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Background: Bariatric surgery (BS) is currently the most effective long-term treatment of severe obesity. However, the interindividual variability observed in surgical outcomes suggests a moderating effect of several factors, including individual genetic background. This study aimed to investigate the contribution of the genetic architecture of body mass index (BMI) to the variability in weight loss outcomes after BS., Methods: A total of 106 patients with severe obesity who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy were followed up for 5 years. Changes in BMI (BMIchange) and percentage of total weight loss (%TWL) were evaluated during the postoperative period. Polygenic risk scores (PRSs), including 50 genetic variants, were calculated for each participant to determine their genetic risk of high BMI based on a previous genome-wide association study. Generalized estimating equation models were used to study the role of the individual's polygenic score and other factors on BMIchange and %TWL in the long term after surgery., Results: This study found an effect of the polygenic score on %TWL and BMIchange, in which patients with lower scores had better outcomes after surgery than those with higher scores. Furthermore, when analyzing only patients who underwent RYGB, the results were replicated, showing greater weight loss after surgery for patients with lower polygenic scores., Discussion: Our results indicate that genetic background assessed with PRSs, along with other individual factors, such as biological sex, age, and preoperative BMI, has an effect on BS outcomes and could represent a useful tool for estimating surgical outcomes in advance., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: There is little information about the effect of single nucleotide polymorphisms (SNP) and nutritional status and weight loss after bariatric surgery. This study investigated the interactive effect of eight obesity-related SNPs and nutritional status on weight loss after Roux-en-Y gastric bypass (RYGB)., Method: This is a case-control study. After 1-year follow-up, the patients who underwent RYGB were dividing into two groups. The case group consisted of patients who lost more than 50% of their excess body weight (EBW%) 1 year after the surgery. The control group included patients who lost < 50% of EBW at same time frame. Then, the relationship between eight SNPs related to UCP2, FTO, LEPR, GHRL, and NPY genes with weight loss were checked., Results: In this study, 160 patients were recruited. The median of age for case and control group were 43 and 42 respectively. The presence of mutant variant NPYrs16147 had a significant relationship in terms of weight loss between the two groups (P > 0.05). In dominant model, two SNPs, UCP2 rs659366 and UCP2 rs660339, showed protective effect of the vitamin D deficiency., Conclusion: In conclusion, the presence mutant variant of NPYrs16147 is directly related to the incidence of weight loss greater than 50% of EBW. However, it is apparent individual behavioral, dietary, and other factors may have more influence on weight loss among patients underwent RYGB., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Transoral outlet reduction (TORe) is a safe and effective technique for management of weight regain (WR) after Roux-en-Y Gastric Bypass (RYGB). Carriers of a heterozygous variant in the leptin melanocortin pathway (LMP) have been shown to be at high risk for WR in the mid- and long-term after RYGB. Our case series includes four patients with heterozygous LMP variants and presents novel data on their weight loss after TORe., Methods: We performed a retrospective study of the Mayo Clinic Biobank and identified adult participants who had been genotyped and found to have or do not have a heterozygous variant in the LMP ("carriers" vs "non-carriers", respectively) and had undergone a TORe procedure. TBWL% at 1, 3, 6, 9, and 12 months ± 15 days were calculated based on baseline weight at TORe procedure., Results: A total of 14 patients were included in the analysis: four patients (mean age 51.0 [5.2] years, 100% females, body mass index [BMI] 40.5 [8.7] kg/m 2 ) with LMP variant and 10 non-carriers (age 55.4 [15.3] years, 90% females, BMI 37.3 [7.7] kg/m 2 ). There were no baseline differences between carriers and non-carriers at time of TORe procedure. After TORE, carriers lost less weight when compared to non-carriers at 3, 6, 9, and 12 months. The difference at 12 months was statistically significant (1.6 vs 12.3%; p = 0.03)., Conclusions: Patients with a LMP variant and that underwent RYGB showed decreased weight loss after undergoing TORe. Further and larger studies are needed to comprehend the effect of TORe on patients with LMP variants., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Single-nucleotide polymorphisms (SNPs) associated with obesity predict laparoscopic Roux-en-Y gastric bypass (LRYGB) and biliopancreatic diversion with duodenal switch (BPD/DS) for weight loss with good efficiency. However, prediction of weight loss after laparoscopic sleeve gastrectomy using SNPs has not been well investigated., Objectives: To predict weight loss after laparoscopic sleeve gastrectomy using obesity-related SNPs and clinical variants in Chinese patients with body mass index (BMI) ≥ 32.5 kg/m 2 ., Methods: We detected 29 SNPs. Binary logistic regression was used to screen SNPs and clinical variables with predictive value. Receiver operating characteristic (ROC) curves were plotted for clinical variables, SNPs, and their combination, and areas under the ROC curve (AUC) were compared. Internal and external validation tests were performed., Results: rs12535708, rs651821, and rs5082 were constructed as the genetic risk score (GRS). Preoperative BMI was constructed as the clinical risk score (CRS). Preoperative BMI and SNPs were constructed as the cumulative genetic risk score (CGRS). ROC curves of GRS, CRS, and CGRS showed that the optimal cutoffs were 0.831 (AUC = 0.840; sensitivity, 92.96%; specificity, 64.29%), 43.46 kg/m 2 (AUC = 0.830; sensitivity, 76.06%; specificity, 85.71%), and 0.921 (AUC = 0.931; sensitivity, 77.46%; specificity, 92.86%), respectively. The AUC of CGRS was significantly greater than that of CRS (P < 0.05) and greater than GRS without statistical significance., Conclusion: In Chinese patients with BMI ≥ 32.5 kg/m 2 , GRS and CRS could predict weight loss success. However, CGRS was superior to GRS or CRS alone., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The present study aimed to investigate the influence of food intake on body weight loss (WL) and the association of gene polymorphisms, 1 year after Roux-en-Y gastric bypass (RYGB) surgery., Methods: In total, 95 obese women (age ranged 20-50 years) in a Brazilian cohort underwent RYGB surgery and completed the study. Anthropometric measurements and food intake were assessed before and 1 year after surgery. Twelve gene polymorphisms (GHRL rs26802; GHSR rs572169; LEP rs7799039; LEPR rs1137101; 5-HT2C rs3813929; UCP2 rs659366; UCP2 rs660339; UCP3 rs1800849; SH2B1 rs7498665; TAS1R2 rs35874116; TAS1R2 rs9701796; and FTO rs9939609) were determined using a real-time polymerase chain reaction and a TaqMan assay. The subjects were divided into quartiles regarding percentage of excess weight loss (%EWL). The effect of genetic variants on energy and macronutrient intake was evaluated by simple logistic regression, followed by multiple logistic regression., Results: Subjects in the first and second quartiles showed a higher initial body mass index. Energy and macronutrient intake before and 1 year after RYGB surgery did not differ between the %EWL quartiles. None of gene polymorphisms investigated showed an association with the estimated energy intake 1 year after surgery., Conclusions: In conclusion, the estimate energy and food intake did not predict a greater body WL 1 year after RYGB surgery. In addition, the 12 gene polymorphism investigated did not affect the energy intake among female patients., (© 2021 The British Dietetic Association Ltd.)

