Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

BACKGROUND AND AIMS: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. METHODS: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. RESULTS: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). CONCLUSIONS: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

Effect of reverse Trendelenburg position and positive pressure ventilation on safe non-hypoxic apnea period in obese, a randomized-control trial.

PURPOSE: There is an elevated incidence of hypoxemia during the airway management of the morbidly obese. We aimed to assess whether optimizing body position and ventilation during pre-oxygenation allow a longer safe non-hypoxic apnea period (SNHAP). METHODS: Fifty morbidly obese patients were recruited and randomized for this study. Patients were positioned and preoxygenated for three minutes in the ramp position associated with spontaneous breathing without additional CPAP or PEEP (RP/ZEEP group) or in the reverse Trendelenburg position associated with pressure support ventilation mode with pressure support of 8 cmH2O and an additional 10 cmH2O of PEEP while breathing spontaneously (RT/PPV group) according to randomization. RESULTS: The SNHAP was significantly longer in the RT/PPV group (258.2 (55.1) vs. 216.7 (42.3) seconds, p = 0.005). The RT/PPV group was also associated to a shorter time to obtain a fractional end-tidal oxygen concentration (FEtO2) of 0.90 (85.1(47.8) vs 145.3(40.8) seconds, p < 0.0001), a higher proportion of patients that reached the satisfactory FEtO2 of 0.90 (21/24, 88% vs. 13/24, 54%, p = 0.024), a higher FEtO2 during preoxygenation (0.91(0.05) vs. 0.89(0.01), p = 0.003) and a faster return to 97% oxygen saturation after ventilation resumption (69.8 (24.2) vs. 91.4 (39.2) seconds, p = 0.038). CONCLUSION: In the morbidly obese population, RT/PPV, compared to RP/ZEEP, lengthens the SNHAP, decreases the time to obtain optimal preoxygenation conditions, and allows a faster resuming of secure oxygen saturation. The former combination allows a more significant margin of time for endotracheal intubation and minimizes the risk of hypoxemia in this highly vulnerable population. TRIAL REGISTRATION: NCT02590406, 29/10/2015.

Dietary intakes in pregnant women with previous bariatric surgery.

PURPOSE: To (1) assess dietary intakes of pregnant women with previous bariatric surgery in comparison with Dietary Reference Intakes (DRIs); (2) compare their dietary intakes as well as their diet quality with a control group of pregnant women with no history of bariatric surgery. METHODS: Twenty-eight (28) pregnant women with previous surgery (sleeve gastrectomy, n = 7 and biliopancreatic diversion with duodenal switch, n = 21) were matched for pre-pregnancy body mass index with 28 pregnant women with no history of bariatric surgery. In at least one trimester, participants completed a minimum of 2 Web-based 24-h dietary recalls from which energy, macro- and micronutrient intakes as well as the Canadian Healthy Eating Index (C-HEI) were derived. RESULTS: No differences were observed for energy intake between groups. All women had protein intakes within the recommended range, but most women with previous surgery had carbohydrate (67%) and dietary fiber intakes (98%) below recommendations. In both groups, mean total fat, saturated fatty acids, free sugars and sodium intakes were above recommendations, as opposed to mean vitamin D, folic acid and iron dietary intakes below recommendations for most women. Compared with the control group, pregnant women with previous bariatric surgery had lower overall C-HEI scores. CONCLUSION: These results suggest that pregnant women with previous bariatric surgery would benefit from a nutritional follow-up throughout their pregnancy. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Neuroanatomical changes in white and grey matter after sleeve gastrectomy.

