Molecular remodeling of adipose tissue is associated with metabolic recovery after weight loss surgery.

BACKGROUND: Bariatric surgery is an effective therapy for individuals with severe obesity to achieve sustainable weight loss and to reduce comorbidities. Examining the molecular signature of subcutaneous adipose tissue (SAT) following different types of bariatric surgery may help in gaining further insight into their distinct metabolic impact. RESULTS: Subjects undergoing biliopancreatic diversion with duodenal switch (BPD-DS) showed a significantly higher percentage of total weight loss than those undergoing gastric bypass or sleeve gastrectomy (RYGB + SG) (41.7 ± 4.6 vs 28.2 ± 6.8%; p = 0.00005). Individuals losing more weight were also significantly more prone to achieve both type 2 diabetes and dyslipidemia remission (OR = 0.75; 95%CI = 0.51-0.91; p = 0.03). Whole transcriptome and methylome profiling showed that bariatric surgery induced a profound molecular remodeling of SAT at 12 months postoperative, mainly through gene down-regulation and hypermethylation. The extent of changes observed was greater following BPD-DS, with 61.1% and 49.8% of up- and down-regulated genes, as well as 85.7% and 70.4% of hyper- and hypomethylated genes being exclusive to this procedure, and mostly associated with a marked decrease of immune and inflammatory responses. Weight loss was strongly associated with genes being simultaneously differentially expressed and methylated in BPD-DS, with the strongest association being observed for GPD1L (r2 = 0.83; p = 1.4 × 10-6). CONCLUSIONS: Present findings point to the greater SAT molecular remodeling following BPD-DS as potentially linked with higher metabolic remission rates. These results will contribute to a better understanding of the metabolic pathways involved in the response to bariatric surgery and will eventually lead to the development of gene targets for the treatment of obesity. Trial registration ClinicalTrials.gov NCT02390973.

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.

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.

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.

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.

Ten-year remission rates in insulin-treated type 2 diabetes after biliopancreatic diversion with duodenal switch.

BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) confers the highest rate of type 2 diabetes (T2D) remission compared with other bariatric procedures. Previous studies suggest that type of antidiabetic therapy used before surgery and duration of disease influence postsurgical glycemic outcomes. Short-term, progressive improvement in insulin sensitivity and beta-cell function after metabolic surgery in patients with noninsulin-treated T2D has been demonstrated. Whether patients with more advanced disease can achieve sustained remission remains unclear. OBJECTIVE: The aim of this study was to assess long-term glycemic outcomes in insulin-treated patients with T2D after BPD-DS and identify predictors of sustained diabetes remission or relapse. SETTING: University-affiliated tertiary care center. METHODS: Data from 141 patients with insulin-treated T2D who underwent BPD-DS between 1994 and 2006 with 10 years of follow-up data were collected from a prospective electronic database. RESULTS: Follow-up was available in 132 patients (91%). At 10 years after metabolic surgery, 90 patients (68.1%) had a complete remission of diabetes, 3 (2.3%) had a partial remission, 21 (15.9%) had an improvement, and 3 (2.3%) were unchanged in their diabetes status. Fourteen patients died during the 10-year follow-up period. Relapse after an initial period of remission occurred in 15 (11.4%) patients. Insulin discontinuation was achieved in 97%. Duration of diabetes was an independent predictor of nonremission at 10 years. CONCLUSIONS: The BPD-DS maintains remission at 10 years postoperatively in patients with more advanced diabetes. Long-term benefits of the BPD-DS on weight loss and glycemic control should be considered when offering metabolic surgery to patients with insulin-treated T2D.

Long Alimentary Limb Duodenal Switch (LADS): an Exploratory Randomized Trial, Results at 2 Years.