Background: Although effective, the impact of bariatric surgery on weight loss is variable, and little is known about the influence of single-nucleotide polymorphisms (SNPs). The present study investigated the association of eleven SNPs related to obesity with weight loss 1 year after Roux-Y gastric bypass (RYGB) surgery in female patients., Methods: This prospective study included 351 women with obesity. The genotypes for eleven SNPs (GHRL-rs26802; GHSR-rs572169; LEP-rs7799039; LEPR-rs1137101; 5HT2C-rs3813929; UCP2-rs659366; UCP3-rs1800849; SH2B1-rs7498665; TAS1R2-rs35874116; TAS1R2-rs9701796; FTO-rs9939609) were determined using a real-time polymerase chain reaction and TaqMan assays. Anthropometric measurements were performed before and 1 year after RYGB surgery. To evaluate the factors that influenced the proportion of weight loss 1 year after surgery, beta regression analysis was used. The models were estimated using the GLIMMIX procedure in SAS statistical software. p < 0.05 was considered statistically significant., Results: The mean ± SD percentage of total body weight loss in 1 year was 64.4 ± 5.8% and the median was 65.0%. When assessing the proportion of weight loss in 1 year after surgery, using univariate analysis (beta regression), no SNPs influenced weight loss. Furthermore, in the multiple analysis, with stepwise process of variable selection, no variable was significant to compose the multiple model., Conclusions: The 11 SNPs investigated did not influence weight loss 1 year after RYGB surgery in female patients. This result indicates that individual behaviours and other factors might better contribute to the magnitude of loss weight loss in a short period after bariatric surgery., (© 2022 The British Dietetic Association Ltd.)

Introduction: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown., Methods: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB., Results: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m 2 , and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8)., Conclusions: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 (r 2  = 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., (© 2022. The Author(s).)

Introduction: Pathogenic heterozygous MC4R variants are associated with hyperphagia and variable degrees of obesity. Several research groups have reported short-term weight loss outcomes after bariatric surgery in a few patients with MC4R variants, but lack of longer-term data prevents evidence-based clinical decision-making., Materials and Methods: Bariatric surgery patients with heterozygous (likely) pathogenic MC4R variants, from three collaborating centers in the Netherlands, France, and the UK, were compared to matched controls (matched 2:1 for age, sex, preoperative BMI, surgical procedure, and diabetes mellitus, but without MC4R mutations). Weight loss and regain outcomes up to 6 years of follow-up were compared., Results: At 60 months of follow-up after RYGB, cases with MC4R variants showed weight regain with a mean of 12.8% (± 10.4 SD) total weight loss (TWL) from nadir, compared to 7.9% (± 10.5 SD) in the controls (p = 0.062). Among patients receiving SG, the cases with MC4R variants experienced inferior weight loss (22.6% TWL) during the first year of follow-up compared to the controls (29.9% TWL) (p = 0.010)., Conclusions: This multicenter study reveals inferior mid-term weight outcomes of cases with MC4R variants after SG, compared to RYGB. Since adequate weight loss outcomes were observed after RYGB, this procedure would appear to be an appropriate surgical approach for this group. However, the pattern of weight regain seen in cases with MC4R variants after both RYGB and SG highlights the need for pro-active lifelong management to prevent relapse, as well as careful expectation management., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Uncoupling protein 2 (UCP2) plays an important role in energy expenditure regulation. Previous studies have associated the common -866G/A (rs659366) and Ins/Del polymorphisms in the UCP2 gene with metabolic and obesity-related phenotypes. However, it is still unclear whether these polymorphisms influence weight loss after bariatric surgery., Objectives: To investigate whether UCP2 -866G/A and Ins/Del polymorphisms are associated with weight loss outcomes after bariatric surgery., Setting: Longitudinal study in a university hospital., Methods: We retrospectively evaluated 186 patients who underwent Roux-en-Y gastric bypass (RYGB) surgery for clinical and laboratory characteristics in the preoperative period, 6, 12, and 18 months after RYGB. The -866G/A (rs659366) polymorphism was genotyped using real-time PCR, while the Ins/Del polymorphism was genotyped by direct separation of PCR products in 2.5% agarose gels., Results: Patients with the -866A/A genotype showed higher body mass index (BMI) after 6, 12, and 18 months of surgery and excess body weight after 6 and 12 months compared with G/G patients. They also showed lower excess weight loss (EWL%) after 6 and 12 months of surgery. Ins allele carriers (Ins/Ins + Ins/Del) had lower delta (Δ) BMI 12 months after surgery compared with Del/Del patients. Accordingly, patients carrying haplotypes with ≥2 risk alleles of these polymorphisms had higher BMI and excess weight and lower EWL% during follow-up., Conclusion: UCP2 -866A/A genotype is associated with higher BMI and excess weight and lower EWL% during an 18-month follow-up of patients who underwent RYGB, while the Ins allele seems to be associated with lower ΔBMI 12 months after surgery. Further studies are needed to confirm the associations of the -866G/A and Ins/Del polymorphisms with weight loss after bariatric surgery., (Copyright © 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The mechanisms of weight loss and metabolic improvements following bariatric surgery in skeletal muscle are not well known; however, epigenetic modifications are likely to contribute. The aim of our study was to investigate skeletal muscle DNA methylation after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery. Muscle biopsies were obtained basally from seven insulin-resistant obese (BMI > 40 kg/m 2 ) female subjects (45.1 ± 3.6 years) pre- and 3-month post-surgery with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. Four lean (BMI < 25 kg/m 2 ) females (38.5 ± 5.8 years) served as controls. We performed reduced representation bisulfite sequencing next generation methylation on DNA isolated from the vastus lateralis muscle biopsies., Results: Global methylation was significantly higher in the pre- (32.97 ± 0.02%) and post-surgery (33.31 ± 0.02%) compared to the lean (30.46 ± 0.02%), P < 0.05. MethylSig analysis identified 117 differentially methylated cytosines (DMCs) that were significantly altered in the post- versus pre-surgery (Benjamini-Hochberg q < 0.05). In addition, 2978 DMCs were significantly altered in the pre-surgery obese versus the lean controls (Benjamini-Hochberg q < 0.05). For the post-surgery obese versus the lean controls, 2885 DMCs were altered (Benjamini-Hochberg q < 0.05). Seven post-surgery obese DMCs were normalized to levels similar to those observed in lean controls. Of these, 5 were within intergenic regions (chr11.68,968,018, chr16.73,100,688, chr5.174,115,531, chr5.1,831,958 and chr9.98,547,011) and the remaining two DMCs chr17.45,330,989 and chr14.105,353,824 were within in the integrin beta 3 (ITGB3) promoter and KIAA0284 exon, respectively. ITGB3 methylation was significantly decreased in the post-surgery (0.5 ± 0.5%) and lean controls (0 ± 0%) versus pre-surgery (13.6 ± 2.7%, P < 0.05). This decreased methylation post-surgery was associated with an increase in ITGB3 gene expression (fold change + 1.52, P = 0.0087). In addition, we showed that ITGB3 promoter methylation in vitro significantly suppressed transcriptional activity (P < 0.05). Transcription factor binding analysis for ITGB3 chr17.45,330,989 identified three putative transcription factor binding motifs; PAX-5, p53 and AP-2alphaA., Conclusions: These results demonstrate that weight loss after RYGB alters the epigenome through DNA methylation. In particular, this study highlights ITGB3 as a novel gene that may contribute to the metabolic improvements observed post-surgery. Future additional studies are warranted to address the exact mechanism of ITGB3 in skeletal muscle.

