Adiponectin ; Ghrelin ; physiology ; Growth Hormone-Releasing Hormone ; Humans ; Leptin ; Receptors, Ghrelin ; Resistin

There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients' quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation.
Animals ; Constipation ; Defecation ; Delivery of Health Care ; Gastrointestinal Motility ; Ghrelin* ; Half-Life ; Humans ; Pharmacokinetics ; Quality of Life ; Receptors, Ghrelin*

PURPOSE: Ghrelin is the known orexigenic hormone as well as an endogenous ligand for the growth hormone secretagogue receptor and has been shown to be related with the regulation of energy homeostasis. To investigate the changes of plasma ghrelin levels in response to weight loss induced by exercise, we measured fasting plasma ghrelin levels in obese and control groups before and after exercise intervention. METHODS: According to body mass index (BMI), total 32 adult women were divided into obese group (n=14, BMI> or =25 kg/m2) and control group (n=18, BMI<25 kg/m2). All subjects underwent weight reduction exercise intervention for 3 months. Before and after exercise, we measured body compositions, serum lipid profiles, serum glucose, plasma ghrelin levels in all subjects. RESULTS: At baseline, the plasma ghrelin levels in obese group were significantly lower than those in the control group. After the exercise intervention, the plasma ghrelin levels increased significantly from 174.8+/-40.8 to 235.9+/-53.1 pg/mL (P<0.05) in obese group and from 244.4+/-42.6 to 276.5+/-45.1 pg/mL (P<0.05) in control group. The changes of plasma ghrelin levels in obese group (38.7+/-30.8 pg/mL) were significantly higher than those of the control group (14.6+/-20.3 pg/mL, P<0.05). However, there was no significant relationship between the changes of plasma ghrelin levels and various parameters in the obese group after exercise. CONCLUSION: In this study, the plasma ghrelin levels in obese adults were significantly increased than those in the control group associated with exercise-induced weight loss. Further studies are needed to establish the precise roles of ghrelin in the regulation of energy homeostasis in obesity.
Adult ; Blood Glucose ; Body Composition ; Body Mass Index ; Fasting ; Female ; Ghrelin* ; Homeostasis ; Humans ; Obesity ; Plasma* ; Receptors, Ghrelin ; Weight Loss

PURPOSE:Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor, and stomach is the major site of ghrelin secretion. The purpose of this study is to compare the serum ghrelin concentrations between patients with type 2 diabetes mellitus (DM) and normal adults. We studied also whether serum ghrelin levels in the patients with type 2 DM are correlated with body mass index (BMI), serum insulin, lipid profiles, and creatinine levels. METHODS:Forty patients with type 2 DM and forty normal adults were included in this study. We measured heights and weights of the subjects and calculated their BMIs. Blood samples were obtained to measure the ghrelin concentration and their sera were stored at -20degreeC until used. In all subjects, serum ghrelin levels were measured using the commercially available Ghrelin(human) EIA kit. RESULTS:No differences of mean values were detected between the control group and the type 2 diabetic group for age, body weight, BMI, and the levels of serum total cholesterol, triglyceride, HDL cholesterol, and creatinine. But ghrelin level of the type 2 diabetic group (71.1+/-30.5 ng/L) was significantly lower than the control group (139.7+/-36.9 ng/L). In the control group, the ghrelin level showed positive correlation with HDL cholesterol (Pearson's correlation coefficient=0.37, P<0.05). In the diabetic group, the ghrelin level showed weakly positive correlation with insulin concentration. However, there was no significant relationship between serum ghrelin and various parameters in the diabetic patients group. CONCLUSION: In this study, ghrelin concentration in type 2 diabetic patients was lower than that in the control group. In the control group, serum ghrelin concentrations were positively correlated with HDL cholesterol. In the type 2 diabetic group, there was no significant correlation between insulin and ghrelin concentrations.
Adult ; Body Mass Index ; Body Weight ; Cholesterol ; Cholesterol, HDL ; Creatinine ; Diabetes Mellitus ; Diabetes Mellitus, Type 2* ; Ghrelin* ; Humans ; Insulin ; Receptors, Ghrelin ; Stomach ; Triglycerides ; Weights and Measures

