Jean-Pierre Chanoine

Healthy Buddies: A Novel, Peer-Led Health Promotion Program for the Prevention of Obesity and Eating Disorders in Children in Elementary School

OBJECTIVE. We designed and tested a novel health promotion program for elementary schools that was based on peer teaching from older to younger schoolchildren (“Healthy Buddies”). SUBJECTS AND METHODS. This prospective pilot study compared the effect of our program (2–3 hours/week, 21 weeks) in 2 Canadian elementary schools (intervention: n = 232 children, the whole school implementing the program; control: n = 151). Older students (4th through 7th grade) were given direct instruction from 1 intervention teacher and were paired with younger students (kindergarten through 3rd grade) for the whole school year. Students in 4th through 7th grade then acted as teachers for their younger “buddies.” All lessons included 3 components of healthy living: nutrition, physical activity, and healthy body image. The students first learned how to be positive buddies and learned the 3 components of a healthy life. Thereafter, they learned how to overcome challenges to living a healthy life. Outcome measures (intervention and control schools at the beginning and end of the school year) included validated questionnaires that assessed healthy-living knowledge, behavior and attitude, a 9-minute fitness run, self-competence, body satisfaction, disordered eating symptoms, and anthropometry (BMI, blood pressure, and heart rate). RESULTS. Compared with control students, both older and younger intervention students showed an increase in healthy-living knowledge, behavior, and attitude scores and a smaller increase in systolic blood pressure. BMI and weight increased less in the intervention students in 4th through 7th grade and height more in the intervention students in kindergarten through 3rd grade. CONCLUSIONS. Our student-led curriculum improved knowledge not only in older schoolchildren but also in their younger buddies. It also decreased weight velocity in the older students. Student-led teaching may be an efficient, easy-to-implement way of promoting a healthy lifestyle from kindergarten to 7th grade.

Immunoreactive Ghrelin in human cord blood : Relation to anthropometry, leptin, and growth hormone

Background Ghrelin is secreted by the stomach, the hypothalamus, and the placenta in humans and has growth hormone–secreting and orexigenic properties. Leptin is secreted mainly by the adipocyte, plays a major role in energy balance, and reflects fat mass in infants as well as adults. Leptin and ghrelin central effects are mediated, at least partly, through the neuropeptide Y/Y1 receptor pathway in the hypothalamus. Methods We determined whether ghrelin is also present in the fetus and investigated its relationship to leptin, growth hormone, birth weight, and calf and abdominal circumferences in 90 full-term neonates. Results Immunoreactive ghrelin was detected in all cord samples (mean ± SD, 187 ± 88 pmol/L; range, 66—594 pmol/L). In contrast to leptin, ghrelin concentrations of boys and girls were not statistically different. In female neonates, ghrelin is inversely correlated with anthropometric measures. In male neonates, ghrelin is positively correlated with leptin and negatively with growth hormone. Conclusion The presence of significant ghrelin concentrations in all neonates before the first feeding is intriguing. Unlike the fairly constant concentrations and effects of leptin over the short term, the wide variability of ghrelin concentrations observed in newborns raises the possibility that ghrelin secretion causes short-term changes in feeding behavior. We suggest that ghrelin may play a physiologic role in the initiation of feeding.

Obestatin, acylated and total ghrelin concentrations in the perinatal rat pancreas

Background: Ghrelin and obestatin are encoded by the preproghrelin gene and originate from posttranslational processing of the preproghrelin peptide. The fetal rat pancreas contains acylated and desacylated ghrelin peptides, as well as growth hormone secretagogue receptor -1a mRNA. Acylated ghrelin inhibits insulin secretion. We investigated the plasma and tissue ontogeny of ghrelin and obestatin in the rat. Methods: We measured obestatin and acylated and total ghrelin concentrations in plasma, pancreas and stomach from rat fetuses (F20) and neonates at postnatal day (PN) 1, 6, 12 and 21). Results: Overall, obestatin concentrations were markedly lower than total ghrelin concentrations. In plasma, total ghrelin concentrations decreased abruptly after birth (p < 0.05), contrasting with a 3 times increase in the concentration of acylated ghrelin between F20 and PN1 (p < 0.05). In pancreas, total ghrelin and obestatin concentrations decreased progressively from PN1 to PN21 but acylated ghrelin concentrations increased 6–7 times from F20 (18 [6] pg/ml) to PN6 (122 [59] pg/ml). The percent of acylated ghrelin increased from 1.8 (0.6) at F20 to 39.7 (13.0) % of total ghrelin immunoreactivity at PN12 (p < 0.05). There were significant positive correlations between postnatal obestatin, acylated or total ghrelin and insulin concentrations in the pancreas (all p < 0.02, r2 > 0.21) and between postnatal total ghrelin and obestatin (in pancreas, r2 = 0.37) or acylated ghrelin (in stomach, r2 = 0.27) (p < 0.001). Conclusion: Ghrelin and obestatin are present in the perinatal pancreas where they could potentially affect insulin secretion.

