The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

Introduction: Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). Methods: Whole genome sequences of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2 and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. Results: We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. Conclusion: These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity.

The Global Spread of Severe Obesity in Toddlers, Children and Adolescents – a Systematic Review & Meta Analysis

Introduction: Severe obesity among children and adolescents has emerged as a public health concern in multiple places around the world. Methods: We searched the Medline database for articles on severe obesity rates in children published between January 1960 and January 2020. For studies with available prevalence rates for an early and a more recent time period, the relative increase in prevalence was imputed. Results: In total, 874 publications were identified, of which 38 contained relevant epidemiological data. Rates of severe obesity varied significantly according to age, gender, geographic area, and the definition of severe obesity. The highest rates of class II and III obesity in the US according to the Centers of Disease Control cutoff were 9.5% and 4.5%, respectively. Seventeen studies reported prevalence rates in at least two time periods. Data for 9,190,718 individuals showed a 1.71 (95%CI, 1.53-1.90) greater odds for severe obesity in 2006-2017 (N=5,029,584) vs. 1967-2007 (N=4,161,134). In an analysis limited to studies from 1980s’ with a minimum follow-up of 20 years, a 9.16(95%CI, 7.76-10.80) greater odds for severe obesity in recent vs. earlier time was found. An analysis limited to studies from 2000, with a follow-up of 5-15 years, a 1.09 (95%CI, 0.99-1.20) greater odds was noted when comparing (2011-2017; N=4,991,831) vs. (2000-2011; N=4,134,340). Conclusion: Severe pediatric obesity is escalating with a marked increase from the1980’s and a slower rate from 2000.

Preoperative plasma aldosterone predicts complete remission of type 2 diabetes after bariatric surgery

Introduction: Bariatric surgery (BS) has beneficial effects on body weight and type 2 diabetes. However, 44–52%, 20–40%, and 19–25% of patients with type 2 diabetes who undergo sleeve gastrectomy, sleeve gastrectomy with duodenal-jejunal bypass, and Roux-en-Y gastric bypass, respectively, show insufficient improvement 1 year after BS. It is thus important to predict the improvement in type 2 diabetes before BS. Many hormones are related to hyperglycemia. However, the relationship between hormones and improvement in type 2 diabetes after BS has not been studied. We aimed to evaluate the relationship between the improvement in type 2 diabetes and hormones in patients with obesity and type 2 diabetes who underwent BS. Methods: We retrospectively reviewed 79 patients with obesity and type 2 diabetes who underwent BS, with a follow-up period of 12 months. We analyzed the relationship between some clinical parameters and complete remission (CR) of type 2 diabetes after BS. Patients were divided in two groups (type 2 diabetes CR and non-CR). Multiple regression analysis was performed to determine the parameters associated with type 2 diabetes resolution after BS. Results: BS significantly improved body weight and glucose metabolism. Preoperative liver function, glycated hemoglobin (HbA1c), insulin secretion (homeostatic model assessment [HOMA]2-%B), renin activity, plasma aldosterone level, and duration of type 2 diabetes were significantly different between the CR and non-CR groups. Multiple regression analysis showed that preoperative HbA1c, HOMA2-%B, aldosterone concentration, and duration of type 2 diabetes were predictors of CR of type 2 diabetes after BS. Plasma aldosterone was the strongest predictor. Discussion/Conclusion: Preoperative plasma aldosterone levels were related to the CR of type 2 diabetes after BS. Measuring plasma aldosterone levels preoperatively is useful for predicting the CR of type 2 diabetes after BS.