Objective: Laparoscopic Roux-en-Y gastric bypass (RYGB) modulates the low-grade inflammatory state associated with severe obesity. This study sought to investigate whether weight loss is causally implicated with changes in serum levels of inflammatory molecules., Methods: Using the largest genome-wide association study (n = 1,020 individuals), this study curated five genetic variants associated with weight loss following RYGB. Phenome-wide association studies (PheWAS) were performed to identify other phenotypes associated with these variants. Subsequently, two-sample Mendelian randomization was used to study the causal effects of weight loss on the serum levels of 382 inflammatory proteins (measured in 3,033 individuals). This is the first systematic quasi-experimental investigation of weight loss following RYGB and serum markers of inflammation., Results: The PheWAS analysis revealed that four of the five variants are associated with phenotypes relating to metabolism and inflammation, including insulin response and levels of C-reactive protein. Two-sample Mendelian randomization of the 382 serum inflammatory markers revealed that weight loss following RYGB increases serum levels of interleukin 22 (IL-22) (beta = 0.021, P < 10 -3 ; 95% CI: 0.010-0.031). Sensitivity analyses further supported the results and the causal direction., Conclusions: Weight loss following RYGB may cause an increase in IL-22 serum levels, suggesting that weight loss directly contributes to immune modulation following bypass. These results demonstrate the utility of genetic studies to disentangling molecular cause and effect following bariatric surgery., (© 2021 The Obesity Society.)

Background: Bariatric surgery is currently the most effective long-term treatment for severe obesity. However, interindividual variation in surgery outcome has been observed, and research suggests a moderating effect of several factors including baseline co-morbidities (e.g., type 2 diabetes [T2D] and genetic factors). No data are currently available on the interaction between T2D and variants in brain derived neurotrophic factor (BDNF) and its effect on weight loss after surgery., Objectives: To examine the role of the BDNF Val66Met polymorphism (rs6265) and the influence of T2D and their interaction on weight loss after bariatric surgery in a cohort of patients with severe obesity., Setting: University hospital in Spain., Methods: The present study evaluated a cohort of 158 patients with obesity submitted to bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy) followed up for 24 months (loss to follow-up: 0%). During the postoperative period, percentage of excess body mass index loss (%EBMIL), percentage of excess weight loss (%EWL), and total weight loss (%TWL) were evaluated., Results: Longitudinal analyses showed a suggestive effect of BDNF genotype on the %EWL (P = .056) and indicated that individuals carrying the methionine (Met) allele may experience a better outcome after bariatric surgery than those with the valine/valine (Val/Val) genotype. We found a negative effect of a T2D diagnosis at baseline on %EBMIL (P = .004). Additionally, we found an interaction between BDNF genotype and T2D on %EWL and %EBMIL (P = .027 and P = .0004, respectively), whereby individuals with the Met allele without T2D displayed a greater %EWL and greater %EBMIL at 12 months and 24 months than their counterparts with T2D or patients with the Val/Val genotype with or without T2D., Conclusion: Our data showed an association between the Met variant and greater weight loss after bariatric surgery in patients without T2D. The presence of T2D seems to counteract this positive effect., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Emerging evidence suggests that the FK506 binding protein 51 (FKBP5/FKBP51), encoded by the FKBP5 gene, influences weight and metabolic regulation. The T allele of a functional polymorphism in FKBP5 (rs1360780), has been associated with the expression of FKBP51 and weight loss after bariatric surgery., Objective: To examine the role of the FKBP5 rs1360780 polymorphism in relation to age, sex, and type of surgery in weight loss after bariatric surgery in patients with severe obesity., Setting: University Hospital in Spain METHODS: A cohort of 151 obese patients submitted to Roux-en-Y gastric bypass (62.3%) and sleeve gastrectomy (37.7%) were followed-up during 24-months (t 24m ; loss to follow-up: 0%). During the postoperative period body mass index (BMI) and percentage of excess and total weight loss were evaluated., Results: The BMI analysis showed an effect of the interaction FKBP5 genotype by sex (P = .0004) and a tendency to the interaction genotype by surgery (P = .048), so that men carrying the T allele had higher BMI at t 24m than those without the T allele, and T-allele carriers that underwent sleeve gastrectomy had higher BMI at t 24m than the noncarriers. Additionally, we found an interaction between FKBP5 and age for the percentage of excess weight loss and BMI (P = .0005 and P = 1.5e-7, respectively), whereby individuals >48 years with the T allele displayed significant differences for the analyzed variables at t 24m compared with the homozygotes for the alternate C allele showing lower weight loss., Conclusion: FKBP5 rs1360780 genotype has specific effects on weight loss outcomes after bariatric surgery depending on sex, age, and type of surgery, suggesting worse results in older males carrying the T allele who have undergone sleeve gastrectomy., Competing Interests: Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Interleukin (IL)-1β is involved in obesity-associated inflammation and in the pathogenesis of type 2 diabetes (T2D) mellitus. Our aim was to correlate serum IL-1β and caspase-1 levels with weight loss, glucose metabolism, and insulin resistance (IR) after bariatric surgery., Methods: A total of 32 patients with morbid obesity and T2D (Ob-T2D) and 29 patients with morbid obesity and normal glucose tolerance (Ob-NGT), treated by Roux-en-Y gastric bypass, were studied before and 1 year after surgery. Sixteen healthy individuals served as a control (HC) group. IR was assessed by the oral glucose insulin sensitivity method. Plasma IL-1β levels and caspase-1 were measured., Results: Presurgery BMI was similar in Ob-NGT and Ob-T2D. IR was progressively impaired in Ob-NGT and Ob-T2D (P < 0.0001). Fasting plasma IL-1β and caspase-1 levels were lower in HCs than in patients with Ob-NGT or Ob-T2D (P < 0.02; P = 0.05), and both were inversely correlated with IR (P = 0.01; P = 0.02). After surgery, BMI decreased and IR improved to a similar extent in Ob-NGT and Ob-T2D (P < 0.0001). Plasma caspase-1 concentrations normalized in both groups (P < 0.0001), whereas plasma IL-1β levels normalized only in Ob-NGT., Conclusions: Plasma IL-1β and caspase-1 levels were inversely correlated with IR. Caspase-1 levels normalized after weight loss, whereas IL-1β normalized only in people without T2D, suggesting the persistence of a systemic inflammatory condition in people with T2D., (© 2020 The Obesity Society.)

