Objective: Ghrelin is secreted primarily by the stomach and circulates as both acylated and desacyl ghrelin. Acylated (but not desacyl) ghrelin stimulates appetite. Both concentrations are elevated in Prader-Willi syndrome (PWS), suggesting that ghrelin may contribute to hyperphagia and overweight in these subjects. We evaluated whether long-acting octreotide (Oct) decreases acylated and desacyl ghrelin concentrations, body mass, appetite and compulsive behaviour towards food in adolescents with PWS. Design: A 56-week prospective, randomized, cross-over trial. Methods: Nine subjects with PWS (age 14.6 (10.8-18.9) years, body mass index (BMI) Z-score C1.9 (0.6-3.0)) received either Oct (30 mg) or saline i.m. every 4 weeks for 16 weeks and were switched over to the other treatment after a 24-week washout period. Results: Eight subjects completed the study. Oct caused a decrease in both acylated (K53%) and desacyl (K54%) fasting ghrelin concentrations (P!0.05) but did not significantly affect BMI. Oct had no significant effect on peptide YY concentrations, appetite or compulsive behaviour towards food. Oct caused a decrease in insulin-like growth factor-I concentrations, an increase in HbA1c and transient elevation of blood glucose in two subjects. Three subjects developed gallstones. Conclusions: Oct treatment caused a prolonged decrease in ghrelin concentrations in adolescents with PWS but did not improve body mass or appetite. Future intervention studies aiming at clarifying the role of ghrelin in PWS should focus on the administration of specific inhibitors of ghrelin secretion or ghrelin receptor activity that do not interfere with other appetite-regulating peptides.

Tham E, Liu J, Innis S, Thompson D, Gaylinn BD, Bogarin R, Haim A, Thorner MO, Chanoine JP. Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase. Am J Physiol Endocrinol Metab 296: E1093-E1100, 2009. First published February 24, 2009 doi:10.1152 doi:10. /ajpendo.90866.2008 ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. 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 ϭ 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 Ϯ SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 Ϯ 0.2 vs. 10.2 Ϯ 1.9 ng ⅐ ml Ϫ1 ⅐ 90 min Ϫ1 , P Ͻ 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r ϭ 0.50, P ϭ 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 Ϯ 1.9 vs. 8.6 Ϯ 1.2 ng ⅐ ml Ϫ1 ⅐ 90 min Ϫ1 , P ϭ 0.005). In a second group of subjects (n ϭ 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 Ϯ 0.5 vs. 4.5 Ϯ 0.6 g/ml, P ϭ 0.029) and cholinesterase activity (705 Ϯ 33 vs. 1,013 Ϯ 56 U/ml, P Ͻ 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. In vitro studies suggest that, in humans, circulating ghrelin is deacylated rapidly, at least in part by the enzyme cholinesterase (also known as pseudocholinesterase or butyrylcholinesterase, EC 3.1.1.8) (9).Both AG and DG could potentially play a physiological role in energy balance. Exogenous administration of AG, but not DG, stimulates GH secretion (35) and has orexigenic effects (41) in humans. AG injection also causes hyperglycemia and a decrease in circulating insulin (2). In addition, in rodents, administration of both AG...

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This chimeric RT-SHIV has exhibited productive replication in both macaque and human PBMCs, predominantly CCR5-coreceptor usage for viral entry, and sensitivity to NNRTIs as well as other anti-HIV compounds. This study demonstrates rapid systemic infection in macaques following intravaginal exposure to RT-SHIV. This RT-SHIV/macaque model could be useful for evaluation of NNRTI-based therapies, microbicides, or other preventive strategies.