Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood.

BACKGROUND: The early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course. METHODS: DNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women's Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue. RESULTS: Lower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6-7 years (p = 0.0001) and % fat mass at 6-7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6-7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults. CONCLUSIONS: These data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.

Obesity surgery makes patients healthier and more functional: real world results from the United Kingdom National Bariatric Surgery Registry.

BACKGROUND: The National Bariatric Surgery Registry (NBSR) is the largest bespoke database in the field in the United Kingdom. OBJECTIVES: Our aim was to analyze the NBSR to determine whether the effects of obesity surgery on associated co-morbidities observed in small randomized controlled clinical trials could be replicated in a "real life" setting within U.K. healthcare. SETTING: United Kingdom. METHODS: All NBSR entries for operations between 2000 and 2015 with associated demographic and co-morbidity data were analyzed retrospectively. RESULTS: A total of 50,782 entries were analyzed. The patients were predominantly female (78%) and white European with a mean age of 45 ± 11 years and a mean body mass index of 48 ± 8 kg/m2. Over 5 years of follow-up, statistically significant reductions in the prevalence of type 2 diabetes, hypertension, dyslipidemia, sleep apnea, asthma, functional impairment, arthritis, and gastroesophageal reflux disease were observed. The "remission" of these co-morbidities was evident 1 year postoperatively and reached a plateau 2 to 5 years after surgery. Obesity surgery was particularly effective on functional impairment and diabetes, almost doubling the proportion of patients able to climb 3 flights of stairs and halving the proportion of patients with diabetes related hyperglycemia compared with preoperatively. Surgery was safe with a morbidity of 3.1% and in-hospital mortality of .07% and a reduced median inpatient stay of 2 days, despite an increasingly sick patient population. CONCLUSIONS: Obesity surgery in the U.K. results not only in weight loss, but also in substantial improvements in obesity-related co-morbidities. Appropriate support and funding will help improve the quality of the NBSR data set even further, thus enabling its use to inform healthcare policy.

ANRIL Promoter DNA Methylation: A Perinatal Marker for Later Adiposity.

Experimental studies show a substantial contribution of early life environment to obesity risk through epigenetic processes. We examined inter-individual DNA methylation differences in human birth tissues associated with child's adiposity. We identified a novel association between the level of CpG methylation at birth within the promoter of the long non-coding RNA ANRIL (encoded at CDKN2A) and childhood adiposity at age 6-years. An association between ANRIL methylation and adiposity was also observed in three additional populations; in birth tissues from ethnically diverse neonates, in peripheral blood from adolescents, and in adipose tissue from adults. Additionally, CpG methylation was associated with ANRIL expression in vivo, and CpG mutagenesis in vitro inhibited ANRIL promoter activity. Furthermore, CpG methylation enhanced binding to an Estrogen Response Element within the ANRIL promoter. Our findings demonstrate that perinatal methylation at loci relevant to gene function may be a robust marker of later adiposity, providing substantial support for epigenetic processes in mediating long-term consequences of early life environment on human health.

The use of adjustable gastric bands for management of severe and complex obesity.

BACKGROUND: Obesity levels in the UK have reached a sustained high and ∼4% of the population would be candidates for bariatric surgery based upon current UK NICE guidelines, which has important implications for Clinical Commissioning Groups. SOURCES OF DATA: Summary data from Cochrane systematic reviews, randomized controlled trials (RCTs) and cohort studies. AREAS OF AGREEMENT: Currently, the only treatment that offers significant and durable weight loss for those with severe and complex obesity is surgery. Three operations account for 95% of all bariatric surgery in the UK, but the NHS offers surgery to only a small fraction of those who could benefit. Laparoscopic adjustable gastric banding (gastric banding) has potentially the lowest risk and up-front costs of the three procedures. AREAS OF CONTROVERSY: Reliable Level 1 evidence of the relative effectiveness of the operations is lacking. GROWING POINTS: As a point intervention, weight loss surgery together with the chronic disease management strategy for obesity can prevent significant future disease and mortality, and the NHS should embrace both. AREAS TIMELY FOR DEVELOPING RESEARCH: Better RCT evidence is needed including clinical effectiveness and economic analysis to answer the important question 'which is the best of the three operations most frequently performed?' This review considers the current evidence for gastric banding for the treatment of severe and complex obesity.

Accumulation of 2-deoxy-D-glucose-6-phosphate as a measure of glucose uptake in the isolated perfused heart: a 31P NMR study.

The accumulation of 2-deoxy-D-glucose-6-phosphate (2DG6P), detected using 31P NMR spectroscopy, has been used as a measure of the rate of glucose uptake, yet the accuracy of this measurement has not been verified. In this study, isolated rat hearts were perfused with different substrates or isoproterenol for 30 min before measurement of either 2DG6P accumulation or [2-3H]glucose uptake, without and with insulin. Basal contractile function and metabolite concentrations were the same for all hearts. The basal rates of 2DG6P accumulation differed significantly, depending on the preceding perfusion protocol, and were 38-60% of the [2-3H]glucose uptake rates, whereas insulin-stimulated 2DG6P accumulation was the same or 71% higher than the [2-3H]glucose uptake rates. Therefore the ratio of 2DG6P accumulation/[2-3H]glucose uptake rates varied from 0.38 to 1.71, depending on the prior perfusion conditions or the presence of insulin. The rates of 2DG6P hydrolysis were found to be proportional to the intracellular 2DG6P concentrations, with a K(m) of 17.5mM and V(max) of 1.4 micromol/g dry weight/min. We conclude that the rates of 2DG6P accumulation do not accurately reflect glucose uptake rates under all physiological conditions in the isolated heart and should be used with caution.