PURPOSE: The effectiveness of the standard biliopancreatic diversion with duodenal switch (BPD/DS) in terms of weight loss has been demonstrated. Increasing the strict alimentary limb length while maintaining the length of the common channel could lead to similar weight loss while reducing side effects. MATERIALS AND METHODS: The objective was to evaluate the effect of increasing the strict alimentary limb length on weight loss, comorbidities, nutritional deficiencies, and quality of life 2 years after surgery, compared with standard BPD/DS. An exploratory randomized, double-blind study evaluated the results of LADS at 2 years in comparison with the standard BPD/DS. Common channel was kept at 100 cm in both groups while alimentary limb was created at 100 cm from Treitz angle in the LADS group and at 150 cm total in the BPD/DS group. RESULTS: Twenty patients were recruited from May 2013 to June 2015. Mean percentage of excess weight loss was statistically significantly lower in the LADS group at 24 months (81.6 ± 6.6% in the LADS group and 97.1 ± 11.1% in the BPD/DS group (p = 0.001). No significant difference regarding the rate of remission of comorbidities was noted. Mean calcium, vitamin D, hemoglobin, zinc, and copper levels were statistically lower in the BPD/DS group. Quality of life was significantly improved in both groups, with no statistically significant difference between the two groups. CONCLUSIONS: At 24 months, weight loss was lower in the LADS group. However, no difference was observed in the improvement in quality of life. LADS technique was discontinued following this study. TRIAL REGISTRATION: ClinicalTrial.gov Ref. NCT03097926.

Comparison of Short and Long Term Cardiovascular Outcomes After Bariatric Surgery in Patients With vs Without Coronary Artery Disease.

There is little data regarding the risks and benefits of bariatric surgery in patients with coronary artery disease (CAD). We aimed to assess the short- and long-term cardiovascular outcomes of patients with CAD undergoing bariatric surgery. Patients with a history of CAD were identified from a dedicated database with prospectively collected outcomes, comprising all 6795 patients who underwent bariatric surgery between January 1992 and October 2017. Patients were matched with patients who did not have CAD before the bariatric surgery procedure. The primary endpoints were mortality (cardiac and noncardiac) and major adverse cardiocerebral events (MACCE), including all-cause death, myocardial infarction, stroke, and myocardial revascularization at 30 days after bariatric surgery and throughout follow-up. After propensity score matching, 249 patients with chronic CAD were matched with 249 patients without CAD. Throughout follow-up (7.4 years; interquartile range 4.1 to 11.5, maximum 22 years), mortality (mainly cardiac mortality) remained significantly higher in the CAD compared with the non-CAD group (18% vs 10%, hazard ratio [HR] 1.70, 95% confidence interval [CI]: 1.03 to 2.79, p = 0.037). At 30 days, MACCE rate was significantly higher in the CAD compared with the non-CAD group (3.6% vs 0.4%, p = 0.011), essentially driven by non-ST elevation myocardial infarctions. After 30 days, MACCE rates remained significantly higher in the CAD group (30% vs 14%, HR 2.18, 95% CI: 1.45-3.28, p = 0.0002). In conclusion, patients with severe obesity and CAD referred to bariatric surgery were at a higher risk of early and late MACCE compared with non-CAD severely obese patients. Further study is required to define how this cardiovascular risk compares with nonoperated patients.

Impact of a 12-Week Randomized Exercise Training Program on Lipid Profile in Severely Obese Patients Following Bariatric Surgery.

PURPOSE: The benefit of exercise training on lipid profile in bariatric surgery patients is scarce. We assess the effect of a supervised exercise-training program on lipid profile following bariatric surgery. MATERIALS AND METHODS: A total of 60 patients were prospectively recruited, of those 49 completed the study (age 41 ± 11 years; body mass index 45.9 ± 6.1 kg/m2, 75% women). The bariatric surgery procedures performed were sleeve gastrectomy (SG) (n = 24) and biliopancreatic diversion with duodenal switch (BPD-DS) (n = 25). Of the 49 patients who completed the study, 34 had been randomized to a 12-week supervised exercise training program (exercise group) between the 3rd and the 6th month following bariatric surgery (SG = 17 and BPD-DS = 17). Fasting blood samples and anthropometric measurements were performed preoperatively and at 3, 6, and 12 months after bariatric surgery. RESULTS: At 6 months and 12 months, percentage of weight loss was similar between groups (6 months: - 29.6 ± 5.5 vs. - 27.8 ± 7.7%; P = 0.371; 12 months: - 38.4 ± 10.4 vs. - 37.9 ± 9.5%; P = 0.876 exercise vs. control). Both groups had an increase in HDL values between the 3nd and the 6th month following bariatric surgery. There was a significantly greater increment in HDL values in the exercise group (0.18 ± 0.14 vs. 0.07 ± 0.12 mmol/L, P = 0.014; exercise vs. control). CONCLUSION: Our results showed a beneficial effect of a 12-week supervised exercise-training program in bariatric surgery patients showing similar weight loss on HDL-cholesterol levels without additional effect on LDL-cholesterol levels.