BACKGROUND: MRI studies show that obese adults have reduced grey matter (GM) and white matter (WM) tissue density as well as altered WM integrity. Bariatric surgery can lead to substantial weight loss and improvements in metabolic parameters, but it remains to be examined if it induces structural brain changes. The aim of this study was to characterize GM and WM density changes measured with MRI in a longitudinal setting following sleeve gastrectomy, and to determine whether any changes are related to inflammation and cardiometabolic blood markers. METHODS: 29 participants with obesity (age: 45.9 â€‹± â€‹7.8 years) scheduled to undergo sleeve gastrectomy were recruited. High-resolution T1-weighted anatomical images were acquired 1 month prior to as well as 4 and 12 months after surgery. GM and WM densities were quantified using voxel-based morphometry (VBM). Circulating lipid profile, glucose, insulin and inflammatory markers (interleukin-6, C-reactive protein and lipopolysaccharide-binding protein) were measured at each time point. A linear mixed effect model was used to compare brain changes before and after SG, controlling for age, sex, initial BMI and diabetic status. To assess the associations between changes in adiposity, metabolism and inflammation and changes in GM or WM density, the mean GM and WM densities were extracted across all the participants using atlas-derived regions of interest, and linear mixed-effect models were used. RESULTS: As expected, weight, BMI, waist circumference and neck circumference significantly decreased after SG compared with baseline (p â€‹< â€‹0.001 for all). A widespread increase in WM density was observed after surgery, particularly in the cerebellum, brain stem, cerebellar peduncle, cingulum, corpus callosum and corona radiata (p â€‹< â€‹0.05, after FDR correction). Significant increases in GM density were observed 4 months after SG compared to baseline in several brain regions such as the bilateral occipital cortex, temporal cortex, postcentral gyrus, cerebellum, hippocampus and insula as well as right fusiform gyrus, right parahippocampal gyrus, right lingual gyrus and right amygdala. These GM and WM increases were more pronounced and widespread after 12 months and were significantly associated with post-operative weight loss and the improvement of metabolic alterations. A linear mixed-effect model also showed associations between post-operative reductions in lipopolysaccharide-binding protein, a marker of inflammation, and increased WM density. To confirm our results, we tested whether the peak of each significant region showed BMI-related differences in an independent dataset (Human Connectome Project). We matched a group of individuals who were severely obese with a group of individuals who were lean for age, sex and ethnicity. Severe obesity was associated with reduced WM density in the brain stem and cerebellar peduncle as well as reduced GM density in cerebellum, regions that significantly changed after surgery (p â€‹< â€‹0.01 for all clusters). CONCLUSIONS: Bariatric surgery-induced weight loss and improvement in metabolic alterations is associated with widespread increases in WM and GM densities. These post-operative changes overlapped with baseline brain differences between participants who were severely obese and those who were normal-weight in a separate dataset, which may suggest a recovery of WM and GM alterations after bariatric surgery.

Totally endoscopic implant to effect a gastric bypass: 12-month safety and efficacy outcomes.

BACKGROUND: Only a small percentage of candidates for bariatric surgery ever undergo a procedure for weight loss. Devices duplicating key effects of bariatric surgeries with removable, fully trans-oral implants could extend their benefits to patients unwilling to undergo anatomy-altering abdominal surgeries. METHODS: Thirty-two obese subjects (mean BMI: 42.3) were enrolled in a prospective, multicenter, single-arm, feasibility trial of the first fully trans-oral endoscopic gastrointestinal bypass device. The device is a cuff attached to the distal esophagus by transmural anchors and connected to a 120-cm sleeve diverting undigested nutrients to the jejunum. Bodyweight, vital signs, adverse events, medications, HbA1c, fasting glucose, and lipids were collected at baseline and follow-up visits. Device status was endoscopically assessed every 6 months. RESULTS: The fully trans-oral procedure was successful in all subjects without intraoperative adverse events or postoperative infections. Twenty-eight of 32 subjects (88%) remained implanted with continuing follow-up beyond their 12-month visit. At 12 months, the 32 subjects had lost an average of 44.8% of excess body weight, 17.6% of total body weight, 20.8 kg, and 7.5 BMI points. Weight loss depended on capture of ingesta by the esophageal cuff, with 18 of 32 subjects without visible gaps around their cuffs at the 6 month endoscopy having significantly greater EWL (53.6 vs. 33.4% in the remaining subjects, p < 0.002). Mean HbA1c and fasting glucose declined by 1.1% points and 29 mg/dL in type 2 diabetic subjects, 80% of whom had remission of their diabetes at 12 months. CONCLUSION: This study demonstrates the feasibility, safety, and efficacy of a fully trans-oral gastrointestinal bypass implant. This purely endoscopic device may provide a valuable addition to the armamentarium of treatment available for the management of morbid obesity.

Effect of position and positive pressure ventilation on functional residual capacity in morbidly obese patients: a randomized trial.

