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Purpose: Variants in the leptin-melanocortin pathway (LMP) are associated with severe obesity. We evaluated weight loss of patients with or without heterozygous LMP variants, with weight recurrence after Roux-en-Y gastric bypass, who underwent endoscopic transoral outlet reduction (TORe)., Materials and Methods: We retrospectively reviewed patients genotyped for an LMP who had undergone TORe, classified as "carriers" or "non-carriers" of genetic variants., Results: We included 54 patients (22 carriers, 32 non-carriers). We identified 34 genetic variants in 21 different genes in 22 patients. Total body weight loss (%TBWL) after TORe was significantly different at 9 and 12 months (12 months: 0.68 ± 7.5% vs. 9.6 ± 8.2%, p < 0.01). This difference in weight loss was present even when analyzed in subgroups of patients who had undergone tubular TORe technique, and TORe plus APC. At 3, 6, and 12 months, the percentage of carriers achieving ≥ 5% and ≥ 10% TBWL was lower than non-carriers., Conclusions: Patients with LMP variant who underwent RYGB had decreased weight loss 1 year after undergoing TORe., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.)

Purpose: Obesity is a risk factor for many chronic diseases. This study aimed to investigate the effect of bariatric surgery on the gut microbiota from patients with obesity., Materials and Methods: The microbiota composition from stool samples before and after bariatric surgery were identified using bacterial 16S rRNA gene sequencing. Based on the speed of weight loss, patients were classified as the slow-loss group and fast-loss group. The ɑ- and β-diversity analysis was done to compare the species richness, evenness, and overall structure of the microbiota between different groups. Next, linear discriminant analysis effect size (LEfSe) and receiver operating characteristic (ROC) analysis were implemented to identify high-dimensional biomarkers and significantly different species of microbial taxa between different groups. Finally, the pathway analysis was inferred using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to predict the functional profiling of microbial communities., Results: β-diversity analysis suggested that species diversity of preoperative samples of slow-loss group was significantly higher than the fast-loss group. High levels of Oscillospira and Abiotrophia in the preoperative gut microbiota may lead to poor postoperative weight loss. For patients with poor postoperative weight loss due to changes in gut microbiota, the gut microbiota is mainly composed of Lactobacillus. For patients with good postoperative results, the gut microbiota is mainly composed of Escherichia, Robinsonella, and Dialister. In addition, multiple metabolic-related pathways were significantly different between the four groups., Conclusion: This comparative study revealed biomarker species based on microfloral composition in patients with obesity before and after bariatric surgery., (© 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.)

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.)

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.)

This systematic review synthesized research evaluating the relationship between genetic predictors and weight loss after bariatric surgery. Fifty-seven studies were identified that examined single genes or genetic risk scores. Uncoupling protein (UCP) rs660339 was associated with excess weight loss after surgery in 4 of 6 studies. The most commonly assessed genes were fat mass and obesity-associated (FTO) gene (n = 10) and melanocortin-4 receptor (MC4R) (n = 14). Both were inconsistently related to weight loss. Genetic risk scores predicted weight loss in 6 of 7 studies. This evidence suggests the potential of using genetic variants and genetic risk scores to predict the amount of weight loss anticipated after bariatric surgery and identify patients who may be at risk for suboptimal weight reduction., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Morbid obesity could last for a long period of life and increase the risk of morbidity as well as premature mortality. Although bariatric surgery benefits patients by quick weight loss, not all bariatric patients lose the same percentage of weight after a long time from surgery, which may be the result of diet, physical activity, and genetic components., Objectives: In this study, we evaluated the association between the MC4R gene and both excess weight loss percentage (EWL%) and excess BMI loss percentage (EBMIL%) in a cohort of bariatric surgery patients after 6 and 12 months from surgery., Methods: A total of 424 bariatric surgery patients who had participated in the Tehran Obesity Treatment Study and had weight measurements after 6 and 12 months from surgery were included in the study. Four SNPs in the MC4R gene were selected for evaluating the associations., Results: We found that rs17773430 had a significant effect on both EWL% and EBMIL%, especially after 12 months of bariatric surgery. Furthermore, three other SNPs, rs17782313, rs476828, and rs11152213, did not show any significant association with EWL% and EBMIL%., Conclusion: This study was the first to report on the association of rs17773430 with both EWL% and EBMIL% in a cohort of patients after bariatric surgery. We found that weight loss after surgery is influenced by genetic factors, and there were significant differences between the distribution of EWL% and EBMIL% in morbid obese bariatric patients who have two minor alleles of the rs17773430 and other SNPs.