Background: Bariatric surgery rapidly induces improvements in type 2 diabetes (T2D) in concert with reduction in systemic markers of inflammation. The impact of bariatric surgery on local intestinal immunity is not known. We hypothesize that sleeve gastrectomy (SG) and gastric bypass (RYGB) surgeries resolve obesity-induced intestinal inflammation, thereby promoting T2D resolution., Methods: SG and RYGB, or control surgery was performed in SD rats (n = 4-6/group). Key cytokines involved in insulin resistance (TNF-α, IFN-γ), inflammasome activation (IL-1β, IL-18), inflammation resolution (IL-10, IL-33), and Th17 cell responses (IL-17, IL-23) were measured by qPCR in mucosal scrapings of jejunum at 4 weeks post-surgery. Intestinal cytokine expressions were correlated with weight change, systemic and portal glucose, and insulin levels in response to an enteral glucose load., Results: SG downregulated IL-17 and IL-23 in both proximal and distal jejunum, and IFN-γ was reduced only in distal jejunum (p < 0.05). Jejunal IL-17 and IL-23 expression correlated positively with weight changes after SG (0.93 and 0.98, respectively; p < 0.05). Changes in IFN-γ correlated strongly with insulin levels in portal and systemic circulation (0.99 and 0.95, respectively, p < 0.05). As with SG, IFN-γ, IL-17, and IL-23 were significantly reduced by RYGB. RYGB also reduced TNF-α and IL-18 and increased IL-33 levels (p < 0.05)., Conclusions: RYGB and SG reduce expression of pro-inflammatory cytokines IL-17, IL-23, and IFN-γ in the jejunum. RYGB showed attenuation of additional pro-inflammatory cytokines and enhanced expression of IL-33. Post-surgical changes in intestinal IL-17, IL-23, and IFN-γ correlate strongly with changes in weight and glucose-triggered insulin responses.

Background and Purpose: Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective treatments for obesity and type 2 diabetes. Despite this, the mechanisms through which it acts are still not well understood. Bile acid signaling through the transmembrane G-protein-coupled receptor TGR5 has been shown to have significant effects on metabolism and has recently been reported to be necessary for the full effects of vertical sleeve gastrectomy (VSG), a bariatric surgery with similar effects to RYGB. The goal of the current study is therefore to investigate the role of bile acid signaling through TGR5 to see if it is necessary to obtain the full effects of RYGB., Methods: High-fat diet-induced obese TGR5 -/- and wildtype mice (WT) were subjected to RYGB, sham surgery, or weight matching (WM) to RYGB mice via caloric restriction. Body weight, body composition, food intake, energy expenditure, glucose tolerance, insulin sensitivity, and liver weight were measured., Results: Although the difference in fat mass 20 weeks after surgery between RYGB and sham-operated mice was slightly reduced in TGR5 -/- mice when compared to wildtype mice, loss of body weight and fat mass from preoperative levels, reduction of food intake, increase of energy expenditure, and improvement in glycemic control were similar in the two genotypes. Furthermore, improvements in glycemic control were similar in non-surgical mice weight-matched to RYGB., Conclusions: We conclude that bile acid signaling through TGR5 is not required for the beneficial effects of RYGB in the mouse and that RYGB and VSG may achieve their similar beneficial effects through different mechanisms.

Objectives: After bariatric surgery, modifications to signaling pathway networks including those of the metabolic regulator called mammalian or mechanistic target of rapamycin (mTOR) may lead to molecular alterations related to energy source availability, systemic nutrients, and catabolic and anabolic cellular processes. This study aimed to identify gene expression changes with regard to the mTOR complex 2 subunit signaling pathway in obese patients before and after bariatric surgery., Methods: The experimental group included 13 obese women who were examined before (preoperative) and 6 mo after (postoperative) Roux-en-Y gastric bypass (RYGB) surgery. The control group included nine apparently eutrophic women matched by age and without any other metabolic diseases (i.e., no diabetes and no liver or kidney diseases). Peripheral blood mononuclear cell samples were collected for RNA extraction and subsequent microarray analysis., Results: After this methodological procedure, we identified 47 000 differentially expressed genes. A subsequent bioinformatic analysis showed that three diferentially expressed genes (rapamycin-insensitive companion of mTOR [RICTOR], phosphoinositide-3-kinase regulatory subunit 1 [PIK3 R1], and hypoxia inducible factor 1 alpha subunit 1A [HIF1 A]) participated in the mTOR signaling pathway. Real-time quantitative polymerase chain reaction revealed that RICTOR, PIK3 R1, and HIF1 A were upregulated 6 mo after RYGB surgery (P <0.05). In addition, patients in the experimental group lost weight significantly and presented significant improvement in biochemical/metabolic variables., Conclusions: The weight loss that was induced by RYGB surgery alters the mTOR signaling pathway and specifically the mTOR complex 2 subunit. The increased expression of genes that act in this pathway such as RICTOR, PIK3 R1, and HIF1 A reflects the induced weight loss and improved metabolic indicators (e.g., insulin resistance and lipolysis) that are evidenced in this study., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Increased inflammation and oxidative stress associated with obesity can accelerate aging. Telomere length (TL) has the capacity to serve as an aging indicator at the cellular level. Obesity has a known association with shorter TL. This study evaluated TL of immune cells in a population of obese individuals who underwent gastric bypass surgery. Pre- and post-operative DNA samples were available for 50 subjects who had gastric bypass surgery. DNA was analyzed via quantitative polymerase chain reaction to determine TL. Changes in TL were evaluated by comparing TL at baseline to TL at 3-5 years post gastric bypass surgery. Sixty percent of the individuals in the study observed an increase in TL. Significant lengthening was observed for those with the shortest baseline TL (P=0.0011), but not for those with intermediate baseline TL (P=0.411) or longest baseline TL (P=0.207). Change in TL was negatively correlated with age and triglycerides but not correlated with weight loss induced by bariatric surgery. This study confirms that TL lengthening is observed post bariatric surgery and is the first to detect TL lengthening 3-5 years after surgery.