PURPOSE: In morbidly obese patients, the position and ventilation strategy used during pre-oxygenation influence the safe non-hypoxic apnea time and the functional residual capacity (FRC). In awake morbidly obese volunteers, we hypothesized that the FRC would be higher after a five-minute period of positive pressure ventilation compared with spontaneous ventilation at zero inspiratory pressure. METHODS: Using a prospective crossover randomized trial design, obese subjects underwent, in a randomized order, a combination of one of three positions, supine (S), beach chair (BC), and reverse Trendelenburg (RT), and one of two ventilation strategies, spontaneous ventilation at zero inspiratory pressure (ZEEP-SV) or with positive pressure (PP-SV) set to an inspiratory pressure of 8 cmH2O, positive end-expiratory pressure of 10 cmH2O, and fraction of inspired oxygen of 0.21. RESULTS: Seventeen obese volunteers with a mean (standard deviation; SD) body mass index of 50 (8) kg·m-2 were included. Mean (SD) FRC in the three positions (S, BC, RT) was significantly higher using PP-SV compared with ZEEP-SV [2571 (477) vs 2215 (481) mL, respectively; mean difference, 356; 95% confidence interval (CI), 209 to 502; P < 0.001]. Mean (SD) FRC was significantly higher in the RT compared with BC position [2483 (521) vs 2338 (469) mL, respectively; mean difference, 145; 95% CI, 31 to 404; P = 0.01], while there was no difference between S and BC [2359 (519) mL vs 2338 (469) mL, respectively; mean difference, 21; 95% CI, -93 to 135; P = 0.89]. CONCLUSION: In awake morbidly obese volunteers, an increase in the FRC is observed when spontaneous ventilation at zero inspiratory pressure is switched to positive pressure. Compared with S positioning, the BC position had no measurable impact on the FRC. The RT position resulted in an optimal FRC. TRIAL REGISTRATION: clinicaltrials.gov (NCT02121808). Registered 24 April 2014.

A CpG-SNP Located within the ARPC3 Gene Promoter Is Associated with Hypertriglyceridemia in Severely Obese Patients.

AIMS: To test the potential association of cytosine-phosphate-guanine dinucleotides (CpG)-single-nucleotide polymorphisms (SNPs) located within actin-related protein 2/3 complex subunit 3 (ARPC3), a gene recently linked to adipogenesis and lipid accumulation, with metabolic syndrome (MetS) features in severely obese patients. METHODS: Prioritized SNPs within the ARPC3 locus were genotyped and tested for associations with MetS features in a cohort of 1,749 obese patients with and without MetS. Association testing with CpG methylation levels was performed in a methylation sub-cohort of 16 obese men. RESULTS: A significant association was found between the CpG-SNP rs3759384 (C>T) and plasma triglyceride (TG) levels (false discovery rate-corrected p = 3.5 × 10-2), with 0.6% of the phenotypic variance explained by the CpG-SNP, and with TT homozygotes showing the highest plasma TG levels (1.89 mmol/l). The carriers of the rs3759384 T allele also showed a significant decrease in methylation levels of the ARPC3 promoter-associated CpG site cg10738648 in both visceral adipose tissue and blood. ARPC3 expression levels showed a strong correlation with plasma TG levels (r = 0.70; p = 0.02). CONCLUSIONS: The increased plasma TG levels found in homozygous rs3759384 T allele carriers argue for a relevant role of this CpG-SNP in lipid management among obese individuals, which may be driven by an epigenetic-mediated mechanism.

Leptin and adiponectin DNA methylation levels in adipose tissues and blood cells are associated with BMI, waist girth and LDL-cholesterol levels in severely obese men and women.