Background:Ghrelin is a new endogenous ligand for the growth hormone secretagogue receptor. It activates the release of growth hormone from the pituitary and it also participates in the regualtion of energy homeostasis. The aims of the study were to characterize the changes in plasma ghrelin levels in obese subjects compared with lean control or overweight subjects, and their relationship to various parameters in obese subjects. METHODS:In this study, 121 elementary school children were divided into 3 groups according to their body mass index (BMI). The lean control subjects consisted of 28 children who had less than 85 percentile of BMI. The overweight subjects consisted of 22 children who had 85-95 percentile of BMI. The obese subjects consisted of 71 children who had over 95 percentile of BMI. All subjects in 3 groups were evaluated according to their age, height, weight, obesity index, plasma ghrelin, serum lipid, glucose and insulin levels. Leu72Met mutation of prepro-ghrelin gene was directly detected by digesting the PCR fragments with Bsrl. RESULTS:Among antropometric data, body weight, BMI and obesity index were higher in obesity and overweight subjects than those of lean control subjects (P<0.05). The plasma ghrelin levels were significantly lower in overweight and obese subjects (P<0.05). In addition, serum triglyceride and LDL cholesterol levels were significantly higher in these groups compared to the control subjects (P<0.05). The concentrations of plasma ghrelin were significantly negatively correlated with BMI, obesity index, serum triglyceride, LDL cholesterol and insulin in all the children. However, there was no significant relationship between plasma ghrelin levels and any various parameters in obese subjects. Leu72Met mutation was detected in about 30% of obese children. However, we could not find any differences between lean control and obese children. CONCLUSION: We proved a significantly lower plasma ghrelin levels in overweight and obese subjects. Further studies are now needed to establish the role of ghrelin in the pathogenesis of human obesity.
Body Mass Index ; Body Weight ; Child* ; Cholesterol, LDL ; Ghrelin* ; Glucose ; Growth Hormone ; Homeostasis ; Humans ; Insulin ; Obesity* ; Overweight ; Plasma* ; Polymerase Chain Reaction ; Receptors, Ghrelin ; Triglycerides

OBJECTIVETo investigate the effect of the expression of ghrelin receptors on the postoperative small intestine dysmotility in rat models.

METHODSThe effect of different concentrations of ghrelin (0, 0.01, 0.1, 0.5, 1.0 μmol/L) on the contraction of smooth muscle strips of rat small intestine in the presence or absence of carbachol was observed in vitro. End-to-side anastomosis was performed in the study group and sham controls were used. The expression of ghrelin receptors(GHS-R1a) in small intestine muscle layers was detected by immunohistochemistry and Western blot.

RESULTSIn vitro, ghrelin enhanced the contraction of smooth muscle strips in the presence of carbachol, and the differences in contraction induced by different concentrations of ghrelin(0.1, 0.5, 1.0 μmol/L) were statistically significant [(223±18)%, (245±22)%, (264±25)%, P<0.01]. Immunohistochemistry study showed that GHS-R1a mainly located in the muscular layer of the bowel wall. The expression of GHS-R1a in the circular and longitudinal muscle was significantly weaker than that in the control group. The expression of ghrelin receptors after surgery was down-regulated in the study group, which was lower than that in the control group(0.51±0.02 vs. 0.71±0.01, P<0.01).

CONCLUSIONDown regulation of ghrelin receptors in small intestine muscle layers may contribute to the occurrence of small intestine dysmotility after intestinal surgery.

