Acylated ghrelin level in patients with OSA before and after nasal CPAP treatment

Background and objective: Patients with newly diagnosed OSA have been reported to have recent weight gain prior to diagnosis. Ghrelin stimulates food intake and increases weight gain. Plasma ghrelin is decreased in obese and increased in lean individuals. Of the two circulating forms of ghrelin, acylated and unacylated, the former is thought to be essential for the biological activity of ghrelin. Methods: The plasma levels of the two forms of ghrelin were measured in 21 OSA patients (with a mean of 46.2 sleep‐disordered events/h) before and after 1 month of nasal CPAP (nCPAP) treatment, and were compared with those in 14 untreated OSA patients and 13 individuals without OSA. Results: The BMI was significantly higher in the 21 OSA patients than in the non‐OSA group as were the baseline acylated (11.4 ± 5.86 vs 7.19 ± 3.80 fmol/mL, P = 0.03) and unacylated (84.2 ± 50.6 vs 48.3 ± 23.2 fmol/mL, P = 0.02) ghrelin levels. The total ghrelin level was positively correlated with the number of sleep‐disordered breathings (P = 0.002). After 1 month of nCPAP treatment, the acylated ghrelin level significantly decreased (P = 0.02) while the unacylated ghrelin level did not (P = 0.09). Conclusions: Treatment of OSA may play an important role in the management of obesity in these patients by reducing the acylated ghrelin level.     

Different effects of ghrelin, des-acyl ghrelin and obestatin on gastroduodenal motility in conscious rats

Three peptides, ghrelin, des-acyl ghrelin and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. To examine the effects of these peptides, we applied the manometric mea- surement of gastrointestinal motility in freely moving conscious rat models. Ghrelin exerts stimulatory ef- fects on the motility of antrum and duodenum in both fed and fasted state of animals. Des-acyl ghrelin exerts inhibitory effects on the motility of antrum, but not on the motility of duodenum in the fasted state of ani- mals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state, but not in the fasted state of animals. NPY Y2 or Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptors in the brain mediate the action of des-acyl ghrelin, whereas CRF type 1 and type 2 receptors in the brain mediate the action of obestatin. Vagal afferent pathways might be involved in the action of ghre- lin, but not involved in the action of des-acyl ghrelin, whereas vagal afferent pathways might be partially involved in the action of obestatin.     

Hunger-satiety signals in patients with Graves' thyrotoxicosis before, during, and after long-term pharmacological treatment

Patients with Graves’ thyrotoxicosis lose weight despite increased appetite and food intake, thus suggesting a disturbed balance between energy intake and expenditure. Underlying mechanisms are not fully elucidated. The objective of this study was to investigate whether hormonal factors, known to affect hunger/satiety, change significantly over time as pharmacological treatment turns hyperthyroidism into euthyroidism. For that purpose 11 patients with Graves’ thyrotoxicosis were given thiamazole and I-thyroxine for 18–20 mo. They were investigated on three occasions: Test 1: before pharmacological therapy; Test 2: during medication; Test 3: a few months after conclusion of the pharmacological treatment. Sixteen healthy subjects were also investigated for comparison. The participants were fasted overnight. Blood samples for determination of plasma glucose and serum concentrations of free T₃ and T₄, TSH, albumin, cortisol, insulin, GH, IGF-1, IGFBP-1, leptin, and ghrelin were drawn in the morning from an antecubital vein. Laboratory data obtained in test 1 were statistically compared with those in tests 2 and 3. The study showed that the free T₃ level declined from 42.8±4.3 pmol/L in test 1 to 6.0±0.8 pmol/L in test 2 (85±2% decline), and 5.5±0.3 pmol/L in test 3 (86±2% decline). The free T₄ level fell concomitantly from 65.2±4.8 to 16.6±1.7 and 14.4±1.2 pmol/L. The glucose level was significantly higher during hyperthyroidism (test 1) than during euthyroidism (tests 2 and 3), whereas cortisol, insulin, GH, IGF-1, and leptin levels were similar. The IGFBP-1 level was initially high (48.8±8.5 μg/L in test 1), but with a relative decline in free T₃ of 85±2% (test 2) the IGFBP-1 level declined by 34±13%, and with a free T₃ decline of 86±2% (test 3) the binding protein fell by 39±29%. This brought about increased IGF-1 bioavailability as reflected by a rising IGF-1/IGFBP-1 ratio from 5.1±1.1 to 13.8±2.9 (p<0.01). The ghrelin level was low (2454±304 ng/L) in test 1. It increased to 3127±397 ng/L in test 2 (p<0.05), and to 3348±279 ng/L in test 3 (p<0.01). Conclusion: Both ghrelin secretion and IGF-1 bioavailability are low in patients with untreated thyrotoxicosis, but increase markedly as pharmacotherapy makes them euthyroid. These metabolic changes may be caused by the transition of hyperthyroidism into euthyroidism rather than by the pharmacotherapy per se, since the metabolic changes prevailed also in the posttreatment period.     

Do growth hormone-releasing peptides act as ghrelin secretagogues?