BACKGROUND: Leptin (LEP) and adiponectin (ADIPOQ) genes encode adipokines that are mainly secreted by adipose tissues, involved in energy balance and suspected to play a role in the pathways linking adiposity to impaired glucose and insulin homeostasis. We have thus hypothesized that LEP and ADIPOQ DNA methylation changes might be involved in obesity development and its related complications. The objective of this study was to assess whether LEP and ADIPOQ DNA methylation levels measured in subcutaneous (SAT) and visceral adipose tissues (VAT) are associated with anthropometric measures and metabolic profile in severely obese men and women. These analyses were repeated with DNA methylation profiles from blood cells obtained from the same individuals to determine whether they showed similarities. METHODS: Paired SAT, VAT and blood samples were obtained from 73 severely obese patients undergoing a bioliopancreatic diversion with duodenal switch. LEP and ADIPOQ DNA methylation and mRNA levels were quantified using bisulfite-pyrosequencing and qRT-PCR respectively. Pearson's correlation coefficients were computed to determine the associations between LEP and ADIPOQ DNA methylation levels, anthropometric measures and metabolic profile. RESULTS: DNA methylation levels at the ADIPOQ gene locus in SAT was positively associated with BMI and waist girth whereas LEP DNA methylation levels in blood cells were negatively associated with body mass index (BMI). Fasting LDL-C levels were found to be positively correlated with DNA methylation levels at LEP-CpG11 and -CpG17 in blood and SAT and with ADIPOQ DNA methylation levels in SAT (CpGE1 and CpGE3) and VAT (CpGE1). CONCLUSIONS: These results confirm that LEP and ADIPOQ epigenetic profiles are associated with obesity. We also report associations between LDL-C levels and both LEP and ADIPOQ DNA methylation levels suggesting that LDL-C might regulate their epigenetic profiles in adipose tissues. Furthermore, similar correlations were observed between LDL-C and LEP blood DNA methylation levels suggesting a common regulatory pathway of DNA methylation in both adipose tissues and blood.

Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances.

Obesity is associated with an increased risk of Type 2 diabetes and cardiovascular diseases (CVD). The severely obese population is heterogeneous regarding CVD risk profile. Our objective was to identify metabolic pathways potentially associated with development of metabolic syndrome (MetS) through an analysis of overrepresented pathways from differentially methylated genes between severely obese men with (MetS+) and without (MetS-) the MetS. Genome-wide quantitative DNA methylation analysis in VAT of severely obese men was carried out using the Infinium HumanMethylation450 BeadChip. Differences in methylation levels between MetS+ (n = 7) and MetS- (n = 7) groups were tested. Overrepresented pathways from the list of differentially methylated genes were identified and visualized with the Ingenuity Pathway Analysis system. Differential methylation analysis between MetS+ and MetS- groups identified 8,578 methylation probes (3,258 annotated genes) with significant differences in methylation levels (false discovery rate-corrected DiffScore ≥ |13| ∼ P ≤ 0.05). Pathway analysis from differentially methylated genes identified 41 overrepresented (P ≤ 0.05) pathways. The most overrepresented pathways were related to structural components of the cell membrane, inflammation and immunity and cell cycle regulation. This study provides potential targets associated with adipose tissue dysfunction and development of the MetS.

Preoperative predictors of type 2 diabetes remission after bilio-pancreatic diversion with duodenal switch.

BACKGROUND: Many patients achieve short-term type 2 diabetes (T2D) remission after bariatric surgery, but relapses are common. Diabetes outcomes after bariatric surgery vary across procedures and populations. T2D remission scores are simple clinical tools developed to predict remission after bariatric surgery. However, they have never been tested after Biliopancreatic diversion with duodenal switch (BPD-DS). OBJECTIVES: The aim of this study was to compare the predictive value of T2D remission scores and preoperative diabetes characteristics in predicting T2D remission after BPD-DS. SETTING: Quebec Heart and Lung Institute - Laval University. METHODS: We retrospectively identified 918 patients with preoperative T2D who had undergone BPD-DS. Retrospective chart review was performed and variables used to calculate predictive scores were captured. T2D status was assessed annually for up to 10 years postop. Predictive values for each score (DiarRem, Ad Diarem, and Diabetter) and single preoperative diabetes characteristics used to construct these algorithms were evaluated by area under receiver operating characteristic curves (AUC). RESULTS: Diabetter showed greater performance for prediction of durable diabetes remission than other algorithms with acceptable discriminative ability (AUC between .69 and .79), but was not superior to T2D duration as a single predictor (P = .24 and P = .18). At 10 years, T2D duration had a better discriminative ability for the prediction of T2D remission than all 3 predictive models (AUC = .85, P < .05). CONCLUSIONS: Better chances for T2D remission following BPD-DS are associated with a shorter duration or T2D before surgery. Duration of T2D alone offers an excellent predictive ability and is a convenient alternative to diabetes remission scores to estimate chances of long-term diabetes remission after BPD-DS.

Attitudes and Behaviors towards Food and Weight in Late Pregnancy: A Comparative Approach between Individuals with and without Previous Bariatric Surgery.