Animals ; Down-Regulation ; Gastrointestinal Motility ; drug effects ; physiology ; Ghrelin ; pharmacology ; Intestine, Small ; drug effects ; metabolism ; physiology ; surgery ; Male ; Postoperative Period ; Rats ; Rats, Sprague-Dawley ; Receptors, Ghrelin ; metabolism

OBJECTIVETo investigate the expression of ghrelin and its receptor, growth hormone secretagogue receptor (GHS-R), in the hypothalamus and gastrointestinal tract in rats with chronic renal failure (CRF) and explore their relationship with the disorder of gastrointestinal tract motility.

METHODSSD rats were randomly divided into sham-operated group (n=8) and CRF group (n=16), and in the latter group, the rats were subjected to 5/6 nephrectomy to induce CRF. Real-time PCR and immunohistochemical staining were used to detect the distribution of mRNA and protein of ghrelin and GHS-R in the gastric fundus, duodenum, and hypothalamus.

RESULTSThe rats in the CRF group showed a significantly higher expression of ghrelin mRNA and protein in the gastric fundus but a lower expression in the hypothalamus than those in the sham-operated group (P<0.01), but the expression in the duodenum was similar between the two groups (P>0.05). The expression of GHS-R mRNA and protein in the gastric fundus was significantly higher in the CRF group than in the sham-operated group (P<0.01), while in the hypothalamus and duodenum, the expression was significantly lower in the CRF group (P<0.01).

CONCLUSIONThe different distribution patterns of ghrelin and GHS-R in the tissues may be an important pathological basis of gastrointestinal motility disorder in CRF.

Animals ; Gastrointestinal Tract ; metabolism ; Ghrelin ; genetics ; metabolism ; Hypothalamus ; metabolism ; Kidney Failure, Chronic ; metabolism ; Male ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Ghrelin ; genetics ; metabolism

OBJECTIVETo study the relationship between Ghrelin and growth hormone secretagogue receptor (GHSR) expression and the catch-up growth in rats with intrauterine growth restriction (IUGR).

METHODSThe rat model of IUGR was established by food restriction during pregnancy. The small for gestational age (SGA) and appropriate for gestational age (AGA) rat pups from the pregnant rats were used as the experimental group. The AGA rat pups from the pregnant rats without food restriction served as the control group. The samples from the stomach fundus and hypothalamus were taken postnatal days 0, 20 and 40. Ghrelin mRNA and GHSR mRNA expression were determined by real-time fluorescence quantitative PCR (real-time FQ-PCR). Ghrelin protein and GHSR protein expression were examined by immunohistochemistry (IHC).

RESULTSAt postnatal day 0, both Gherlin mRNA and protein levels in the stomach fundus were significantly higher, while GHSR mRNA expression in the hypothalamus were significantly lower in SGA rats from food restriction group than those in AGA rats from restriction and control groups. At postnatal day 20, the ghrelin protein expression in the stomach of fundus, and GHSR mRNA and protein expression in the hypothalamus in SGA catch-up rats were significantly higher than those in SGA non-catch-up growth rats and AGA rats from the control group. At postnatal day 40, there were no significant differences among SGA catch-up growth rats, SGA non-catch-up growth rats and normal AGA rats.

CONCLUSIONSGhrelin-GHSR might be involved in the physiological regulation and pathological process in IUGR rats. It is also possibly involved in the regulation of catch-up growth in the early life of SGA rats.

Animals ; Female ; Fetal Growth Retardation ; physiopathology ; Gastric Fundus ; chemistry ; Ghrelin ; analysis ; genetics ; physiology ; Growth ; Hypothalamus ; chemistry ; Immunohistochemistry ; Pregnancy ; Rats ; Receptors, Ghrelin ; analysis ; genetics

OBJECTIVETo explore the effect of electroacupuncture (EA) on the expression of Ghrelin and mRNA expression of its receptor in functional dyspepsia (FD) rats.