Background/objectives: Roux-en-Y gastric bypass (RYGB) surgery improves insulin sensitivity (S I ) and β-cell function in obese non-diabetic subjects. Exercise also improves S I and may be an effective adjunct therapy to RYGB surgery. However, the mechanisms by which exercise or weight loss improve peripheral S I after RYGB surgery are unclear. We hypothesized that microRNAs (miRNAs) mediate at least some of the regulatory processes driving such mechanisms. Consequently, this work aimed at profiling plasma miRNAs in participants of the Physical Activity Following Surgery Induced Weight Loss study (clinicaltrials.gov identifier: NCT00692367), to assess whether miRNA levels track with improvements in S I and cardiometabolic risk factors., Subjects/methods: Ninety-four miRNAs implicated in metabolism were profiled in plasma samples from 22 severely obese subjects who were recruited 1-3 months after RYGB surgery and followed for 6 months of RYGB surgery-induced weight loss, with (exercise program (EX), N=11) or without (CON, N=11) an exercise training intervention. The subjects were selected, considering a priori sample size calculations, among the participants in the parent study. Mixed-effect modeling for repeated measures and partial correlation analysis was implemented in the R environment for statistical analysis., Results: Mirroring results in the parent trial, both groups experienced significant weight loss and improvements in cardiometabolic risk. In the CON group, weight loss significantly altered the pattern of circulating miR-7, miR-15a, miR-34a, miR-106a, miR-122 and miR-221. In the EX group, a distinct miRNA signature was altered: miR-15a, miR-34a, miR-122, miR-135b, miR-144, miR-149 and miR-206. Several miRNAs were significantly associated with improvements in acute insulin response, S I , and other cardiometabolic risk factors., Conclusions: These findings present novel insights into the RYGB surgery-induced molecular changes and the effects of mild exercise to facilitate and/or maintain the benefits of a 'comprehensive' weight-loss intervention with concomitant improvements in cardiometabolic functions. Notably, we show a predictive value for miR-7, miR-15a, miR-106b and miR-135b.

Background: Several patients encompass a scarce weight loss after Roux-en-Y gastric bypass (RYGB). As such event is not related to surgical complications, finding markers able to identify "well responders" and to predict weight loss outcome is clinically relevant. Ghrelin regulates appetite and energy balance. Common single nucleotide polymorphisms (SNPs) in its encoding genes have been associated with body weight regulation. Other peptides involved in satiety modulation, like the CD40/CD40L complex, are less explored., Methods: One hundred, otherwise healthy, obese subjects (aged 45 ± 11 years, 65 females, BMI 48.0 ± 0.7 kg/m 2 ) were sequentially enrolled in years 2014-2015. SNPs rs2241766 for adiponectin gene, rs490683 for ghrelin receptor, rs696217 and rs27647 for the preproghrelin/ghrelin gene, and rs1126535 for the CD40L gene were determined on DNA extracted from circulating lymphomonocytes. Patients were reevaluated at 6 (n = 100), 26 (n = 91), and 52 weeks (n = 79) after RYGB., Results: Subjects carrying the rs696217 T allele encompassed a significantly greater reduction in BMI 52 weeks after surgery (GG vs GT 30.5 ± 1.1 vs 38.1 ± 2.1 %; p < 0.001). Carrying the rs1126535 C allele in the CD40L gene was associated with a significantly lower BMI reduction at week 52 (TT vs CT 33.2 ± 1.1 vs 28.1 ± 2.3 %, p = 0.049). rs490683 and rs27647 SNPs of ghrelin and rs2241766 for adiponectin gene did not show any difference between carriers and non-carriers of the mutant allele., Conclusion: Carrying a G to T substitution in rs696217 (preproghrelin gene) seems to mark a successful weight loss outcome; we also report for the first time that the rs1126535 C allele (CD40L gene) may predict a worse response to bariatric surgery.

This study aimed to investigate the association between twelve gene polymorphisms and body weight loss, 12 months after Roux-en-Y gastric bypass (RYGB) surgery. Three hundred and fifty-one obese women participated in this study. The statistical software WEKA was used to identify which gene polymorphisms were potential predictors of postoperative percentage of excess weight loss (%EWL). Our results indicate that the only gene polymorphism that predicted %EWL was rs3813929, which is related to the serotonin receptor gene (5-HT2C). Therefore, the 5-HT2C gene polymorphism rs3813929 (more specifically, the TT genotype) predicted greater %EWL 12 months after RYGB surgery among female patients., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Background: Bariatric surgery is the most effective treatment choice for severe obesity. Recent literature indicates that FK506-binding protein 51 (FKBP51) could play a role in energy homeostasis, influencing adipogenesis and weight., Objective: To evaluate if the presence of the T allele of the FKBP5 SNP rs1360780, associated with increased FKBP51 expression, could influence weight loss after bariatric surgery., Setting: Hospital de Clínicas de Porto Alegre, Brazil., Methods: Forty-two patients awaiting bariatric surgery were included, and the presence of the FKBP5 rs1360780 polymorphism was evaluated. During the postoperative period, a 26-month follow-up of weight loss was performed (n = 42, 36, 35, 35, and 30, from the first to fifth postoperative evaluation, respectively; loss to follow-up: 28.6%)., Results: Carriers of the T allele presented significantly lower weight loss compared with patients with the C/C genotype after the 12th to 14th month follow-up period. Differences in weight loss between genotypes ranged from 14.2% to 19.9% of excess weight loss (P = .045 and .004, respectively) and from 7.6% to 9.0% of total weight loss (P = .002 for both comparisons). Furthermore, carriers of the T allele also presented an earlier cessation of weight loss after surgery., Conclusion: The presence of the T allele of the FKBP5 SNP rs1360780 was associated with weight loss after bariatric surgery. Bariatric surgery can interact with genes involved in metabolic regulation, leading to different weight loss outcomes., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Bariatric surgery is the most efficient treatment of severe obesity. We investigated to what extent BMI- or waist-hip ratio (WHR)-related genetic variants are associated with excess BMI loss (EBMIL) two years after Roux-en-Y gastric bypass (RYGB) surgery, and elucidated the affected biological pathways., Methods: Two-hundred fifty-one obese patients (age: 43 ± 10.7, preoperative BMI: 45.1 ± 6.1 kg/m(2), 186 women) underwent RYGB surgery and were followed up after two years with regard to BMI. Patients were genotyped for 32 single-nucleotide polymorphisms (SNPs) that were investigated with regard to their impact on response to RYGB and preoperatively measured Three Factor Eating Questionnaire (TFEQ) scores., Results: Homozygous T carriers of the SNP rs4846567 in proximity to the Lysophospholipase-like 1 (LYPLAL1) gene showed a 7% higher EBMIL compared to wild-type and heterozygous carriers (p = 0.031). TT-allele carriers showed furthermore lower scores for Hunger (74%, p < 0.001), lower Disinhibition (53%, p < 0.001), and higher Cognitive restraint (21%, p = 0.017) than GG/GT carriers in the TFEQ. Patients within the lowest quartile of Hunger scores had a 32% greater EBMIL compared to patients in the highest quartile (p < 0.001)., Conclusion: The LYPLAL1 genotype is associated with differences in eating behavior and loss of extensive body weight following RYGB surgery. Genotyping and the use of eating behavior-related questionnaires may help to estimate the RYGB-associated therapy success.