The aims of this study were to compare, between pregnant individuals with and without bariatric surgery: (1) eating behaviors, (2) intuitive eating components and, (3) attitudes towards weight gain. This retrospective study included data collected in healthy pregnant individuals with and without previous bariatric surgery who were recruited at the Centre Hospitalier Universitaire (CHU) de Québec-Université Laval. Pregnant individuals who underwent bariatric surgery (biliopancreatic bypass with duodenal switch [n = 14] or sleeve gastrectomy [n = 5]) were individually matched, for age (±0.4 years) and body mass index (BMI) (±0.3 kg/m2), with pregnant individuals who have not received bariatric surgery. In the second trimester, participants completed the Three Factor Eating Questionnaire (TFEQ) and the Intuitive Eating Scale 2 (IES-2). In the third trimester, participants completed the French version of the Pregnancy Weight Gain Attitude Scale assessing attitudes towards weight gain. Pregnant individuals who have had bariatric surgery had a higher score for flexible restraint and a lower score for situational susceptibility to disinhibition compared to individuals who have not had undergone bariatric surgery (2.89 ± 1.15 vs. 1.95 ± 1.31; p = 0.04 and 1.11 ± 1.29 vs. 2.79 ± 1.44, respectively; p < 0.001). Regarding intuitive eating, pregnant individuals who experienced bariatric surgery had a higher score for reliance on internal hunger and satiety cues and a lower one for unconditional permission to eat compared with those who had not experienced bariatric surgery (3.99 ± 0.81 vs. 3.30 ± 1.03; p = 0.02 and 3.28 ± 0.54 vs. 3.61 ± 0.68, respectively; p = 0.03). No difference in attitudes towards weight gain was observed between groups. Overall, pregnant individuals who had undergone bariatric surgery had different eating behaviors and intuitive eating components compared to pregnant individuals without bariatric surgery. These results need to be confirmed in further studies with larger sample sizes.

Impact of maternal cardiometabolic status after bariatric surgery on the association between telomere length and adiposity in offspring.

The impact of bariatric surgery on metabolic and inflammatory status are reflected in the epigenetic profile and telomere length mediated by the changes in the metabolic status of the patients. This study compared the telomere length of children born before versus after maternal bariatric surgery as a surrogate to test the influence of the mother's metabolic status on children's telomere length. DNA methylation telomere length (DNAmTL) was estimated from Methylation-EPIC BeadChip array data from a total of 24 children born before and after maternal bariatric surgery in the greater Quebec City area. DNAmTL was inversely associated with chronological age in children (r = - 0.80, p < 0.001) and significant differences were observed on age-adjusted DNAmTL between children born before versus after the maternal bariatric surgery. The associations found between body mass index and body fat percentage with DNAmTL in children born after the surgery were influenced by maternal triglycerides, TG/HDL-C ratio and TyG index. This study reports the impact of maternal bariatric surgery on offspring telomere length. The influence of maternal metabolic status on the association between telomere length and markers of adiposity in children suggests a putative modulating effect of bariatric surgery on the cardiometabolic risk in offspring.

Thymic stromal lymphopoietin: an immune cytokine gene associated with the metabolic syndrome and blood pressure in severe obesity.

A previous expression profiling of VAT (visceral adipose tissue) revealed that the TSLP (thymic stromal lymphopoietin) gene was less expressed in severely obese men with (n=7) compared with without (n=7) the MetS (metabolic syndrome). We hypothesized that TSLP SNPs (single nucleotide polymorphisms) are associated with TSLP gene expression in VAT and with MetS phenotypes. Following validation of lower TSLP expression (P=0.003) in VAT of severely obese men and women with (n=70) compared with without (n=60) the MetS, a detailed genetic investigation was performed at the TSLP locus by sequencing its promoter, exons and intron-exon splicing boundaries using DNA of 25 severely obese subjects. Five tagging SNPs were genotyped in the 130 subjects from the expression analysis to test whether these SNPs contributed to TSLP expression variability (ANOVAs) and then genotyped in two independent samples of severely obese men (total, n=389) and women (total, n=894). In a sex-stratified multistage experimental design, ANOVAs were performed to test whether tagging SNPs were associated with MetS components treated as continuous variables. We observed that the non-coding SNP rs2289277 was associated with TSLP mRNA abundance (P=0.04), as well as with SBP [systolic BP (blood pressure)] (P=0.004) and DBP (diastolic BP) (P=0.0003) in men when adjusting for age, waist circumference, smoking and medication treating hypertension. These novel observations suggest that TSLP expression in VAT may partly explain the inter-individual variability for metabolic impairments in the presence of obesity and that specific SNPs (rs2289277 and/or correlating SNPs) may influence TSLP gene expression as well as BP in obese men.

