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Genome wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood
Annual Scientific Meeting High use of CPAP increased weight more than high use sham (1.4 kg; 0.04—2.9, p = 0.05) and more than low CPAP use (1.6 kg; 0.4—2.8, p = 0.01). There was no difference between high and low sham users (0.36 kg; −1.0 to 1.7, NS). Neither treatment alone, CPAP dose alone nor the combined effect of both influenced glucose, insulin or insulin resistance. Conclusion: High use CPAP increases weight compared to high use sham and low use CPAP without any subsequent changes in metabolic dysfunction. It is possible an increase in lean muscle mass rather than fat is the cause of the weight gain which may not necessarily have a detrimental effect on health. http://dx.doi.org/10.1016/j.orcp.2014.10.089 69 Genome wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood Rae-Chi Huang 1,∗ , Liz Davis 1,2 , Emma S. Garratt 3 , Hong Pan 4 , Y. Wu 4 , Sheila J. Barton 3 , Graham C. Burdge 3 , Keith M. Godfrey 3 , Joanna D. Holbrook 4 , Karen A. Lillycrop 3 1 Telethon
Kids Institute, Perth, WA,
Australia 2 Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, WA, Australia 3 University of Southampton, Southampton, United Kingdom 4 Singapore Institute for Clinical Sciences, Singapore Introduction: Childhood obesity is a major public health issue. Here we investigated whether differential methylation was associated with morbid childhood obesity. Methods: We studied methylation profiles in whole blood from 79 morbidly obese children (mean BMI z-score 2.6) and 71 age/sex matched controls (mean BMI z-score 0.1). The morbidly obese children were derived from a tertiary clinical referral centre at Princess Margaret Hospital, Perth. Controls were recruited from schools. DNA samples from the obese subjects were pooled and DNA from the control subjects were pooled. These pooled samples were analysed using the HumanMethylation 450K BeadChip array. Results: Comparison of the methylation profiles between obese and control subjects revealed 80 differentially methylated CpG (DMCpG) loci associ-
49 ated with 80 unique genes that had a greater than 10% difference in methylation and a p value < 0.05. The top pathways enriched amongst the DMCpGs were cellular developmental, growth and proliferation and cell to cell signaling. To validate the associations between the methylation of selected DMCpGs with childhood obesity, pyrosequencingbased bisulfite PCR analysis was carried out across the DMCpGs within FYN, IGFBP3, PIWIL4 and TAOK3 in individual subjects. FYN (Cg26846943) was hypermethylated in obese individuals (p = 0.012), while lower methylation of IGFBP3 (Cg17209188, p = 0.001), PIWIL4 (Cg16436, p = 0.003) and TAOK3 (Cg17627898, p = 0.001) were associated with obesity. Conclusions: Our genome wide analysis provides evidence that childhood obesity is associated with changes in DNA methylation in whole blood. These findings suggest that epigenetic processes and early life programming may play a role in the pathogenesis of childhood obesity. Further studies are required to determine the causal direction of this relationship. http://dx.doi.org/10.1016/j.orcp.2014.10.090 6 Functional significance of rosiglitazone treatment on ß-adrenoceptor function on brite adipocytes derived from inguinal white adipose tissue Dana S. Hutchinson 1,∗ , Jon Merlin 1 , Nodi Dehvari 2 , Masaaki Sato 1 , Tore Bengtsson 2 , Roger J. Summers 1 , Bronwyn A. Evans 1 1 Monash
University, Parkville, VIC, Australia 2 Physiology, Wenner-Gren Institute, Stockholm, Sweden The high prevalence of obesity has provoked substantial interest in adipocyte thermogenesis. Several studies have revealed functional BAT in adult humans, and have demonstrated inducible brite (brown in white) adipocytes in animal models by multiple stimuli including the PPAR␥ activator rosiglitazone. Brite adipocytes are characterised by expression of the uncoupling protein UCP1 and although derived from a white adipocyte lineage, they express the brown adipocyte transcriptional co-regulator Prdm16. We determined the effect of rosiglitazone on -adrenoceptor function (assessed by oxygen consumption rates (Seahorse XF96), cyclic AMP assays, glucose uptake assays)
Kids Institute, Perth, WA,
Australia 2 Department of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Perth, WA, Australia 3 University of Southampton, Southampton, United Kingdom 4 Singapore Institute for Clinical Sciences, Singapore Introduction: Childhood obesity is a major public health issue. Here we investigated whether differential methylation was associated with morbid childhood obesity. Methods: We studied methylation profiles in whole blood from 79 morbidly obese children (mean BMI z-score 2.6) and 71 age/sex matched controls (mean BMI z-score 0.1). The morbidly obese children were derived from a tertiary clinical referral centre at Princess Margaret Hospital, Perth. Controls were recruited from schools. DNA samples from the obese subjects were pooled and DNA from the control subjects were pooled. These pooled samples were analysed using the HumanMethylation 450K BeadChip array. Results: Comparison of the methylation profiles between obese and control subjects revealed 80 differentially methylated CpG (DMCpG) loci associ-
49 ated with 80 unique genes that had a greater than 10% difference in methylation and a p value < 0.05. The top pathways enriched amongst the DMCpGs were cellular developmental, growth and proliferation and cell to cell signaling. To validate the associations between the methylation of selected DMCpGs with childhood obesity, pyrosequencingbased bisulfite PCR analysis was carried out across the DMCpGs within FYN, IGFBP3, PIWIL4 and TAOK3 in individual subjects. FYN (Cg26846943) was hypermethylated in obese individuals (p = 0.012), while lower methylation of IGFBP3 (Cg17209188, p = 0.001), PIWIL4 (Cg16436, p = 0.003) and TAOK3 (Cg17627898, p = 0.001) were associated with obesity. Conclusions: Our genome wide analysis provides evidence that childhood obesity is associated with changes in DNA methylation in whole blood. These findings suggest that epigenetic processes and early life programming may play a role in the pathogenesis of childhood obesity. Further studies are required to determine the causal direction of this relationship. http://dx.doi.org/10.1016/j.orcp.2014.10.090 6 Functional significance of rosiglitazone treatment on ß-adrenoceptor function on brite adipocytes derived from inguinal white adipose tissue Dana S. Hutchinson 1,∗ , Jon Merlin 1 , Nodi Dehvari 2 , Masaaki Sato 1 , Tore Bengtsson 2 , Roger J. Summers 1 , Bronwyn A. Evans 1 1 Monash
University, Parkville, VIC, Australia 2 Physiology, Wenner-Gren Institute, Stockholm, Sweden The high prevalence of obesity has provoked substantial interest in adipocyte thermogenesis. Several studies have revealed functional BAT in adult humans, and have demonstrated inducible brite (brown in white) adipocytes in animal models by multiple stimuli including the PPAR␥ activator rosiglitazone. Brite adipocytes are characterised by expression of the uncoupling protein UCP1 and although derived from a white adipocyte lineage, they express the brown adipocyte transcriptional co-regulator Prdm16. We determined the effect of rosiglitazone on -adrenoceptor function (assessed by oxygen consumption rates (Seahorse XF96), cyclic AMP assays, glucose uptake assays)