYGB nutrient delivery by administering a 50 g glucose load either to the stomach or to proximal jejunum, in random order. The next day, plasma glucose excursions for each was replicated with an isoglycemic IV glucose clamp. Gastric administration of glucose produced a ~35% suppression of ghrelin, which was equally matched by the isoglycemic clamp. Jejunal administration of glucose caused a ~65% suppression of plasma ghrelin, while in the concurrent isoglycemic clamp ghrelin was only suppressed ~35%, matching the suppression observed with gastric glucose. These data demonstrate that acyl ghrelin suppression with gastric glucose delivery is primarily due to the elevated post-absorptive glucose levels. However, the suppression seen with administration of a glucose load directly to the proximal jejunum is due to additional suppression of acyl ghrelin that is independent of circulating glucose levels. In conclusion, it appears that the postprandial ghrelin suppression observed after RYGB could be attributed to a ‘negative incretin response’ resulting from rapid intestinal nutrient stimulation.

Ghrelin, a new gastric-derived hormone, probably plays a major role in managing energy balance and the neuroendocrine response to starvation. Information about the age-related variation in ghrelin secretion is scanty. We measured circulating ghrelin levels in 93 full term newborns adequate for gestational age, in 39 normal children and in 19 lean healthy adults. Our findings demonstrate that ghrelin levels are independent of age and gender from birth to adulthood. Interestingly, ghrelin secretion at birth is not associated to body weight and hormonal parameters such as GH, insulin and leptin levels. On the other hand, ghrelin levels seem dependent on the type of delivery, being lower in newborns after caesarean section with respect to those after normal delivery.

This article reviews the effectiveness of Kampo (traditional Japanese herbal medicine) in the treatment of functional gastrointestinal disorders, especially functional dyspepsia (FD) and irritable bowel syndrome (IBS). The results of four randomized, controlled trials (RCTs) suggested the usefulness of rikkunshito in relieving the subjective symptoms of patients with FD. Rikkunshito significantly improved not only gastric symptoms, such as epigastiric discomfort, but also extra-gastric symptoms, such as general fatigue, when compared with control drugs. The therapeutic effects of rikkunshito were more evident when it was prescribed to patients with “kyosho”, i.e., low energy. Two RCTs suggested the efficacy of keishikashakuyakuto for IBS. Basic research studies have demonstrated that these Kampo medicines have multiple sites of action to improve subjective symptoms. For example, rikkunshito improves gastric motility dysfunction, including impaired adaptive relaxation and delayed gastric emptying, gastric hypersensitivity, and anorexia via facilitation of ghrelin secretion. It also exhibits anti-stress effects, i.e., it attenuates stress-induced exacerbation of gastric sensation and anorexia, as well as the hypothalamic-pituitary-adrenocortical axis and sympathetic activation. Keishikashakuyakuto exhibited not only an antispasmodic effect on intestinal smooth muscle, but also antidepressant-like effects. Case series suggest that other Kampo prescriptions are also effective for FD and IBS. However, further studies are necessary to evaluate their efficacy.

Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.

Sir We appreciate Drs Treuer and Karagianis interest in our work and their underscoring yet again the apparent complexity and multidisciplinary nature of the weight gain problems in patients with schizophrenia. The assertion that these problems may arise due to increases in ghrelin secretion from the stomach produced by the second-generation antipsychotic agents (SGAs) is however undermined by the following considerations: (a) preponderance of the studies reporting no or inverse relationship between plasma ghrelin levels and SGAs-induced weight gain (Togo et al, 2004; Palik et al, 2005; Theisen et al, 2005; Sporn et al, 2005; Hosojima et al, 2006); (b) the lack of reported evidence on ghrelin alterations in drug-free patients who are also prone for glucoregulatory abnormalities and for obesity; and (c) undetermined (primary vs secondary) mechanisms of the SGAs ghrelin effects. We have discussed the inconclusive ghrelin findings in the text (page 15) and in the tabulated format (Elman et al, 2006). Nonetheless the letter by Drs Treuer and Karagianis raises an important question concerning reciprocity between central nervous system and gastrointestinal (GI) pathologies, the entity addressed by the discipline of neurogastroenterology. Indeed, embryonically, the central and the enteric nervous systems are derived from the same neural crest tissue and are subsequently linked via the vagus nerve. Furthermore, the GI tract is abundant with the same hormones and neurotransmitters that are mediating reward and homeostatic processes in the brain; to name a few, cholecystokinin, insulin, opiates, gamma-aminobutyric acid, dopamine, serotonin, glutamate, and norepinephrine. The GI concentrations of these chemicals are comparable to or are even exceed those in the brain (Gershon, 1998). Hence, it is in the realm of possible that the same prenatal lesion driving the development of schizophrenia neuropathology (Weinberger, 1987) may also result in corresponding alterations of the GI system, including impaired regulatory mechanisms of ghrelin secretion. Such a concept could gain indirect support from high prevalence of celiac disease in schizophrenic patients and their first-degree relatives (Eaton et al, 2004, 2006). In more general terms, the dynamic view of the brain–periphery interactions, rather than an either/or approach to the ailments afflicting both domains may provide heuristic value to clinical neuroscience and bring us closer to solving the mind–body mystery. In sum, although available clinical evidence renders elevated ghrelin an unlikely cause of weight gain during SGAs therapy, further research in this area is warranted.