Weight Change Alters the Small RNA Profile of Urinary Extracellular Vesicles in Obesity

Introduction: Various kidney diseases reportedly show different urinary extracellular vesicles (EVs) RNA profiles. Although obesity is one of the main causes of chronic kidney disease, the expression pattern of urinary EVs RNA in obesity is uncertain. Our aim was to sequence the small RNA profiles of urinary EVs in obese patients before and after weight reduction and compared them to those of healthy volunteers (HVs). Methods: We recruited age-sex matched obese patients and HVs. The small RNA profiles of urinary EVs were analyzed using RNA sequencing. To evaluate the effect of weight reduction, small RNA profiles of urinary EVs 6 months after bariatric surgery were also analyzed. Results: The proportion of urinary EVs transfer RNA and microRNA of obese patients differed from that of HVs. Obese patients showed differential expression of 1343 small RNAs in urinary EVs compared to HVs (|fold change| ≥ 2 and p value < 0.05). Among those, 61 small RNAs were upregulated in obese patients and downregulated after weight reduction, whereas 167 small RNAs were downregulated in obese patients and upregulated after weight reduction. RNA sequencing revealed the correlation between the specific urinary EVs small RNAs and clinical parameters including body weight, low-density lipoprotein cholesterol, triglyceride, high-density lipoprotein cholesterol, serum glucose, estimated glomerular filtration rate, and albuminuria. Conclusion: Obese patients showed distinct urinary EVs small RNA profiles compared to HVs. Weight reduction altered urinary EVs small RNA profiles in obese patients.

Issue of Waist Circumference for the Diagnosis of Metabolic Syndrome Regarding Arterial Stiffness: Possible Utility of a Body Shape Index in Middle-Aged Nonobese Japanese Urban Residents Receiving Health Screening

<b><i>Introduction:</i></b> Abdominal obesity as a risk factor for diagnosing metabolic syndrome (MetS) is evaluated using waist circumference (WC), although WC does not necessarily reflect visceral adiposity. This cross-sectional study aimed to clarify whether replacing WC with “A Body Shape Index (ABSI),” an abdominal obesity index, in MetS diagnosis detects individuals with arterial stiffening assessed by cardio-ankle vascular index (CAVI). <b><i>Methods:</i></b> A retrospective cross-sectional study was conducted in 46,872 Japanese urban residents (median age 40 years) who underwent health screening. Exclusion criteria were current treatments and a past history of cardiovascular disease (CVD). The Japanese, International Diabetes Federation, and NCEP-ATPIII criteria were used to diagnose MetS. High CAVI was defined as CAVI ≥9.0. <b><i>Results:</i></b> CAVI correlated positively with ABSI (β = 0.127), but negatively with WC (β = −0.186), independent of age, sex, systolic blood pressure, fasting plasma glucose, and high-density lipoprotein--cholesterol. Receiver operating characteristic (ROC) analysis showed that ABSI had a stronger contribution to high CAVI (area under the ROC curve [AUC] = 0.730) than WC (AUC = 0.595) and body mass index (AUC = 0.520). ABSI ≥0.080 was defined as abdominal obesity based on the results of ROC analysis for high CAVI and estimated glomerular filtration rate &#x3c;60 mL/min/1.73 m². Logistic regression analysis revealed that replacing high WC with ABSI ≥0.080 in MetS diagnosis enhanced the detection of subjects with high CAVI. <b><i>Discussion/Conclusion:</i></b> Use of ABSI can detect subjects with arterial stiffening, which may lead to efficient stratification of CVD risk. Further studies are needed to confirm whether MetS diagnosis using ABSI predicts CVD morbidity and mortality.

De-novo and depot-specific androgen production in human adipose tissue - a source of hyperandrogenism in women with obesity

Introduction: Obesity in women is often associated with hyperandrogenism but the role of adipose tissue (AT) in androgen synthesis remains unclear. Therefore, we studied whether AT could be a source of androgens promoting hyperandrogenism. Methods: Subcutaneous and visceral AT was collected from lean and obese women. Androgen levels were evaluated in serum, AT and cell culture supernatant. Gene and protein expression of steroidogenic enzymes were determined. Results: Obese subjects had elevated serum androgen levels, which reduced after weight loss. Androgens were measurable in AT and in cell culture supernatants of adipocytes. Steroids were higher in AT from obese women, with the highest difference for testosterone in visceral AT (+7.9 fold, p=0.032). Steroidogenic enzymes were expressed in human AT with depot-specific differences. Obese women showed a significantly higher expression of genes of the backdoor pathway and of CYP19 in visceral AT. Conclusion: The whole steroidogenic machinery of the classical and backdoor pathways of steroidogenesis, and the capacity for androgen biosynthesis, were found in both AT depots and cultured adipocytes. Therefore, we hypothesize that AT is a de novo site of androgen production and the backdoor pathway of steroidogenesis might be a new pathomechanism for hyperandrogenism in women with obesity.