Background: Currently, Roux-en Y gastric bypass (RYGB) is the most efficient therapy for severe obesity. Weight loss after surgery is, however, highly variable and genetically influenced. Genome-wide association studies have identified several single nucleotide polymorphisms (SNP) associated with body mass index (BMI) and waist-hip ratio (WHR). We aimed to identify two genetic risk scores (GRS) composed of weighted BMI and WHR-associated SNPs to estimate their impact on excess BMI loss (EBMIL) after RYGB surgery., Methods: Two hundred and thirty-eight obese patients (BMI 45.1 ± 6.2 kg/m(2), 74 % women), who underwent RYGB, were genotyped for 35 BMI and WHR-associated SNPs and were followed up after 2 years. SNPs with high impact on post-surgical weight loss were filtered out using a random forest model. The filtered SNPs were combined into a GRS and analyzed in a linear regression model., Results: An up to 11 % lower EBMIL with higher risk score was estimated for two GRS models (P = 0.026 resp. P = 0.021) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608, MAP2K5, GNPDA2, and MTCH2) and of three WHR-associated SNPs (closest genes: HOXC13, LYPLAL1, and DNM3-PIGC). Patients within the lowest GRS quartile had higher EBMIL compared to patients within the other three quartiles in both models., Conclusions: We identified two GRSs composed of BMI and WHR-associated SNPs with significant impact on weight loss after RYGB surgery using random forest analysis as a SNP selection tool. The GRS may be useful to pre-surgically evaluate the risks for patients undergoing RYGB surgery.

Homozygous or compound heterozygous melanocortin-4 receptor (MC4R) mutations are rare with fewer than 10 patients described in current literature. Here we report the short- and long-term outcomes for four children ages 4.5-14 who are homozygous for loss-of-function mutations in the MC4R and underwent laparoscopic sleeve gastrectomy. All four patients experienced significant weight loss and improvement in, or resolution of, their comorbidities in the short term. One patient, however, has had significant weight regain in the long term. We conclude that MC4R signaling is not required for short-term weight loss after laparoscopic sleeve gastrectomy in children. Behavior modification may be more important for long-term weight maintenance, but patients with homozygous MC4R deficiency should not be excluded from consideration for sleeve gastrectomy. However, as at least one copy of functional MC4R is necessary and sufficient to induce long-term postoperative weight loss benefits, patients with complete loss of MC4R functionality might be less likely to exhibit the same benefits resulting from bariatric surgery.

Background: The changes in the transcriptomic profiling of subcutaneous adipose tissue (SAT) when weight loss stabilizes after a Roux-en-Y gastric bypass (RYGB) are still largely unknown., Objectives: To investigate the changes produced in SAT gene expression of morbidly obese women when their weight loss stabilizes 2 years after RYGB., Setting: University hospital., Methods: SAT biopsies of the periumbilical area were taken before and 2 years after RYGB. Gene expression levels were assessed by microarray analysis and significant differences in gene expression were validated by real-time quantitative polymerase chain reaction. The findings were also confirmed in an independent population of morbidly obese women., Results: Microarray analysis revealed that the overexpressed differentially expressed genes have a prominent role in the pathways involved in biosynthetic processes, especially lipid or carboxylic ones (stearoyl-Coenzyme A desaturase-1, fatty acid desaturase-1, fatty acid elongase-6, ATP citrate lyase, fatty acid synthase, lipin-1, monoacylglycerol O-acyltransferase, patatin-like phospholipase domain containing-3, phosphate cytidylyltransferase-2, cholesteryl ester transfer protein, transmembrane 7 superfamily member 2, pyruvate carboxylase, and glycogen synthase 2). Most of the underexpressed differentially expressed genes are related with immune system and inflammation processes (immune responses, response to stress, cell death, regulation of biological quality, immune effector process, the response to endogenous stimulus, and the response to other types of stimulus)., Conclusion: An improvement of the SAT inflammatory and immune profile and an induction of genes involved in the regulation of lipid metabolism are shown when weight loss stabilizes 2 years after RYGB. Most of the genes shown are clearly linked to obesity and other metabolic disorders., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Surgical weight loss response is variable, with suboptimal outcomes in some patients. We hypothesized that genetic biomarkers may be related to weight change., Methods: We tested 330 single nucleotide polymorphisms (SNPs) in genes relevant to metabolic regulation in 161 patients whose decrease in body mass index (BMI), 1 year after laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB), was small (lowest quartile response) or large (highest quartile response). LAGB patients whose BMI decreased≤4.7 or≥10.2 units comprised groups I (n = 43) and II (n = 40), respectively. RYGB patients whose BMI decreased≤13.6 or≥19.8 units comprised groups III (n = 39) and IV (n = 39), respectively. Within each surgery, SNPs with large differences in reference allele frequency (z score>2, corresponding to values displaced 2 standard deviations [SD] from the mean for all SNPs) in low versus high quartiles, were identified. We compared reference allele frequencies, within surgical procedure, using the χ(2) test (using Bonferroni correction for multiple testing)., Results: The mean percent excess weight losses (±SD) corresponding to groups I, II, III, and IV were: 16 (±12), 64 (±30), 55 (±16), and 75 (±17), respectively. SNPs with z score>2 were identified in genes involved in LAGB response, lipid metabolic regulation (APOE, rs439401; APOC4, rs2288911), neural processes (DRD3, rs167771; HTR3 B, rs3758987), and xeno- or endobiotic metabolism (CYP3 A4, rs12333983); and for RYGB response, in lipid transport (SCARB1, rs10846744), folate metabolism (MTHFR, rs2066470), regulation of glycolysis in immune cells (HIF1 A, rs1951795), vitamin K cycling (VKORC1, rs2359612), and xeno- or endobiotic metabolism (CYP3 A4, rs2242480). For LAGB response, APOE SNP frequencies were significantly different., Conclusions: With further validation, information derived from patient DNA may be useful to predict surgical weight loss outcomes and guide selection of surgical approach., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: A recent study in children demonstrated that the rs9939609 single-nucleotide polymorphism in the fat mass and obesity (FTO) gene influences prospective weight gain, however, only in those who were vitamin D-deficient. If this might also be the case for Roux-en-Y gastric bypass (RYGB), surgery-induced weight loss is however unknown. The objective of this study is to examine if the magnitude of RYGB surgery-induced weight loss after 2 years depends on patients' FTO rs9939609 genotype (i.e., TT, AT, and AA) and presurgery vitamin D status (<50 nmol/L equals deficiency)., Methods: Before and at 24 months after RYGB surgery, BMI was measured in 210 obese patients (mean BMI 45 kg/m(2), 72 % females). Serum 25-hydroxyvitamin D3 levels were also repeatedly measured. Following surgery, vitamin D was supplemented. Possible weight loss differences between genotypes were tested with multiple linear regressions., Results: The per-allele effect of each FTO A-allele on excessive BMI loss (EBMIL) was 3 % (P = 0.02). When split by baseline status, the EBMIL of vitamin D-deficient patients carrying AA exceeded that of vitamin D-deficient patients carrying TT by ~14 % (P = 0.03). No such genotypic differences were found in patients without presurgery vitamin D deficiency. Post-surgery serum levels of vitamin D did not differ between groups., Conclusions: Our data suggest that presurgery vitamin D levels influence the size of genotype effects of FTO rs9939609 on RYGB surgery-induced weight loss in obese patients.

