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Information regarding the early effects of obesogenic diets on feeding patterns and behaviors is limited. To improve knowledge regarding the etiology of obesity, young male Wistar rats were submitted to high-fat (HFD) or regular chow diets (RCDs) for 14 days. Various metabolic parameters were continuously measured using metabolic chambers. Total weight gain was similar between groups, but heavier visceral fat depots and reduced weight of livers were found in HFD rats. Total calorie intake was increased while individual feeding bouts were shorter and of higher calorie intake in response to HFD. Ambulatory activity and sleep duration were decreased in HFD rats during passive and active phase, respectively. Acylated and unacylated ghrelin levels were unaltered by the increased calorie intake and the early changes in body composition. This indicates that at this early stage, the orexigenic signal did not adapt to the high-calorie content of HFD. We hereby demonstrate that, although total weight gain is not affected, a short-term obesogenic diet alters body composition, feeding patterns, satiation, ambulatory activity profiles, and behaviours in a young rat model. Moreover, this effect precedes changes in weight gain, obesity, and ensuing metabolic disorders. [ABSTRACT FROM AUTHOR]

Background. Protein-energy wasting (PEW) in end-stage renal disease (ESRD) patients is associated with increased morbidity and mortality, but options for treatment are limited. Growth hormone (GH) increases insulin-like growth factor 1 (IGF-1), with improved nutritional parameters, but must be given subcutaneously and does not provide normal GH secretion patterns. MK-0677, an oral ghrelin receptor agonist (GRA), maintains normal GH secretion and increases lean body mass in normal subjects; it has not been studied in dialysis patients, an essential step in assessing efficacy and safety prior to clinical trials. Methods. We performed a randomized crossover double-blind study in assessing the effect of MK-0677 versus placebo on IGF-1 levels, the primary outcome, in hemodialysis patients. In total, 26 subjects enrolled and 22 completed the 3-month crossover study. Results. The geometric mean IGF-1 was 1.07-fold greater [95% confidence interval (CI) 0.89-1.27; P=0.718] after placebo. In patients receiving MK-0677, the geometric mean IGF-1 were 1.76-fold greater (95% CI 1.48-2.10; P<0.001) following MK-0677. When the data were adjusted for preintervention IGF-1 concentration, the ratio of geometric means (MK-0677 relative to placebo) for the pre- versus postintervention change in the IGF-1 was 1.65 (95% CI 1.33-2.04; P<0.001). These data demonstrate a 65% greater increase (95% CI 33-104%) in IGF-1 in MK-0677-dosed subjects compared with placebo. There were no serious adverse effects attributable to MK-0677. Conclusions. MK-0677 increased serum IGF-1 levels with minimal adverse effects in hemodialysis subjects. Studies are needed to evaluate whether long-term therapy with MK-0677 improves PEW, lean body mass, physical strength, quality of life and survival in CKD/ESRD patients. [ABSTRACT FROM AUTHOR]

Bariatric surgery improves glucose homeostasis and alters gut hormones partly independent of weight loss. Leptin plays a role in these processes; levels are decreased following bariatric surgery, creating a relative leptin insufficiency. We previously showed that leptin administration in a weight-reduced state after Roux-en-Y gastric bypass (RYGB) caused no further weight loss. Here, we discuss the impact of leptin administration on gut hormones, glucostasis, and appetite. Weight stable women after RYGB were randomized to receive placebo or recombinant human metreleptin (0.05mg/kg twice daily). At weeks 0 and 16, a liquid meal challenge was performed. Glucose, insulin, C-peptide, GLP-1, PYY, glucagon, and ghrelin (total, acyl, and desacyl) were measured fasting and postprandially. Appetite was assessed using a visual analog scale. Mean post-op period was 53 ± 2.3 months; mean BMI was 34.6 ± 0.2 kg/m. At 16 weeks, there was no significant change in weight within or between groups. Fasting PYY was significantly different between groups and the leptin group had lower sweets craving at week 16 than the placebo group (P < 0.05). No other differenceswere observed. Leptin replacement does not alter gut hormones or glucostasis but may diminish sweet cravings compared to placebo in this population of post-RYGB women. [ABSTRACT FROM AUTHOR]