NN703 is an orally active and selective growth hormone secretagogue (GHS) that was derived from growth hormone-releasing peptide-1 (GHRP-1) via ipamorelin by a peptidomimetic approach and has now entered into phase II clinical trials. When the disposition in rats of NN703 and GHRP-6 was studied using whole-body autoradiography following administration of an iv dose of radiolabeled material, we found that a substantial amount of these secretagogues accumulate in the glandular part of the stomach. Because this is the site of synthesis and secretion of ghrelin, the endogenous GHS, we investigated the effect of resection of the gastrointestinal (GI) tract on growth hormone (GH) release induced by GHRP-6. This procedure significantly attenuated the GH secretion response by 60–70%. By contrast, the effect of GH-releasing hormone on GH release was not inhibited. The binding of GHRPs to the glandular part of the stomach and the blunted GH response to GHRP-6 following resection of the GI tract suggest a role for ghrelin as a mediator of part of the GH-releasing effect of GHRPs.     

Influence of Ghrelin and Growth Hormone Deficiency on AMP‐Activated Protein Kinase and Hypothalamic Lipid Metabolism

Current evidence demonstrates that the stomach‐derived hormone ghrelin, a potent growth hormone (GH) secretagogue, promotes feeding through a mechanism involving the short‐term activation of hypothalamic AMP‐activated protein kinase (AMPK), which in turn results in decreased hypothalamic levels of malonyl‐CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. Despite this evidence, no data have been reported about the effect of chronic, central ghrelin administration on hypothalamic fatty acid metabolism. In the present study, we examined the differences in hypothalamic fatty acid metabolism in the presence and absence of GH, by using a model for the study of GH‐deficiency, namely the spontaneous dwarf rat and the effect of long‐term central ghrelin treatment and starvation on hypothalamic fatty acid metabolism in this animal model. Our data showed that GH‐deficiency induces reductions in both de novo lipogenesis and β‐oxidation pathways in the hypothalamus. Thus, dwarf rats display reductions in fatty acid synthase (FAS) mRNA expression both in the ventromedial nucleus of the hypothalamus (VMH) and whole hypothalamus, as well as in FAS protein and activity. CPT1 activity was also reduced. In addition, in the present study, we show that chronic ghrelin treatment does not promote AMPK‐induced changes in the overall fluxes of hypothalamic fatty acid metabolism in normal rats and that this effect is independent of GH status. By contrast, we demonstrated that both chronic ghrelin and fasting decreased FAS mRNA expression in the VMH of normal rats but not dwarf rats, suggesting GH status dependency. Overall, these results suggest that ghrelin plays a dual time‐dependent role in modulating hypothalamic lipid metabolism. Understanding the molecular mechanism underlying the interplay between GH and ghrelin on hypothalamic lipid metabolism will allow new strategies for the design and development of suitable drugs for the treatment of GH‐deficiency, obesity and its comorbidities.     

Ghrelin与动脉粥样硬化

Ghrelin是近年来发现的一种促进生长激素分泌的多肽,是生长激素促分泌物受体的内源性配体。研究发现,ghrelin除了具有增加摄食及调节能量代谢的作用外,还具有降低血压、对抗炎症反应、保护血管内皮细胞等多种生物学效应,提示其在心血管疾病尤其是在动脉粥样硬化方面具有潜在的治疗效应。     

Modulation of ghrelin axis influences the growth of colonic and prostatic cancer cells in vitro

BackgroundThe risk of different cancers seems to be associated with obesity. Moreover, low ghrelin levels observed in obese people may be implicated in cancer development and progression. The aim of this study was to examine the direct effects of both forms of ghrelin (acylated and unacylated) and ghrelin receptor type 1a antagonist (D-Lys-GHRP-6) on the growth of murine colon cancer MC38 and human prostate cancer DU145 cell lines in vitro.MethodsThe cells were cultured for 72 h in the presence of rat or human acylated ghrelin (rG, hG), human unacylated ghrelin (hUAG), D-Lys-GHRP-6 (GHS-RA) applied either alone or jointly. The cell line growth was assessed by the colorimetric Mosmann method.ResultshUAG (10^?6, 10^?7 and 10^?10 M) inhibited MC38 cancer cell growth and, at some concentrations (10^?8, 10^?9, 10^?10 M), enhanced the antineoplastic effect of GHS-RA (10^?4 M). In turn, GHS-RA evoked a biphasic effect on MC38 cancer growth: inhibitory at 10^?4 M and stimulatory at 10^?5 and 10^?6 M. Moreover, GHS-RA at the highest examined concentration (10^?4 M) enhanced the cytostatic effect of FU. Human acylated and unacylated ghrelin and GHS-RA inhibited DU145 cancer growth with moderate and different potencies. A dose-response effect was observed for the inhibitory action of hG together with the synergistic effect of hUAG and GHS-RA.ConclusionThe obtained results indicate an involvement of the ghrelin axis in the growth regulation of colon and prostate cancers and may suggest new therapeutic options for these neoplasms.     