Background: The melanocortin 4 receptor (MC4R) critically regulates feeding and satiety. Rare variants in MC4R are predominantly found in obese individuals. Though some rare variants in MC4R discovered in patients have defects in localization, ligand binding and signaling to cAMP, many have no recognized defects., Subjects/methods: In our cohort of 1433 obese subjects that underwent Roux-en-Y Gastric Bypass (RYGB) surgery, we found fifteen variants of MC4R. We matched rare variant carriers to patients with the MC4R reference alleles for gender, age, starting BMI and T2D to determine the variant effect on weight-loss post-RYGB. In vitro, we determined expression of mutant receptors by ELISA and western blot, and cAMP production by microscopy., Results: While carrying a rare MC4R allele is associated with obesity, carriers of rare variants exhibited comparable weight-loss after RYGB to non-carriers. However, subjects carrying three of these variants, V95I, I137T or L250Q, lost less weight after surgery. In vitro, the R305Q mutation caused a defect in cell surface expression while only the I137T and C326R mutations showed impaired cAMP signaling. Despite these apparent differences, there was no correlation between in vitro signaling and pre- or post-surgery clinical phenotype., Conclusions: These data suggest that subtle differences in receptor signaling conferred by rare MC4R variants combined with additional factors predispose carriers to obesity. In the absence of complete MC4R deficiency, these differences can be overcome by the powerful weight-reducing effects of bariatric surgery. In a complex disorder such as obesity, genetic variants that cause subtle defects that have cumulative effects can be overcome after appropriate clinical intervention.

Objective: Bariatric surgery represents a powerful tool for morbid obesity treatment. However, after stabilization of weight loss that follows surgical interventions, ex-obese patients face the problem of residual tissues removal. Actually, it is unknown whether the characteristics of this residual subcutaneous adipose tissue (SAT) are 'restored' with regard to molecular and morphological features., Design: To clarify this issue, we compared the SAT gene expression profile of ex-obese patients (ExOB-SAT, mean body mass index (BMI): 27.2±1.3 kg m(-2)) with that of lean (normal weight, NW-SAT, mean BMI: 22.6±1.1 kg m(-2)), overweight (OW-SAT, BMI: 27.65±0.2 kg m(-2)) and obese patients, according to BMI classes (OB1-SAT: 30 > or = BMI < or = 34.9, OB2-SAT: 35 > or = BMI < or = 39.9, OB3-SAT: BMI > or = 40)., Subjects and Methods: A total of 58 samples of SAT were collected during surgical interventions. Gene expression levels were assessed by microarrays and significant genes were validated by RT-qPCR. Adipocyte hypertrophy, inflammatory infiltration and fibrosis were assessed by morphological techniques., Results: Global gene expression in ExOB-SAT was closely related to gene expression of OB3-SAT by hierarchical clustering procedures, in spite of different BMI. Metallothioneins (MT1A and MT2A) were the key over-expressed genes in both groups. At morphologic level, adipocyte hypertrophy and inflammatory infiltration improved after weight loss in ExOB-SAT, despite a persistence of fibrosis., Conclusions: Taken together, these results demonstrate that SAT gene expression is not fully restored, even after an extensive and stable weight loss. The persistence of 'obesity molecular features' in ExOB-SAT suggests that the molecular signature of adipose tissue is not solely dependent on weight loss and may need longer time period to completely disappear.

The amount of weight loss attained after Roux-en-Y gastric bypass (RYGB) surgery follows a wide and normal distribution, and recent evidence indicates that this weight loss is due to physiological, rather than mechanical, mechanisms. To identify potential genetic factors associated with weight loss after RYGB, we performed a genome-wide association study (GWAS) of 693 individuals undergoing RYGB and then replicated this analysis in an independent population of 327 individuals undergoing RYGB. We found that a 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after RYGB. Expression of ST8SIA2 in omental fat of these individuals at baseline was significantly associated with weight loss after RYGB. Gene expression analysis in RYGB and weight-matched, sham-operated (WMS) mice revealed that expression of St8sia2 and Slco3a1 was significantly altered in metabolically active tissues in RYGB-treated compared to WMS mice. These findings provide strong evidence for specific genetic influences on weight loss after RYGB and underscore the biological nature of the response to RYGB., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Context: Factors that influence long-term weight loss after Roux-en Y gastric bypass (RYGB) surgeries are poorly defined. The melanocortin system plays an important role in regulating energy homeostasis, satiety, and glucose metabolism. Variations of the MC4R comprise the most prevalent monogenetic obesity disorder., Objective: The objective of the study was to examine the role of MC4R variants and diabetic status in long-term weight loss after RYGB., Participants and Methods: In 1433 extremely obese patients who underwent RYGB, we sequenced for genetic variants of MC4R. We examined the MC4R genotype and its relationship with weight loss profile, and clinical phenotypes accumulated during a 48-month period before and after surgery., Results: We found 80 subjects with rare and common variants of MC4R in the RYGB cohort. Among these, 26 and 36 patients carry the I251L and V103I variants, respectively. These common alleles are negatively associated with obesity. Remarkably, after the 12-month presurgery caloric restriction and RYGB, I251L allele carriers lost 9% more weight (∼9 kg) compared with the noncarriers, continued rapid weight loss longer, regained less weight, and had lower presurgery homeostatic model assessment for insulin resistance values. Normoglycemic, I251L allele carriers lost more weight compared with their diabetic and prediabetic counterparts and maintained their weight loss. Among noncarriers, normoglycemic individuals initially lost more weight compared with dysglycemics, but this difference was not maintained in the long term., Conclusions: Individuals carrying the I251L common allele are predisposed to better clinical outcome, reduced risk of type 2 diabetes, and better weight loss during diet and surgical interventions. Diabetic status has only a small, short-term effect on weight loss after RYGB.