Acute and Chronic Impact of Biliopancreatic Diversion with Duodenal Switch Surgery on Plasma Lipoprotein(a) Levels in Patients with Severe Obesity.

BACKGROUND: Elevated lipoprotein(a) (Lp(a)) level is an independent risk factor for cardiovascular diseases. Lifestyle intervention studies targeting weight loss revealed little to no significant changes in Lp(a) levels. The impact of interventions that induce substantial weight loss, such as bariatric surgery, on Lp(a) levels is currently unclear. OBJECTIVE: To determine the acute and long-term impact of bariatric surgery on Lp(a) levels in patients with severe obesity. METHODS: Sixty-nine patients with severe obesity underwent biliopancreatic diversion with duodenal switch (BPD-DS) surgery. The lipid profile was evaluated and Lp(a) levels were measured before surgery and at 6 and 12 months after BPD-DS surgery. RESULTS: Median Lp(a) levels at baseline were 11.1 (4.1-41.6) nmol/L. Six months and 12 months after the BDP-DS surgery, we observed an improvement of lipid profile. At 6 months, we observed a 13% decrease in Lp(a) levels (9.7 (2.9-25.6) nmol/L, p < 0.0001) but this decrease was not sustained at 12 months (11.1 (3.9-32.8) nmol/L, p = 0.8). When the patients were separated into tertiles according to Lp(a) levels at baseline, we observed that the Lp(a) reduction at 12 months after BPD-DS surgery remained significant but modest in patients of the top Lp(a) tertile. CONCLUSION: Our results suggest that BPD-DS surgery modestly reduces Lp(a) levels in the short term (6 months) in patients with severe obesity but this improvement is sustained over time only in patients with higher Lp(a) levels.

Progesterone metabolism in adipose cells.

The aim of the present study was to investigate pathways of progesterone metabolism in human adipose cells. Adipose tissue samples from the omental (OM) and subcutaneous (SC) fat compartments were surgically obtained in women. In isolated mature adipocytes, progesterone was converted to 20alpha-hydroxyprogesterone as the main metabolite, most likely through the activity of aldo-keto reductases 1C1, 2 and 3 (20alpha-HSD, 3alpha-HSD type 3 and 17beta-HSD type 5, respectively). In cultured preadipocytes, progesterone was converted to several metabolites identified using bidimensional thin layer chromatography, with or without the dual inhibitor of 5alpha-reductase type 1 and 2 (17beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5alpha-androstan-3-one (4-MA)). Major metabolites identified in OM and SC preadipocytes which were incubated for 24h with (14)C-labelled progesterone were 20alpha-hydroxyprogesterone, 5alpha-pregnane-3alpha/beta-ol-20-one, 5alpha- and 5beta-pregnanedione, 5alpha- and 5beta-pregnane-20alpha-ol-3-one, 5alpha-pregnane-3alpha/beta-ol-20-one and 5beta-pregnane-3alpha/beta-20alpha-diol. Induction of preadipocyte differentiation increased expression levels of AKR1C1 and modified the pattern of progesterone metabolism substantially, leaving 20alpha-hydroxyprogesterone as the main metabolite generated. On the other hand, progesterone itself showed no consistent effect on adipocyte differentiation. In conclusion, preadipocytes and lipid-storing, mature adipocytes efficiently generate progesterone metabolites in women, which is consistent with rather modest effects progesterone on abdominal fat cell differentiation.

Duodenal switch improved standard biliopancreatic diversion: a retrospective study.

BACKGROUND: This was a retrospective study, performed 10 years after surgery, to compare the results between biliopancreatic diversion (BPD) with distal gastrectomy (DG) versus BPD with duodenal switch (DS). METHODS: Complete follow-up data were available for 96% of patients, allowing a comparison of weight loss, revision, side effects, and complications at 10 years. RESULTS: After BPD-DS, weight loss was 25% greater than after BPD-DG (46.8 +/- 21.7 kg versus 37.5 +/- 22 kg, respectively; P <.0001). The need for revision decreased from 18.5% to 2.7% (P <.0001), and the prevalence of vomiting during the previous month was 50% less (23.7-50.6%, P <.0001) after BPD-DS compared with after BPD-DG. Late complications were the same for both procedures. Blood analysis showed that, after BPD-DS, the levels of calcium, iron, and hemoglobin were significantly greater and the parathyroid hormone level was lower than after BPD-DG (71.3 +/- 44.2 versus 103.0 +/- 64.0 ng/L, respectively; P <.0001). CONCLUSION: The DS greatly improved the BPD, as it was initially proposed. The use of the DS increased weight loss, decreased the need for revision, resulted in fewer side effects, and improved the absorption of nutrients.