Increased Adipose Tissue Indices of Androgen Catabolism and Aromatization in Women With Metabolic Dysfunction.

CONTEXT: Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue. OBJECTIVE: Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity. METHODS: Samples from 40 bariatric candidates (31 women, 9 men) were included in the study. Visceral (VAT) and subcutaneous adipose tissue (SAT) were collected during surgery. Adipose tissue morphology was measured by a combination of histological staining and semi-automated quantification. Following extraction, intra-adipose and plasma steroid concentrations were determined by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Aromatase activity was estimated using product over substrate ratio, while AKR1C2 activity was measured directly by fluorogenic probe. Gene expression was measured by quantitative PCR. RESULTS: VAT aromatase activity was positively associated with VAT adipocyte hypertrophy (P valueadj < 0.01) and negatively with plasma high-density lipoprotein (HDL)-cholesterol (P valueadj < 0.01), while SAT aromatase activity predicted dyslipidemia in women even after adjustment for waist circumference, age, and hormonal contraceptive use. We additionally compared women with high and low visceral adiposity index (VAI) and found that VAT excess is characterized by adipose tissue dysfunction, increased androgen catabolism mirrored by increased AKR1C2 activity, and higher aromatase expression and activity indices. CONCLUSION: In women, increased androgen catabolism or aromatization is associated with visceral adiposity and adipose tissue dysfunction.

Trimester-specific gestational weight gain in women with and without previous bariatric surgeries.

OBJECTIVES: The study aimed 1) to compare trimester-specific and total gestational weight gain (GWG) between mothers who had undergone biliopancreatic diversion with duodenal switch (BPD) and two control groups of unoperated women and 2) to examine the associations between GWG, intrauterine fetal growth and neonatal birthweight. METHODS: This retrospective study included data collected in medical records of newborns and mothers from 3 groups: the first control group (PP) included mothers (n = 158) with a pre-pregnancy BMI similar to that of the surgical group (n = 63) and the second one (PS) included mothers (n = 85) with a pre-pregnancy BMI corresponding to that of the surgical group prior to BPD or a BMI > 40 kg/m2. Trimester-specific GWG was obtained using linear interpolation and compared to the recommendations. RESULTS: Women exposed to BPD have an increased prevalence of insufficient weight gain in the second and third trimesters as well as for the whole pregnancy in comparison with women in the PP group. The weekly GWG rate in the third trimester was significantly lower in women exposed to BPD, compared to both control groups. Although the newborns of women with previous BPD were significantly smaller during pregnancy and at birth, no association was found with GWG. CONCLUSION: Women exposed to BPD are at substantial risk of insufficient GWG, however, mechanisms and long-term impacts require further investigation.

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

Comparison between arterial and venous sampling of circulating hormones, substrates and peptides in severe obesity.

PURPOSE: Severely obese patients are being encountered more frequently in clinical practice. Factors implicated in the relationship between obesity and cardiovascular disease may be measured from a blood sample obtained through arterial access in a cardiology setting, such as during cardiac catheterization or heart surgery. The comparability of a given sample site (arterial vs. venous) with regards to blood parameters is yet to be established. METHODS: Fifteen severely obese patients undergoing bariatric surgery were recruited. Fasting blood samples were collected simultaneously from the radial artery (A) and the superior vena cava (V), both representing general circulating levels, after anesthesia but before the surgical procedure. Blood samples were analysed for glucose, insulin, non-esterified fatty acids (NEFA), leptin, adiponectin, total ghrelin, high sensitive C-reactive protein (hs-CRP) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. RESULTS: Arterial and venous concentrations of all factors analysed showed no statistical difference (all p values > 0.1); leptin A: 39 ± 16 vs. V: 42 ± 18 ng/mL; total ghrelin A : 0.86 ± 0.27 vs. V : 0.76 ± 0.35 ng/mL; adiponectin A: 7.7 ± 3.3 vs. V: 7.7 ± 3.6 µg/mL; insulin A: 17.9 ± 9.7 vs. V: 18.6 ± 10.5 µU/mL; glucose A: 8.3 ± 2.1 vs. V: 7.9 ± 2.2 mM; NEFA A: 0.98 ± 0.93 vs. V: 0.89 ± 0.38 mM ; hs-CRP A: 10.17 ± 7.68 vs. V: 10.27 ± 7.30 µg/mL and NT-proBNP A: 54.3 ± 47.9 vs. V: 54.7 ± 49.3 pg/mL. CONCLUSION: These results suggest that radial artery and superior vena cava blood collection sites are comparable and may be used clinically with respect to fasting glucose, NEFA, leptin, adiponectin, total ghrelin, hs-CRP and NT-proBNP concentrations in a group of severely obese patients.