Context: The use of Roux-en-Y gastric bypass (RYGB) surgery to treat severe obesity has grown dramatically. RYGB is highly effective, but the response in individual patients varies widely, and clinical predictors have been able to explain only a fraction of this variation., Objective: Our objective was to determine whether there is a significant genetic contribution to weight loss after RYGB., Methods: We genotyped 848 patients undergoing RYGB. Using identity-by-descent methods, we identified 13 pairs of first-degree relatives. We identified an additional 10 pairs of individuals who were living together but are not genetically related and randomly paired the remaining 794 individuals. We then compared weight loss within and across pairs., Results: First-degree relative pairs had a similar response to surgery, with a 9% mean difference in excess weight loss between members of each pair. This similarity was not seen with cohabitating individuals (26% mean difference; P = 0.005 vs. first-degree pairs) or unrelated individuals (25% mean difference; P = 0.001). Cohabitating individuals had within-pair differences in weight loss no more similar than randomly paired individuals (P = 0.60). The pair relationship explained a significant portion of the variation in weight loss in first-degree relatives [intraclass correlation coefficient (ICC) = 70.4%; P = 0.02] but not in random subjects (ICC = 0.9%; P = 0.48) or genetically unrelated cohabitating individuals (ICC = 14.3%; P = 0.67)., Conclusions: Genetic factors strongly influence the effect of RYGB on body weight. Identification of the specific genes that mediate this effect will advance our understanding of the biological mechanisms of weight loss after RYGB and should help identify patients who will benefit the most from this intervention.

Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m(2)) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/m(2). Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI.

Background: Heterozygous mutations in melanocortin-4 receptor (MC4R) are the most frequent genetic cause of obesity. Bariatric surgery is a successful treatment for severe obesity. The mechanisms of weight loss after bariatric surgery are not well understood., Methods: Ninety-two patients who had Roux-en-Y gastric bypass (RYGB) surgery were screened for MC4R mutations. We compared percent excess weight loss (%EWL) in the four MC4R mutation carriers with that of two control groups: 8 matched controls and with the remaining 80 patients who underwent RYGB., Results: Four patients were heterozygous for functionally significant MC4R mutations. In patients with MC4R mutations, the %EWL after RYGB (66% EWL) was not significantly different compared to matched controls (70% EWL) and non-matched controls (60% EWL) after 1 year of follow-up., Conclusions: This study suggests that patients with heterozygous MC4R mutations also benefit from RYGB and that weight loss may be independent of the presence of such mutations.

Context: Gastric bypass surgery is the most commonly performed bariatric surgical procedure in the United States. Variable weight loss following this relatively standardized intervention has been reported. To date, a method for reliable profiling of patients who will successfully sustain weight loss for the long term has not been established. In addition, the mechanisms of action in accomplishing major weight loss as well as the explanation for the variable weight loss have not been established., Objective: To examine whether gene expression in perioperative omental adipose is associated with gastric bypass-induced weight loss., Design: Cross-sectional study of gene expression in perisurgical omental adipose tissues taken/available at the time of operation and total excess weight loss (EWL)., Subjects: Fifteen overweight individuals who underwent Roux-en-Y gastric bypass (RYGB) surgery at the University of California Davis Medical Center (BMI: 40.6-72.8 kg/m(2))., Measurements: Body weight before and following weight stabilization 18-42 months after surgery. Perioperative omental adipose RNA isolated from 15 subjects was hybridized to Affymetrix HG-U133A chips for 22,283 transcript expression measurements., Results: Downstream analysis identified a set of genes whose expression was significantly correlated with RYGB-induced weight loss. The significant individual genes include acyl-coenzyme A oxidase 1 (ACOX1), phosphodiesterase 3A cGMP-inhibited (PDE3A) and protein kinase, AMP-activated, beta 1 non-catalytic subunit (PRKAB1). Specifically, ACOX1 plays a role in fatty acid metabolism. PDE3A is involved in purine metabolism and hormone-stimulated lipolysis. PRKAB1 is involved in adipocytokine signaling pathway. Gene network analysis revealed that pathways for glycerolipid metabolism, breast cancer and apoptosis were significantly correlated with long-term weight loss., Conclusion: This study demonstrates that RNA expression profiles from perioperative adipose tissue are associated with weight loss outcome following RYGB surgery. Our data suggest that EWL could be predicted from preoperative samples, which would allow for informed decisions about whether or not to proceed to surgery.

Background: Variability in weight loss has been observed from morbidly obese patients receiving bariatric operations. Genetic effects may play a crucial role in this variability., Methods: 304 morbidly obese patients (BMI > or =39) were recruited, 77 receiving laparoscopic adjustable gastric banding (LAGB) and 227 laparoscopic mini-gastric bypass (LMGB), and 304 matched non-obese controls (BMI < or =24). Initially, all subjects were genotyped for 4 SNPs (single nucleotide polymorphisms) on UCP2 gene in a case-control study. The SNPs significantly associated with morbid obesity (P < 0.05) were considered as candidate markers affecting weight change. Subsequently, effects on predicting weight loss of those candidate markers were explored in LAGB and LMGB, respectively. The peri-operative parameters were also compared between LAGB and LMGB., Results: The rs660339 (Ala55Val), on exon 4, was associated with morbid obesity (P = 0.049). Morbidly obese patients with either TT or CT genotypes on rs660339 experienced greater weight loss compared to patients with CC after LAGB at 12 months (BMI loss 12.2 units vs 8.1 units) and 24 months (BMI loss 13.1 units vs 9.3 units). However, this phenomenon was not observed in patients after LMGB. Although greater weight loss was observed in patients receiving LMGB, this procedure had a higher operative complication rate than LAGB (7.5% vs. 2.8%; P < 0.05)., Conclusion: Ala55Val may play a crucial role in obesity development and weight loss after LAGB. It may be considered as clinicians incorporate genetic susceptibility testing into weight loss prediction prior to bariatric operations.