EFFECT OF OBESITY AND ROUX-EN-Y GASTRIC SURGERY ON OMEPRAZOLE PHARMACOKINETICS

Background: The prevalence of obesity is increasing globally. Objectives: To evaluate whether gastric bypass surgery modifies the bioavailability and pharmacokinetic (PK) parameters of Omeprazole. Setting: Hospital Clínico San Carlos, Madrid, Spain. Methods: Controlled, open-label, bioavailability clinical trial in patients undergoing Roux-en-Y gastric bypass (RYGB). Healthy patients with obesity (BMI>35) were included and assessed for Omeprazole PK before RYGB and after (1 and 6 months). PK sampling was done at baseline and several times up to 12 h after drug dosing. Pre- and post-surgery parameters were compared using paired ANOVA or Wilcoxon tests, and Control vs. Cases using ANOVA or Mann Whitney tests. Given the post-surgery change in body weight, parameters were corrected by dose/body-weight. Results: Fourteen Case and 24 Control subjects were recruited, 92% were women (N= 35/38). In patients who underwent RYGB, Cmax was significantly reduced at 1 and 6 months after surgery compared with pre-surgery values (p=0.001). Regarding the AUC, the values are lower at 1 and 6 months after surgery than at baseline (p<0.001).The drug clearance was also increased in the first month after surgery. No differences were found between patients 6 months after surgery and Controls. Cmax and AUC corrected by dose/body-weight were significantly different between the baseline surgery subjects and Controls. Conclusions: Omeprazole bioavailability is reduced in patients with obesity at 1 and 6 months after RYGB. However, Omeprazole PK parameters 6 months after RYGB are similar to control subjects, and thus no dose correction is required after RYGB for a given indication.

Effect of Hedan tablets on body weight and insulin resistance in patients with metabolic syndrome

Introduction: Apart from their recognized lipid-lowering effect, Hedan tablets, a mixture of Chinese herbal medicines, have demonstrated a certain weight-loss effect in clinical practice. The aim of this randomized, double-blind, placebo-controlled study is to verify the effect of Hedan tablets on body weight (BW) and insulin resistance (IR) in patients with metabolic syndrome (MetS). Methods: A total of 62 eligible patients with MetS were divided into two groups: the treatment group (Hedan tablets at 4.38 g/day tid) and the control group (placebo treatment). Both groups attended follow-ups at 8, 16, and 24 weeks during the process. The parameters of the assessment include lipid level, BW, triglyceride (TG) to high-density lipoprotein cholesterol (HDLc) ratio (TG/HDLc), homeostasis model assessment for IR (HOMA-IR) index, and adiponectin. Results: Patients in the treatment group showed a significant decrease in BW compared with the control group (−4.47 vs. 0.06 kg) after 8 weeks of treatment. A significant decrease in body mass index was also observed in the treatment group after 16 weeks of treatment (−1.79 vs. −0.03 kg/m2). In the treatment group, 20 out of 31 (64.5%) patients lost 5–10% BW and 4 out of 31 (12.9%) patients lost over 10% BW after 24 weeks of treatment. Although there were no significant changes in the patients’ HOMA-IR, the treatment group showed a significant reduction in TG/HDLc (−0.98 vs. −0.19) after 8 weeks of treatment and a significant increase in adiponectin (6.87 vs. −0.43) after 16 weeks of treatment. Discussion/Conclusion: The Hedan tablets significantly improve BW, BMI, TG/HDLc, and adiponectin in patients with MetS. Thus, Hedan tablets may be used as an adjunct to existing MetS management methods.