METHODSTotally 80 rats were divided into the normal group, the model group, the drug therapy group, and the EA group according to random digit table, 20 in each group. FD model was duplicated by clipping tail modeling. Drug containing cisapride [2 mL/100 g, 0.09 g/(kg x d)] was administered to rats in the drug therapy group from the 3rd day after successful modeling, once per day. EA at Zusanli (ST36) (0.3-0.5 cun) and Taichong (LR3) (0.1-0.2 cun) was performed in the EA group. The twirling of needle was performed to the subsidence of needle, and then the needle was connected to HANS-200A Acupoint Nerve Stimulating Device using disperse-dense wave at 2 Hz, 2 mA, 30 min each time, once per day. Six days consisted of one therapeutic course, two courses in total with an interval of one day. The intestinal propulsive rate of ink was observed. Ghrelin protein expression in gastric tissue was detected by Western blot. mRNA expression of growth hormone secretagogue receptor (GHS-R) in stomach, hypothalamus, and hippocampus was detected using Real-time PCR respectively.

RESULTSCompared with the normal group, the intestinal propulsive rate of ink, Ghrelin protein expression in gastric tissue, mRNA expression of GHS-R in stomach, hypothalamus, and hippocampus decreased in the model group (P < 0.05, P < 0.01). Compared with the model group, the intestinal propulsive rate of ink, Ghrelin protein expression in gastric tissue, mRNA expression of GHS-R in stomach, hypothalamus, and hippocampus increased in the EA group (P < 0.01); mRNA expression of GHS-R in stomach, hypothalamus, and hippocampus increased in the drug therapy group (P < 0.01). Compared with the drug therapy group, Ghrelin protein expression in gastric tissue, mRNA expression of GHS-R in hypothalamus increased in the EA group (P < 0.05, P < 0.01).

CONCLUSIONEA could regulate Ghrelin content and GHS-R mRNA expression of FD rat hypothalamus, hippocampus, and gastric tissue, and promote the intestinal propulsive rate of ink.

Acupuncture Points ; Animals ; Dyspepsia ; metabolism ; therapy ; Electroacupuncture ; Ghrelin ; metabolism ; Hippocampus ; metabolism ; Hypothalamus ; metabolism ; RNA, Messenger ; metabolism ; Random Allocation ; Rats ; Receptors, Ghrelin ; metabolism ; Stomach ; metabolism

To directly test if elevated glucocorticoids are required for fasting-induced regulation of growth hormone (GH)-releasing hormone (GHRH), GHRH receptors (GHRH-R) and ghrelin receptors (GHS-R) expression, male rats were bilaterally adrenalectomized or sham operated. After 7 days, animals were fed ad libitum or fasted for 48 h. Bilateral adrenalectomy increased hypothalamic GHRH to 146% and decreased neuropeptide Y (NPY) mRNA to 54% of SHAM controls. Pituitary GHRH-R and GHS-R mRNA levels were decreased by adrenalectomy to 30% and 80% of sham-operated controls. In sham- operated rats, fasting suppressed hypothalamic GHRH (49%) and stimulated NPY (166%) mRNA levels, while fasting increased pituitary GHRH-R (391%) and GHS-R (218%) mRNA levels. However, in adrenalectomized rats, fasting failed to alter pituitary GHRH-R mRNA levels, while the fasting-induced suppression of GHRH and elevation of NPY and GHS-R mRNA levels remained intact. In fasted adrenalectomized rats, corticosterone replacement increased GHRH-R mRNA levels and intensified the fasting-induced decrease in GHRH, but did not alter NPY or GHS-R response. These data suggest that elevated glucocorticoids mediate the effects of fasting on hypothalamic GHRH and pituitary GHRH-R expression, while glucocorticoids are likely not the major determinant in fasting-induced increases in hypothalamic NPY and pituitary GHS-R expression.
Adrenalectomy ; Animals ; Corticosterone ; Fasting ; Glucocorticoids ; Growth Hormone ; Humans ; Male ; Neuropeptide Y ; Rats ; Receptors, Ghrelin ; Receptors, Neuropeptide ; Receptors, Pituitary Hormone-Regulating Hormone ; RNA, Messenger ; Salicylamides