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: The weight loss after bariatric surgery shows considerable individual variation. Twin studies of response to dietary interventions and studies of bariatric surgery patients suggest that genetic differences may play a role. This study aimed to examine the effect of three genetic risk scores on the inter-individual variation in excess body mass index loss (EBMIL) after Roux-en-Y gastric bypass. Furthermore, we searched among known adiposity-related single nucleotide polymorphisms (SNPs) for genetic determinants of the inter-individual variation in EBMIL., Methods: Patients with morbid obesity underwent Roux-en-Y gastric bypass and were genotyped (n = 577). Two genetic risk scores for weight loss after bariatric surgery and a genetic risk score for body mass index were calculated. Associations between the genetic risk scores and EBMIL were evaluated. Lasso regression was performed on 126 SNPs known to be associated with adiposity., Results: The average EBMIL was 76.9% (range 21.7-149.2%). EBMIL was 81.1% (SD 20.6) and 73.9% (SD 21.7) in the high and low tertile groups of a genetic risk score for weight loss. Patients with a low genetic risk score for body mass index (in the lowest 5% percentile) had an EBMIL of 68.8% (SD 20.6, p = 0.018). Thirteen adiposity-related SNPs were identified to associate with EBMIL through lasso regression., Discussion: A genetic risk score was associated with EBMIL after bariatric surgery, but may not yet be applicable to clinical practice. Patients genetically predisposed to low body mass index had lower weight loss after bariatric surgery.

Objectives: Bariatric surgery is emerging as the most effective treatment option for patients with obesity. Hypothalamic arcuate nucleus plays an important role in metabolic homeostasis. However, the influence of mutations related to the feeding center on weight loss after bariatric surgery is still unclear. We aimed to diagnose monogenic obesity by whole exome sequencing (WES) and explore whether monogenic mutations influence the effectiveness of bariatric surgery., Methods: We collected obese patients aged 15 to 55 with a BMI > 28 kg/m 2 and who underwent laparoscopic sleeve gastrectomy from March 2011 to June 2017 in Shanghai. Data related to weight loss and metabolic characteristics preoperatively and postoperatively were collected, including fasting blood glucose (FBG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. WES was performed in obese patients using genomic DNA from whole blood samples., Results: We investigated the proportion of 131 obese adults with one mutation as high as to 8.4% and then evaluated the association between these mutations and weight loss. Mutation carriers had less weight loss over both short-term and long-term periods. Survival analyses indicated it was harder to attain the goal of 20% weight loss for mutation carriers (P log-rank  = 0.001; P breslow  < 0.001), and the difference remained significant with a Cox regression model. Improvement in FBG, HDL cholesterol, and triglyceride levels postoperatively was observed in both groups, while there were significant differences between the two groups., Conclusions: Our data indicated that 8.4% of obesity cases were caused by change in genetics, and mutations had negative effects on the efficacy of bariatric surgery.

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.

Purpose: Differences in weight loss outcomes after bariatric surgery may be related to individual preoperative characteristics. The aim of this study was to evaluate the potential effect of fatty acid binding protein-2 (rs1799883), leptin receptor (LEP223, rs1137101 and LEP656, rs1805094), and fat mass and obesity-related (rs9939609) genotypes on weight loss 2 years after bariatric surgery in Brazilian patients., Materials and Methods: Prospective observational study involving 105 patients (lost to follow-up, 25.7%). In the preoperative period, patients were clinically evaluated and a fasting blood sample for genetic analysis (by real-time DNA amplification technique) was collected. From the patient's medical records, follow-up weight loss (3, 6, 12, 24 months) was obtained. Percentage of excess weight loss (%EWL) was examined by pairwise comparison across the polymorphisms., Results: At baseline, the mean weight was 127.5 (23.3) kg and age 43.1 (10.9) years old. The %EWL was significant over time (p < 0.01). Only the LEP223 genotype showed association (p < 0.01). Up to 6 months after surgery, no differences were observed. At 12 months, a significant difference (p = 0.03) between AA (n = 19) and GG (n = 34) groups was observed, with 76.5% EWL versus 52.0%, respectively. This difference remained at 24 months. Other genotypes did not present any significant association., Conclusions: There is a different evolution of weight loss in carriers of the LEP223 after bariatric surgery. The AA genotype seems to be associated with a higher weight loss. However, this pattern was evident only at 12 months after surgery.