Acute and chronic effect of bariatric surgery on circulating autotaxin levels.

Autotaxin (ATX), an adipose tissue-derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short- (24 h, 5 days) and longer-term (6 and 12 months) impact of bariatric surgery; as well as the short-term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2 ), before and after biliopancreatic diversion with duodenal switch surgery (BPD-DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3-day CR protocol before their BPD-DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA-IR) as well as insulin and leptin levels and negatively with fat-free mass. ATX concentrations decreased 26.2% at 24 h after BPD-DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P < 0.0001) and by 16.4% at 12 months after BPD-DS (342.9 ± 152.3 pg/mL to 286.8 ± 182.6 pg/mL, P = 0.04). ATX concentrations were unchanged during follow-up in the control group (P = 0.4), and not influenced by short-term CR. In patients with severe obesity, bariatric surgery induced a rapid and sustained decrease in plasma ATX levels. Acute changes in ATX may not be explained by bariatric surgery-induced CR.

ZFP36: a promising candidate gene for obesity-related metabolic complications identified by converging genomics.

BACKGROUND: Few genes have been associated with the metabolic syndrome (MS), although its genetic component is well accepted. The aim of this study was to compare the adipose tissue gene expression profiles of obese men with and without the MS and to apply an integrative genomic approach to propose new candidate genes. METHODS: Affymetrix HG-U133 plus 2 arrays have been used for expression profiling of omental adipose tissue of non-diabetic obese men with (n=7) and without (n=7) the MS, as defined by the NCEP-ATPIII, that undergo a bariatric operation. RESULTS: Omentum expresses a total of 23 055 transcripts. Overall, 489 genes were differentially expressed between the two groups. A total of 80 differentially expressed genes were located within a previously identified region of linkage. In this subset of genes, zinc finger protein 36 (ZFP36) gene has been identified as the most promising genetic target for the MS-based mean fold expression differences and on biological plausibility. 2 out of 5 identified ZFP36 gene polymorphisms have been genotyped in a cohort of 698 obese subjects. The minor allele of these polymorphisms was associated with a lower body weight in women (rs251864; P< or =0.01) and glucose level in men (c.1564_1565delTT; P<0.05). The haplogenotype was associated with plasma LDL-cholesterol levels in men and women (P< or =0.02), and weight in women (P< or =0.05). The haplogenotype was also associated with omental adipose tissue ZFP36 mRNA levels (n=83 women; P=0.02), and explained 10.1% of its variance. CONCLUSION: These results suggest that converging genomics is helpful to prioritize MS-related candidate genes and that ZFP36 is a promising candidate gene for obesity-associated metabolic complications.

Duodenal switch: long-term results.

BACKGROUND: This report summarizes our 15-year experience with duodenal switch (DS) as a primary procedure on 1,423 patients from 1992 to 2005. METHODS: Within the last 2 years, follow-up of these patients, including clinical biochemistry evaluation by us or by their local physician is 97%. RESULTS: Survival rate was 92% after DS. The risk of death (Excess Hazard Ratio (EHR)) was 1.2, almost that of the general population. After a mean of 7.3 years (range 2-15), 92% of patients with an initial BMI < or = 50 kg/m2 obtained a BMI < 35 and 83% of those with an initial BMI > 50 obtained a BMI < 40. Diabetes was cured (i.e. medication was discontinued) in 92% and medication decreased in the others. The use of the CPAP apparatus was discontinued in 90%, medication for asthma was decreased in 88%, and the prevalence of a cardiac risk index > 5 was decreased by 86%. Patients' satisfaction in regard to weight loss was graded 3.6 on a basis of 5, and 95% of patients were satisfied with the overall results. Operative mortality was 1% which is comparable with gastric bypass surgery. The need for revision for malnutrition was rare (0.7%) and total reversal was exceptional (0.2%). Failure to lose > 25% of initial excess weight was 1.3%. Revision for failure to lose sufficient weight was needed in only 1.5%. Severe anemia, deficiency in vitamins or bone damage were exceptional, easily treatable, preventable and no permanent damage was documented. CONCLUSION: In the long-term, DS was very efficient in terms of cure rate for morbid obesity and its comorbidities. In terms of risk/benefit, DS was very sucessful with an appropriate system of follow-up.