CPAP Is Not Needed in Every Sleep Apnea Patient Awaiting Bariatric Surgery.

BACKGROUND: Obstructive sleep apnea (OSA) patients are at high risk of postoperative complications following bariatric surgery. The aim of our study was to compare peri- and postoperative outcomes in OSA patients awaiting laparoscopic bariatric surgery who were prescribed CPAP treatment or not before surgery using nocturnal home oximetry and capillary blood gas measurements. METHODS: Data on 1094 eligible patients were analyzed. In accordance with our algorithm, those with ODI < 25/h and pCO2 < 45 mmHg (358 mild/moderate apnea and 447 non-apneic) underwent surgery without previous treatment, whereas those with an ODI ≥ 25/h (n = 289) were prescribed CPAP. We compared peri- and postoperative outcomes in treated and untreated patients. RESULTS: Treated patients were significantly older with a higher body mass index and a higher percentage of men than non-apneic and untreated OSA. Hypertension and diabetes were significantly more prevalent in the treated and untreated OSA patients than in the non-apneic. Regarding the occurrence of cardiopulmonary complications, the incidence of cardiac arrhythmia was higher in the treated patients than in the non-apneic and the untreated OSA (2.4%; 0.6 and 0.5%, p = 0.03). The slightly longer length of hospital stay seen in treated patients compared to those of other groups (2.8 ± 1.7; 2.6 ± 2.1 and 2.6 ± 1.8 days, p = 0.03) was no longer observed after adjusting for age and BMI. CONCLUSIONS: There is no risk increase for complications following bariatric surgery in untreated patients presenting mild/moderate OSA identified by a noninvasive screening algorithm.

Determinants of Cardiorespiratory Fitness After Bariatric Surgery: Insights From a Randomised Controlled Trial of a Supervised Training Program.

BACKGROUND: Severely obese patients have decreased cardiorespiratory fitness (CRF) and poor functional capacity. Bariatric surgery-induced weight loss improves CRF, but the determinants of this improvement are not well known. We aimed to assess the determinants of CRF before and after bariatric surgery and the impact of an exercise training program on CRF after bariatric surgery. METHODS: Fifty-eight severely obese patients (46.1 ± 6.1 kg/m2, 78% women) were randomly assigned to either an exercise group (n = 39) or usual care (n = 19). Exercise training was conducted from the 3rd to the 6th months after surgery. Anthropometric measurements, abdominal and mid-thigh computed tomographic scans, resting echocardiography, and maximal cardiopulmonary exercise testing was performed before bariatric surgery and 3 and 6 months after surgery. RESULTS: Weight, fat mass, and fat-free mass were reduced significantly at 3 and 6 months, without any additive impact of exercise training in the exercise group. From 3 to 6 months, peak aerobic power (V̇O2peak) increased significantly (P < 0.0001) in both groups but more importantly in the exercise group (exercise group: from 18.6 ± 4.2 to 23.2 ± 5.7 mL/kg/min; control group: from 17.4 ± 2.3 to 19.7 ± 2.4 mL/kg/min; P value, group × time = 0.01). In the exercise group, determinants of absolute V̇O2peak (L/min) were peak exercise ventilation, oxygen pulse, and heart rate reserve (r2 = 0.92; P < 0.0001), whereas determinants of V̇O2peak indexed to body mass (mL/kg/min) were peak exercise ventilation and early-to-late filling velocity ratio (r2 = 0.70; P < 0.0001). CONCLUSIONS: A 12-week supervised training program has an additive benefit on cardiorespiratory fitness for patients who undergo bariatric surgery.

IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery.

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.