Serum ghrelin levels are higher in Caucasian men than Japanese men aged 40-49 years

BACKGROUND: Ghrelin, a 28-amino-acid gastric peptide hormone, has an appetite-stimulating effect and controls the energy balance. Serum ghrelin levels inversely correlate with body mass index. Recently, several papers reported the ethnic difference in the ghrelin levels. To our knowledge, however, no studies have compared the serum ghrelin levels between Caucasians in the USA and the Japanese in Japan. METHODS: We conducted a cross-sectional study of 189 men 40-49 years of age (91 US Caucasians in the U.S. and 98 Japanese in Japan) to examine serum ghrelin levels and metabolic and other factors. RESULTS: Serum ghrelin levels correlated with waist circumferences and lipid profiles among Caucasian Americans and the Japanese. Serum ghrelin levels were significantly higher among Caucasian Americans than among the Japanese (904.5 (632.0, 1132.0) pg/mL, 508.0 (399.0, 1378.3) pg/mL (median and 95% confidence interval), respectively, P < 0.01), although Caucasian Americans were much more obese (BMI: 26.9 +/- 3.3 kg/m(2) versus 23.3 +/- 3.1 kg/m(2) respectively, P < 0.01). The ethnic difference remained after adjusting for metabolic factors, smoking status, and other factors (P < 0.01). CONCLUSIONS: We have shown in our population-based study that serum ghrelin levels among men aged 40-49 are significantly higher in Caucasian Americans than in the Japanese in Japan. Reasons for the ethnic difference in the ghrelin levels are largely unknown and warrant further investigation.     

Clinical significance of ghrelin concentration of plasma and tumor tissue in patients with gastric cancer

BACKGROUND: The nutritional status of gastric cancer patients is an important factor determining the outcome after a gastrectomy. Ghrelin is produced primarily in the gastrointestinal tract including the stomach, and has been reported to reflect the nutritional status and control homeostasis by influencing the level of food intake and adiposity. This study examined the difference in the plasma and tissue ghrelin levels according to the clinicopathological features and the extent of a gastric resection in gastric cancer patients who underwent a gastrectomy. PATIENTS AND METHODS: Eighty patients over a 3 mo-period were divided into two groups according to the degree of preoperative weight loss (weight loss > or = 5% or < 5%) and the extent of the gastrectomy (subtotal or total gastrectomy). Blood samples were collected from all patients preoperatively and on postoperative day 7. The gastric tissues samples, including the tumor and normal tissues, were obtained from the resected stomach. The ghrelin levels in the plasma and tissue were measured using a commercial enzyme-linked immunosorbent assay kit. RESULTS: There were no significant differences in the clinical characteristics and ghrelin levels in the plasma, gastric tumor tissue, and normal tissue according to the degree of weight loss. There was no correlation between the ghrelin levels in the plasma and tumor tissue. However, the ghrelin level in the tumor tissue was significantly lower than that in the normal tissue. There was an association between the degree of cellular differentiation and ghrelin production. A gastrectomy decreased the plasma ghrelin levels and nutritional index such as the body mass index, triceps skin fold, mid-arm muscle circumference, and biochemical markers regardless of the extent of the gastric resection. CONCLUSIONS: Gastric cancer affects the production of ghrelin in the gastric mucosa. Moreover, ghrelin is produced mainly in the stomach even though it might be partially covered by the endogenous ghrelin produced by other organs after gastrectomy. However, more study will be needed to determine if there are other factors that have an impact on energy consumption, ghrelin secretion, and the changes in the ghrelin level after a gastrectomy.     

Ghrelin Does Not Predict Adaptive Hyperphagia in Patients With Short Bowel Syndrome

Background: Adaptive hyperphagia is associated with reduced dependence on parenteral nutrition in patients with short bowel syndrome, but mechanisms have not been described. Ghrelin (GHR) has orexigenic effects, whereas peptide YY (PYY) reduces intake. GHR also acts as a hormone to control body fat stores. The authors evaluated whether GHR or PYY was related to caloric intake or absorption in patients with short bowel syndrome and whether GHR was associated with body mass index. Methods: Patients were admitted twice for nutrient balance. Height and body weight were obtained using standardized protocols. Energy intake >40 kcal/kg/day was defined as adaptive hyperphagia. Fasting plasma PYY and GHR were assayed in duplicate with Linco enzyme‐linked immunosorbent assay kits. Results: The median age of the 7 study participants was 62 (range, 45‐66) years, time with short bowel syndrome was 6.6 (range, 2‐29) years, and body mass index was 21.2 kg/m² (range, 19‐27.7). Five patients had adaptive hyperphagia. Neither GHR nor PYY was significantly related to energy intake or absorption (GHR: R = 0.22 and R = –0.233, PYY: R = 0.10 and R = –0.13). Body mass index trended toward an inverse association with GHR (GHR: R = –0.540, P = .211). Conclusion: The rigorous adaptive hyperphagia seen in these patients with short bowel syndrome was not related to fasting GHR or PYY, suggesting the need to explore other mechanisms.