Background: Ghrelin stimulates GH secretion and regulates energy and glucose metabolism. The two circulating isoforms, acyl (AG) and des-acyl (DAG) ghrelin, have distinct metabolic effects and are under active investigation for their therapeutic potentials. However, there is only limited data on the pharmacokinetics of AG and DAG. Objectives: To evaluate key pharmacokinetic parameters of AG, DAG, and total ghrelin in healthy men and women. Methods: In study 1, AG (1, 3, and 5 µg/kg per h) was infused over 65 min in 12 healthy (8 F/4 M) subjects in randomized order. In study 2, AG (1 µg/kg per h), DAG (4 µg/kg per h), or both were infused over 210 min in ten healthy individuals (5 F/5 M). Plasma AG and DAG were measured using specific two-site ELISAs (study 1 and 2), and total ghrelin with a commercial RIA (study 1). Pharmacokinetic parameters were estimated by non-compartmental analysis. Results: After the 1, 3, and 5 µg/kg per h doses of AG, there was a dose-dependent increase in the maximum concentration (Cmax) and area under the curve (AUC(0-last)) of AG and total ghrelin. Among the different AG doses, there was no difference in the elimination half-life, systemic clearance (CL), and volume of distribution. DAG had decreased CL relative to AG. The plasma DAG:AG ratio was ~2:1 during steady-state infusion of AG. Infusion of AG caused an increase in DAG, but DAG administration did not change plasma AG. Ghrelin administration did not affect plasma acylase activity . Conclusions: The pharmacokinetics of AG and total ghrelin appears to be linear and proportional in the dose range tested. AG and DAG have very distinct metabolic fates in the circulation. There is deacylation of AG in the plasma but no evidence of acylation. [ABSTRACT FROM AUTHOR]

Objective: Ghrelin acylation by ghrelin O-acyltransferase (GOAT) has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-offunction models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR) system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation. Methodology: Male and female knockout (KO) mice for GOAT, ghrelin, GHSR, or both ghrelin and GHSR (dKO) were subjected to prolonged calorie restriction (40% of ad libitum chow intake). Body weight, fat mass, and glucose levels were recorded daily and compared to wildtype (WT) controls. Forty-eight hour blood glucose profiles were generated for each individual mouse when 2% or less body fat mass was reached. Blood samples were obtained for analysis of circulating levels of acyl- and desacyl-ghrelin, IGF-1, and insulin. Principal Findings: Chronic calorie restriction progressively decreased body weight and body fat mass in all mice regardless of genotype. When fat mass was depleted to 2% or less of body weight for 2 consecutive days, random hypoglycemic events occurred in some mice across all genotypes. There was no increase in the incidence of hypoglycemia in any of the four loss-of-function models for ghrelin signaling including GOAT KO mice. Furthermore, no differences in insulin or IGF-1 levels were observed between genotypes. Conclusion: The endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction. [ABSTRACT FROM AUTHOR]

The orexigenic hormone ghrelin is secreted from the stomach and has been implicated in the regulation of energy and glucose homeostasis. We hypothesized that ghrelin, like other gastrointestinal (GI) hormones, is present in intestinal lymph, and sampling this compartment would provide advantages for studying ghrelin secretion in rodents. Blood and lymph were sampled from catheters in the jugular vein and mesenteric lymph duct before and after intraduodenal (ID) adminis- tration of isocaloric Ensure, dextrin, or Liposyn meals or an equal volume of saline in conscious Sprague-Dawley rats. Total ghrelin levels were measured using an established radioimmunoassay. Acyl and des-acyl ghrelin were measured using two-site ELISA. Fasting ghrelin levels in lymph were significantly higher than in plasma (means ± SE: 3,307.9 ± 272.9 vs. 2,127.1 ± 115.0 pg/ml, P = 0.004). Postingestive acyl and des-acyl ghrelin levels were also significantly higher, whereas the ratio of acyl:des-acyl ghrelin was similar in lymph and plasma (0.91 ± 0.28 vs. 1.20 ± 0.36, P = 0.76). The principle enzymes responsible for deacylation of ghrelin were lower in lymph than in plasma. Following ID Ensure, maximum ghrelin suppression occurred at 2 h in lymph compared with at 1 h in plasma. The return of suppressed ghrelin levels to baseline was also delayed in lymph. Similarly, dextrin also induced significant suppression of ghrelin (two-way ANOVA: P = 0.02), whereas Liposyn did not (P = 0.32). On the basis of these findings, it appears that intestinal lymph, which includes drainage from the interstitium of the GI mucosa, is enriched in ghrelin. Despite reduced deacylating activity in lymph, there is not a disproportionate amount of acyl ghrelin in this pool. The postprandial dynamics of ghrelin are slower in lymph than plasma, but the magnitude of change is greater. Assessing ghrelin levels in the lymph may be advantageous for studying its secretion and concentrations in the gastric mucosa. [ABSTRACT FROM AUTHOR]

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]

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]