Role of the TGF-ß pathway in dedifferentiation of human mature adipocytes.

Dedifferentiation of adipocytes contributes to the generation of a proliferative cell population that could be useful in cellular therapy or tissue engineering. Adipocytes can dedifferentiate into precursor cells to acquire a fibroblast-like phenotype using ceiling culture, in which the buoyancy of fat cells is exploited to allow them to adhere to the inner surface of a container. Ceiling culture is usually performed in flasks, which limits the ability to test various culture conditions. Using a new six-well plate ceiling culture approach, we examined the relevance of TGF-ß signaling during dedifferentiation. Adipose tissue samples from patients undergoing bariatric surgery were digested with collagenase, and cell suspensions were used for ceiling cultures. Using the six-well plate approach, cells were treated with SB431542 (an inhibitor of TGF-ß receptor ALK5) or human TGF-ß1 during dedifferentiation. Gene expression was measured in these cultures and in whole adipose tissue, the stromal-vascular fraction (SVF), mature adipocytes, and dedifferentiated fat (DFAT) cells. TGF-ß1 and collagen type I alpha 1 (COL1A1) gene expression was significantly higher in DFAT cells compared to whole adipose tissue samples and SVF cells. TGF-ß1, COL1A1, and COL6A3 gene expression was significantly higher at day 12 of dedifferentiation compared to day 0. In the six-well plate model, treatment with TGF-ß1 or SB431542, respectively, stimulated and inhibited the TGF-ß pathway as shown by increased TGF-ß1, TGF-ß2, COL1A1, and COL6A3 gene expression and decreased expression of TGF-ß1, COL1A1, COL1A2, and COL6A3, respectively. Treatment of DFAT cells with TGF-ß1 increased the phosphorylation level of SMAD 2 and SMAD 3. Thus, a new six-well plate model for ceiling culture allowed us to demonstrate a role for TGF-ß in modulating collagen gene expression during dedifferentiation of mature adipocytes.

Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome.

A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10-11) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)-binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels.

Acute and Chronic Impact of Bariatric Surgery on Plasma LDL Cholesterol and PCSK9 Levels in Patients With Severe Obesity.

Context: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein cholesterol (LDL-C) concentrations. In patients with severe obesity, biliopancreatic diversion with duodenal switch (BPD-DS) surgery induces substantial weight loss and influences lipoprotein metabolism. The effect of BPD-DS on PCSK9 levels is unknown. Objectives: To determine the acute and chronic impact of BPD-DS on PCSK9 levels and whether the acute impact of BPD-DS could be explained by BPD-DS-associated caloric restriction (CR). Design, Settings, and Participants: PCSK9 levels were measured in 20 men and 49 women (age, 41.5 ± 11.1 years) with severe obesity before, 24 hours, 5 days, and 6 and 12 months after BPD-DS and in a comparable control group (n = 31) at baseline and at 6 and 12 months. PCSK9 levels were also measured during 3-day CR in patients (n = 7) with severe obesity and type 2 diabetes. Results: PCSK9 levels increased 13.4% after 24 hours (248.7 ± 64.8 to 269.7 ± 63.8 ng/mL; P = 0,02) and decreased 9.5% at 12 months compared with baseline (217.6 ± 43.0 ng/mL; P < 0,0001). LDL-C levels decreased 36.2% after 24 hours (2.6 ± 0.7 to 1.7 ± 0.6 mmol/L; P < 0.0001) and 30% at 12 months compared with baseline (1.7 ± 0.5 mmol/L; P < 0.0001). Compared with baseline levels, PCSK9 levels were lower at day 2 but not at day 1 or 3 after CR. Conclusion: BPD-DS is associated with acute increases in PCSK9 levels that do not appear to be explained by CR but may be due to an acute response following surgery. BPD-DS induces chronic reductions in both PCSK9 and LDL-C levels.