Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

DNA methylation variations are prevalent in human obesity, but evidence of a causative role in disease pathogenesis is limited. In this study, we combine epigenome-wide association and integrative genomics to investigate the impact of subcutaneous and visceral adipocyte DNA methylation variations in extreme human obesity. We identify extensive DNA methylation changes that are robustly associated with extreme obesity in combined discovery and replication analyses (N=190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P<1x10-7). Using functional interaction maps and methylation-expression association testing in human adipocytes, we connect extreme obesity-associated methylation variations to transcriptomic changes at >500 target genes. We find that disease-associated methylation variations localise to active genomic regions and transcription factor binding sites, at which DNA methylation influences transcription factor-target gene co-expression relationships. In Mendelian Randomisation analyses, we infer causal effects of DNA methylation on human obesity and obesity-induced metabolic disturbances, under genetic control, at 28 independent loci. Silencing of two target genes of causal DNA methylation variations, the PRRC2A and LIMD2 genes, further reveals novel metabolic effects in adipocytes. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal genomic and molecular mechanisms through which altered DNA methylation may impact adipocyte cellular functions.

679 Pharmacokinetics of direct oral anticoagulants in patient with atrial fibrillation and extreme obesity

Aims Direct oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight &gt;120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity. Methods and results We enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the two groups. Univariate and multivariate logistic regression analyses were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range. A total of 58 patients [mean (SD) age, 70.93 (8.73) years; 40% female] with extreme obesity [mean (SD) body mass index, 44.43 (3.54) kg/m2] and AF while undergoing DOAC treatment was included in the present study. In nine patients (15.5%), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs. 2%; P &lt; 0.01) and inappropriate DOAC underdosing (56% vs. 4%; P &lt; 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges. Conclusions Patients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.

Impact of Fatty Acids on Obesity-Associated Diseases and Radical Weight Reduction

Purpose Fatty acids (FA), particularly polyunsaturated (PUFA) ones, are involved in the regulation of glycemic control, lipid metabolism, and inflammation. The aim of the study was to assess patient FA profile in relation to obesity, lipid and carbohydrate metabolism disturbances, and weight loss. Materials and Methods The studied group consisted of 51 patients with extreme obesity, 23 of whom achieved radical weight reduction within 1 year after a laparoscopic sleeve gastrectomy (LSG). FA levels were determined using gas chromatography with flame ionization detection. Results Patients with extreme obesity and higher serum PUFA content have lower serum levels of SFA and MUFA (especially myristic, palmitic, lignoceric acids and palmitoleic, oleic acids), as well as lower triglyceride and higher HDL-cholesterol concentrations and it was not influenced by CEPT Taq1B variant. At baseline, the fatty acid profile of patients with type II diabetes differ from patients with dyslipidemia. In patients who had lost weight, significantly lower levels of selected saturated FA and major trans-fatty acid, elaidic, were found. Moreover, the proportion of PUFA was increased. Conclusion In extreme obesity, higher PUFA exert their favorable effects on serum lipids. Significant weight reduction after the bariatric surgery is associated with beneficial changes in the fatty acid profile. Graphical Abstract

Supervised Exercise Immediately After Bariatric Surgery: the Study Protocol of the EFIBAR Randomized Controlled Trial

Background Previous studies have investigated weight loss caused by exercise following bariatric surgery. However, in most cases, the training program is poorly reported; the exercise type, volume, and intensity are briefly mentioned; and the sample size, selection criteria, and follow-up time vary greatly across studies. Purpose The EFIBAR study aims to investigate over 1 year the effects of a 16-week supervised exercise program, initiated immediately after bariatric surgery, on weight loss (primary outcome), body composition, cardiometabolic risk, physical fitness, and quality of life in patients with severe/extreme obesity. Material and Methods The EFIBAR study is a parallel-group, superiority, randomized controlled trial (RCT), comprising 80 surgery patients. Half of the participants, randomly selected, perform a 16-week supervised exercise program, including both strength and aerobic training, starting immediately after the surgery (7–14 days). For each participant, all primary and secondary outcomes are measured at three different time points: (i) before the surgery, (ii) after the intervention (≈4 months), and (iii) 1 year after the surgery. Conclusion The EFIBAR study will provide new insights into the multidimensional benefits of exercise in adults with severe/extreme obesity following bariatric surgery. Trial Registration EFIBAR randomized controlled trial was prospectively registered at Clinicaltrials.gov (NCT03497546) on April 13, 2018. Graphical abstract

Case report: fast reversal of malignant obesity hypoventilation syndrome after noninvasive ventilation and pulmonary rehabilitation

Background Malignant obesity hypoventilation syndrome (MOHS) is described as a subtype condition of OHS, characterized by extreme obesity, obese-related hypoventilation, and multiorgan dysfunction. Because of low awareness and inadequate treatment, MOHS leads to high morbidity and mortality. Case presentation A 53-year-old man was diagnosed with MOHS evidenced by extreme obesity and multiorgan abnormalities. After taken noninvasive ventilation (NIV) treatment, he was rescued. And at the end of the six-month pulmonary rehabilitation (PR) program, improvement in terms of respiratory parameters, BMI, apnea-hypopnea index (AHI), and pulmonary hypertension were observed in the patient. Two years later, the patient was still in good condition. Conclusions This case highlights the awareness and proper use of NIV to rescue MOHS patients. Furthermore, the benefits of PR were explored in this case, which has not been considered within the therapeutic options for MOHS patients.

Impact of obesity on hypertension: A review

The primary cause of extreme obesity and overweight is a disparity between energy consumption and expenditure. Obesity is technically described as the excess deposition of 20% or more body fat over a person's ideal weight of body. The latter is an individual's maximum healthy value, which is measured primarily based on age, build, height, and degree of muscular growth. Obesity, on the other hand, is diagnosed by comparing an individual's weight to his or her height and calculating the BMI. The NIH has set a maximum of 30 kg/m2 as the threshold for being considered obese. As a result, amid World Health Organization warnings, obesity is on the rise in children and adults around the world. Obesity's rise, as well as the scope of related health problems, has significant ramifications for both people and public healthcare systems. Obesity is linked to increased chances of injury, sickness, and death, and it is one of the world's most overlooked public health problems. Obesity is linked to cardiac problems, which are the primary cause of death globally especially hypertension and diabetes. However, the mechanisms underlying obesity-related hypertension and other metabolic disorders have yet to be thoroughly studied. We looked at the connection among obese and heart disease, specifically the biological mechanisms that link obese and hypertension, in this study.