Prevalence of thinness, overweight, obesity and central obesity in Finnish school-aged children: a comparison of national and international reference values

Introduction: The global epidemic of obesity concerns children, and monitoring the prevalence is of highest priority. Body mass index (BMI) with age- and sex-specific cut-off values determine weight status in children, although multiple reference systems exist. Our aim was to compare the prevalence for thinness, normal weight, overweight and obesity in Finnish school-aged children according to national and international reference values, as well as to determine which cut-off values for overweight agree with the criteria for central obesity. Methods: This study includes 10 646 children aged 9─12 years from the Finnish Health in Teens (Fin-HIT) cohort. Height, weight and waist circumference were measured in 2011─2014. BMI (weight [kg]/height [m]2) and waist-to-height ratio (WHtR; waist [cm]/height [cm]) were calculated. The WHtR cut-off of > 0.5 indicated central obesity. We compared the sex-specific prevalence of thinness, overweight and obesity using the International Obesity Task Force (IOTF), World Health Organization (WHO) and Finnish (FIN) BMI-for-age reference values, as well as these three against central obesity based on WHtR. Results: The prevalence of thinness, overweight and obesity were 11.0%, 12.7% and 2.6%, respectively, using IOTF; 2.6%, 15.9% and 5.2% using WHO; and 5.1%, 11.4% and 2.2% using FIN. Overweight and obesity were more common in boys than girls using WHO and FIN, while thinness more common in girls using IOTF and FIN. IOTF versus WHO exhibited moderate agreement (κ = 0.59), which improved for IOTF versus FIN (κ = 0.74). Of those classified as overweight by WHO, 37% and 47% were regarded as normal weight according to IOTF and FIN, respectively. The prevalence of central obesity was 8.7%, and it was more common in boys than girls. WHO provided the highest sensitivity: 95% of individuals with central obesity were classified with overweight or obesity. Using FIN provided the highest specificity (93%). Conclusion: Our findings show that WHO overestimates the prevalence of overweight and obesity, while IOTF overrates thinness. Thus, comparing prevalence rates between studies requires caution. The novelty of this study is the comparison of the cut-off values for overweight with central obesity. The choice of reference system affects the generalizability of the research results.

Effect of a 1-year controlled lifestyle intervention on body weight and other risk markers (the Healthy Lifestyle Community Programme, cohort 2)

Introduction: The prevalence of obesity is high and increasing worldwide. Obesity is generally associated with an increased risk of chronic disease and mortality. The objective of the study was to test the effect of a lifestyle intervention on body weight and other chronic disease risk markers. Methods: A non-randomized controlled trial was conducted, including mostly middle-aged and elderly participants recruited from the general population in rural northwest Germany (intervention: n = 114; control: n = 87). The intervention consisted of a 1-year lifestyle programme focusing on four key areas: a largely plant-based diet (strongest emphasis), physical activity, stress management, and community support. Parameters were assessed at baseline, 10 weeks, 6 months, and 1 year. The control group received no intervention. Results: Compared to control, in the intervention group significantly lower 1-year trajectories were observed for body weight, body mass index (BMI), waist circumference, total cholesterol, calculated LDL cholesterol, non-HDL cholesterol, remnant cholesterol (REM-C), glucose, HbA1c, and resting heart rate (RHR). However, between-group differences at 1 year were small for glucose, HbA1c, and cholesterol (apart from REM-C). No significant between-group differences were found for 1-year trajectories of measured LDL cholesterol, HDL cholesterol, triglycerides, insulin, blood pressure, and pulse pressure. Conclusion: The intervention successfully reduced body weight, BMI, waist circumference, REM-C, and RHR. However, at 1 year, effectiveness of the intervention regarding other risk markers was either very modest or could not be shown.