Family and Population-Based Studies of Variation within the Ghrelin Receptor Locus in Relation to Measures of Obesity

The growth hormone secretagogue receptor (GHSR) is mediating hunger sensation when stimulated by its natural ligand ghrelin. In the present study, we tested the hypothesis that common and rare variation in the GHSR locus are related to increased prevalence of obesity and overweight among Whites.In a population-based study sample of 15,854 unrelated, middle-aged Danes, seven variants were genotyped to capture common variation in an 11 kbp region including GHSR. These were investigated for their individual and haplotypic association with obesity. None of these analyses revealed consistent association with measures of obesity. A -151C/T promoter mutation in the GHSR was found in two unrelated obese patients. One family presented with complete co-segregation, but the other with incomplete co-segregation. The mutation resulted in an increased transcriptional activity (p<0.02) and introduction of a specific binding for Sp-1-like nuclear extracts relative to the wild type. The -151C/T mutation was genotyped in the 15,854 Danes with a minor allele frequency of 0.01%. No association with obesity in carriers (mean BMI: 27+/-4 kg/m(2)) versus non-carriers (mean BMI: 28+/-5 kg/m(2)) (p>0.05) could be shown.In a population-based study sample of 15,854 Danes no association between GHSR genotypes and measures of obesity and overweight was found. Also, analyses of GHSR haplotypes lack consistent associations with obesity related traits. A rare functional GHSR promoter mutation variant was identified, yet there was no consistent relationship with obesity in neither family- nor population-based studies

Maternal protein and folic acid intake during gestation does not program leptin transcription or serum concentration in rat progeny

Maternal nutrition during gestation influences the development of the fetus, thereby determining its phenotype, including nutrient metabolism, appetite, and feeding behavior. The control of appetite is a very complex process and can be modulated by orexigenic and anorexigenic mediators such as leptin, which is involved in the regulation of energy homeostasis by controlling food intake and energy expenditure. Leptin transcription and secretion are regulated by numerous factors, nutrition being one of them. The present study was designed to test whether maternal nutrition can permanently affect leptin gene transcription and leptin serum concentration in rat progeny. Moreover, we analyzed whether leptin expression and secretion in response to high-fat postweaning feeding depends on the maternal diet during gestation. Pregnant rats were fed either a normal protein, normal folic acid diet (the AIN-93 diet); a protein-restricted, normal folic acid diet; a protein-restricted, folic acid-supplemented diet; or a normal protein, folic acid-supplemented diet. After weaning, the progeny was fed either the AIN-93 diet or a high-fat diet. Neither maternal nutrition nor the postweaning diet significantly affected Lep transcription. High-fat feeding after weaning was associated with higher serum leptin concentration, but the reaction of an organism to the fat content of the diet was not determined by maternal nutrition during gestation. There was no correlation between Lep mRNA level and serum leptin concentration. Global DNA methylation in adipose tissue was about 30% higher in rats fed postnatally the high-fat diet (P < 0.01). Our study showed that the protein and folic acid content in the maternal diet had no significant programming effect on Lep transcription and serum leptin concentration in the rats

Etiology of early obesity in children

The aim of the dissertation was to contribute to the understanding of genetic influences that contribute to obesity in childhood. The specific objective was to monitor the cohort of Czech children with early-caused obesity prevalence of mutations of selected genes, which are applied in the pathogenesis of monogenic forms of obesity

Glucose homeostasis and insulin resistance: prevalence, gender differences and predictors in adolescents

BACKGROUND: Adolescence, due to transient pubertal insulin resistance (IR), is associated with a higher risk for disturbances of glucose metabolism. The aim of our study was 1) to investigate the prevalence of disturbances of glucose metabolism, 2) to define gender specific homeostasis model assessment of insulin resistance (HOMA-IR) thresholds associated with increased cardiometabolic risks and 3) to provide predictors of HOMA-IR. METHODS: The studied cohort consisted of Czech adolescents aged 13.0-17.9 years: 1,518 individuals of general population and three studied groups according weight category (615 normal weight, 230 overweight and 683 obese). The prevalence of IR, impaired fasting glucose (IFG) and type 2 diabetes was assessed. Risky HOMA-IR thresholds based on components of metabolic syndrome were investigated. HOMA-IR prediction was calculated taking into account age, blood pressure, multiple anthropometric, biochemical and hormonal parameters. RESULTS: In general population cohort, the prevalence of IFG and type 2 diabetes was 7.0% and <0.5%, respectively. Boys regardless of weight presented significantly higher levels of blood glucose and higher prevalence of IFG than girls. Obese boys were found more insulin resistant than obese girls. HOMA-IR thresholds of 3.6 for girls and 4.4 for boys were associated with increased cardiometabolic risks. For both genders, the model of HOMA-IR prediction was composed of age, BMI, ratio of free triiodthyronine to free thyroxine, gamma-glutamyltransferase activity and levels of triglycerides and sex hormone-binding globulin. CONCLUSIONS: The type 2 diabetes in adolescents, including those who were obese, was rarely diagnosed. Obese adolescent boys were at greater risk for IR and for IFG than obese girls. In adolescence, thresholds of HOMA-IR in contrast to predictors were found gender specific