leptin and Developmental-Disabilities

Until relatively recently, the small number of identifiable inherited human diseases associated with marked obesity were complex, pleiotropic developmental disorders, the molecular basis for which were entirely obscure. The molecular basis for many of these complex syndromes, such as Bardet Beidl syndrome, has been revealed, providing novel insights into processes essential for human hypothalamic function and energy balance. In addition to these discoveries, which were the fruits of positional cloning, the molecular constituents of the signaling pathways responsible for the control of mammalian energy homeostasis have been identified, largely through the study of natural or artificial mutations in mice. We discuss the increasing number of human disorders that result from genetic disruption of the leptin-melanocortin pathways that have been identified. Practical implications of these findings for genetic counseling, prognostication, and even therapy have already emerged.

Topics: Adolescent; Animals; Child; Child, Preschool; Developmental Disabilities; DNA Mutational Analysis; Energy Metabolism; Genetic Counseling; Genetic Diseases, Inborn; Homeostasis; Humans; Leptin; Mice; Mice, Obese; Obesity; Obesity, Morbid; Phenotype; Prognosis; Receptor, Melanocortin, Type 4; Signal Transduction; Syndrome

The purpose of this study was to determine the levels of leptin, ghrelin, and nesfatin-1 to elucidate the causes of poor appetite and growth retardation in patients receiving methylphenidate therapy for attention deficit hyperactivity disorder. The study was performed on 89 male subjects; 48 patients and 41 healthy controls, aged 7-14 years. Following treatment, patients' leptin levels increased and ghrelin levels decreased while no significant change was found in nesfatin-1 levels. Of the 48 patients, 34 developed lack of appetite. In patients who developed lack of appetite, body weight SDS, body mass index (BMI), and BMI SDS were statistically significantly reduced; moreover, height SDS was reduced, though not to a statistically significant extent. This study attempted to elucidate the mechanisms that mediate the association between methylphenidate and appetite and growth, for which no studies have yet to be published.

Topics: Adolescent; Appetite; Attention Deficit Disorder with Hyperactivity; Biomarkers; Body Height; Body Weight; Case-Control Studies; Central Nervous System Stimulants; Child; Developmental Disabilities; Ghrelin; Humans; Leptin; Male; Methylphenidate; Prospective Studies

Identifying those infants most at risk for poor neurodevelopmental outcomes is crucial to allow for targeted surveillance or preventative interventions to be instigated from birth. One intriguing possibility is to use the molecular characteristics of the placenta at birth as a 'molecular barometer' of the in utero experience to predict future infant neurodevelopmental outcomes. Here we highlight the recent advances in the field and discuss the possibilities for an integrated approach across the '-omics' categories.

Topics: Autistic Disorder; Child Development; Developmental Disabilities; Female; Humans; Infant; Infant, Small for Gestational Age; Leptin; Methylation; Placenta; Pregnancy

Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective.

Topics: Analysis of Variance; Animals; Animals, Newborn; Anxiety; Behavior, Animal; Developmental Disabilities; Disease Models, Animal; Drug Administration Schedule; Fear; Frontal Lobe; Interpersonal Relations; Leptin; Mice; Mice, Inbred C57BL; Restraint, Physical; Spatial Learning