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Aims Ghrelin is a gastric-derived hormone that stimulates growth hormone ( GH) secretion and has a multi-faceted role in the regulation of energy homeostasis, including glucose metabolism. Circulating ghrelin concentrations are modulated in response to nutritional status, but responses to ghrelin in altered metabolic states are poorly understood. We investigated the metabolic effects of ghrelin in obesity and early after Roux-en- Y gastric bypass ( RYGB). Materials and methods We assessed central and peripheral metabolic responses to acyl ghrelin infusion (1 pmol kg−1 min−1) in healthy, lean subjects (n = 9) and non-diabetic, obese subjects (n = 9) before and 2 weeks after RYGB. Central responses were assessed by GH and pancreatic polypeptide (surrogate for vagal activity) secretion. Peripheral responses were assessed by hepatic and skeletal muscle insulin sensitivity during a hyperinsulinaemic-euglycaemic clamp. Results Ghrelin-stimulated GH secretion was attenuated in obese subjects, but was restored by RYGB to a response similar to that of lean subjects. The heightened pancreatic polypeptide response to ghrelin infusion in the obese was attenuated after RYGB. Hepatic glucose production and hepatic insulin sensitivity were not altered by ghrelin infusion in RYGB subjects. Skeletal muscle insulin sensitivity was impaired to a similar degree in lean, obese and post- RYGB individuals in response to ghrelin infusion. Conclusions These data suggest that obesity is characterized by abnormal central, but not peripheral, responsiveness to ghrelin that can be restored early after RYGB before significant weight loss. Further work is necessary to fully elucidate the role of ghrelin in the metabolic changes that occur in obesity and following RYGB. [ABSTRACT FROM AUTHOR]

Abstract: Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood actions of acylated ghrelin administration are its orexigenic effects, and the stimulation of GH secretion. Ghrelin also seems to play a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease. [Copyright &y& Elsevier]

Abstract: In humans, growth hormone (GH) is secreted from the anterior pituitary in a pulsatile pattern. The traditional view is that this secretory pattern is driven by two counter regulatory neurohormones, GHRH and somatostatin. Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced in the stomach. Ghrelin is the strongest GH secretagogue known to date, but the role of endogenous ghrelin in the regulation of circulating GH levels remains controversial. The following review examines the evidence suggesting that endogenous ghrelin may be a key regulator of GH peak amplitude and discusses studies of diseases with altered GH levels, where it is found that in these states GH and ghrelin levels change in a similar way. [Copyright &y& Elsevier]

Acylated (octanoylated) ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyryicholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes (n = 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean ± SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 ± 0.2 vs. 10.2 ± 1.9 ng·ml-1·90 min-1, P < 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r = 0.50, P = 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 ± 1.9 vs. 8.6 ± 1.2 ng·ml-1·90 min-1, P = 0.005). In a second group of subjects (n = 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 ± 0.5 vs. 4.5 ± 0.6 μg/ml, P = 0.029) and cholinesterase activity (705 ± 33 vs. 1,013 ± 56 U/ml, P < 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy, likely because of a decrease in the acylation process. Desacyl ghrelin increases in gestational diabetes, possibly reflecting resistance to the inhibitory effect of insulin on ghrelin secretion. [ABSTRACT FROM AUTHOR]

Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85α regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85α levels are associated with insulin resistance through PI 3-kinase-dependent and --independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85α subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85α mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85α protein abundance. We found that p85α expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulin-induced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85α expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess. Diabetes 56:1638-1646, 2007 [ABSTRACT FROM AUTHOR]

Growth hormone releasing hormone receptor (GHRH-R) is a class II G protein-coupled receptor required for normal growth hormone (GH) synthesis and release from the pituitary, and for the normal growth and proliferation of somatotrophs within the pituitary. Mutations of this receptor in mouse and human are associated with GH deficiency, short stature, and pituitary hypoplasia. This signaling system plays important roles in growth and development, metabolism of muscle and fat, and, possibly, the aging process. Among topics touched on in this article are the receptor gene's organization and promoter regulation, receptor signaling pathways, and receptor domains involved in interaction with ligand. Also discussed are alternative mRNA splicing and proposed functions of these splice variants as dominant negative inhibitors of wild-type receptor and in tumor proliferation. Homology among GHRH-Rs from different species is shown and a map of receptor mutations reported to effect function is presented. [ABSTRACT FROM AUTHOR]

The article focuses on ghrelin that is essential for activating the growth hormone and maintenance of blood-glucose levels that is necessary for survival when there is prolonged nutrient constraint. It shows that during nutritional restriction conditions, growth hormones (GH) are high. Furthermore, it reveals that ghrelin is important for asserting the stage of GH that is needed in the avoidance of neuroglycopenia and thus, preservation of life.