Long-acting octreotide treatment causes a sustained decrease in ghrelin concentrations but does not affect weight, behaviour and appetite in subjects with Prader–Willi syndrome

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 +1.9 (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 (-53%) and desacyl (-54%) 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.

Should the Definition of Micropenis Vary According to Ethnicity

Objective: We determined whether the existing reference values for the diagnosis of micropenis are appropriate for optimal care of neonates in a multiethnic environment like Vancouver. Methods: The stretched penile length and width were measured in 105 full-term newborn males of Caucasian (n = 40), Chinese (n = 40) and East-Indian origin (n = 25). Results: Mean length –2.5 SD was used for the definition of micropenis and was 2.6, 2.5 and 2.3 cm for Caucasian, East-Indian and Chinese babies, respectively (p < 0.05). This is close to the widely accepted recommendation that a penile length of 2.4– 2.5 cm be considered as the lowest limit for the definition of micropenis. Conclusion: Mean penile length and diameter are slightly but significantly smaller in newborns of Chinese origin compared to newborns of Caucasian and East-Indian origins.

GnRH-Deficient Phenotypes in Humans and Mice with Heterozygous Variants in KISS1/Kiss1

CONTEXT KISS1 is a candidate gene for GnRH deficiency. OBJECTIVE Our objective was to identify deleterious mutations in KISS1. PATIENTS AND METHODS DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions. RESULTS Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r(2) = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice. CONCLUSIONS Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.

Ghrelin in growth and development.

Exogenous administration of ghrelin increases caloric intake and stimulates growth hormone (GH) secretion, two effects that are mediated through binding of ghrelin to the GH secretagogue receptor (GHS-R). In addition, ghrelin is thought to inhibit adipogenesis by GHS-R-independent mechanisms. In adults, ghrelin is mainly produced by the stomach. In contrast, in the fetal and early postnatal period, ghrelin gene expression is abundant in the pancreas but not in the stomach. While knockout animal studies demonstrate that ghrelin is not required for perinatal development under normal nutritional conditions, the characteristics of ghrelin metabolism during fetal development suggest that ghrelin could contribute to the programming of mechanisms involved in energy balance, such as β-cell maturation, orexigenic pathways and adipogenesis. In humans, ghrelin concentrations progressively decrease during childhood and adolescence, as well as with advancing puberty. In adolescents, similar to adults, ghrelin concentrations are inversely related to body mass index and to circulating insulin. One notable exception is the presence of elevated ghrelin concentrations in subjects with Prader-Willi syndrome, raising the possibility that ghrelin could be part of the etiology of excess food intake in this condition. These data raise a number of fascinating questions on the potential physiologic role of this hormone during growth and development.

Pharmacotherapy and Weight-Loss Supplements for Treatment of Paediatric Obesity

Childhood obesity has become the most common paediatric disorder in the developed world. Treatment of obesity in children may include lifestyle interventions, pharmacotherapy and weight-loss supplements. The outcome of lifestyle interventions, which classically include dietary modifications, increased activity and behavioural modifications, remains insufficient and the adjuvant role of pharmacological agents has been proposed. Among the group of weight-loss medications, orlistat is the only pharmaceutical approved by the US FDA for the treatment of overweight and obese dolescents. The role of metformin needs to be established in larger studies and sibutramine remains an experimental product because of its potential adverse events. Weight-loss supplements lack sufficient data supporting their efficacy and safety, even in adults, and cannot be recommended at this time for adolescents. Preliminary data suggest that the use of fibre supplements, such as glucomannan, provides additional weight loss in individuals receiving a lifestyle intervention. No single approach will successfully treat obesity, and lifestyle modification presently remains the main pillar of any intervention aiming at decreasing bodyweight.

GLP-1 and Appetite Responses to a Meal in Lean and Overweight Adolescents Following Exercise

Objective: Increased physical activity is an integral part of weight loss programs in adolescents. We prospectively investigated the effects of exercise on glucagon‐like peptide‐1 (GLP‐1) concentrations and on appetite markers.

Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase

Acylated (octanoylated) 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 = 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 microg/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.