Background: Differential gene expression in peripheral blood mononuclear cells (PBMCs) after Roux-en-Y gastric bypass (RYGB) is poorly characterized. Markers of these processes may provide a deeper understanding of the mechanisms that underlie these events. The main goal of this study was to identify changes in PBMC gene expression in women with obesity before and 6 months after RYGB-induced weight loss., Methods: The ribonucleic acid (RNA) of PBMCs from 13 obese women was analyzed before and 6 months after RYGB; the RNA of PBMCs from nine healthy women served as control. The gene expression levels were determined by microarray analysis. Significant differences in gene expression were validated by real-time quantitative polymerase chain reaction (RT-qPCR)., Results: Microarray analysis for comparison of the pre- and postoperative periods showed that 1366 genes were differentially expressed genes (DEGs). The main pathways were related to gene transcription; lipid, energy, and glycide metabolism; inflammatory and immunological response; cell differentiation; oxidative stress regulation; response to endogenous and exogenous stimuli; substrate oxidation; mTOR signaling pathway; interferon signaling; mitogen-activated protein kinases (MAPK), cAMP response element binding protein (CREB1), heat shock factor 1 (HSF1), and sterol regulatory element binding protein 1c (SREBP-1c) gene expression; adipocyte differentiation; and methylation., Conclusions: Six months after bariatric surgery and significant weight loss, many molecular pathways involved in obesity and metabolic diseases change. These findings are an important tool to identify potential targets for therapeutic intervention and clinical practice of nutritional genomics in obesity.

Background: The effects of rs1501299 variant of ADIPO gene on weight loss after bariatric surgery have not been evaluated. We decided to investigate the role of this genetic variant on anthropometric and biochemical outcomes such as serum adiponectin levels after biliopancreatic diversion (BPD) surgery in morbidly obese patients during 3 years., Material and Methods: A sample of 64 patients with morbid obesity without diabetes mellitus was operated. Biochemical and anthropometric evaluation were realized at basal visit and at each visit during 3 years (1, 2, and 3 years)., Results: Percent excess weight loss, body mass index, weight, waist circumference, fat mass, blood pressure, fasting glucose, LDL cholesterol, total cholesterol, and triglycerides levels improved in both genotype groups. Fasting insulin levels and HOMA-IR decreased significantly only in non-T allele carriers. The decrease of fasting insulin levels at 3 years (delta -9.2 ± 3.4 vs -2.9 ± 2.2 mUI/L; p = 0.01) and HOMA-IR (delta -1.3 ± 0.3 vs -0.8 ± 0.4 units; p = 0.03) were higher in non-T allele carriers than T carriers. Adiponectin levels increased in all times after surgery in non-T allele carriers, too. The increase of adiponectin levels at 3 years (delta 12.2 ± 3.6 vs 1.8 ± 1.2 ng/mL; p = 0.01) was higher in non-T allele carriers than T carriers., Conclusion: Non-T allele of ADIPOQ gene variant (rs1501299) is associated with increases in adiponectin levels and better improvements of insulin and HOMA-IR after BPD massive weight loss. These parameters remained unchanged in T allele carriers.

Introduction: Obesity is the result of a complex interaction between multiple genetic traits and psychological, behavioral, nutritional and environmental factors., Objectives: The aims of the study were (a) to comparatively evaluate the presence of 20 candidate gene single nucleotide polymorphisms (SNPs) in morbidly obese patients, (2) their association to comorbid conditions and (3) their impact on weight loss after a Roux-en-Y gastric bypass (RYGB)., Patients and Methods: Two hundred forty-nine patients were eligible for this study. Clinical, anthropometric, biochemical and demographic variables were analyzed. Body mass index (BMI) and composition were assessed by bioelectrical impedance. Twenty SNPs were included for analysis., Results: There were 168 Mexican mestizos (67.5 %) and 81 (32.5 %) patients with other ancestral origin. One hundred fifty-nine (64.1 %) were females. Mean ± SD age of the general cohort was 41.1 ± 11.3 years (17-71). Preoperative mean ± SD BMI was 42.5 ± 6.5 kg/m 2 . There were no significant differences between mestizo and non-mestizo for most SNPs except for IFI, LIPC, and ST8SIA2. FTO (OR = 1.71; CI 95 %  = 1.14-2.57; p = 0.008) and APOB (OR = 0.31; CI 95 %  = 0.14-0.72; p = 0.004) result is statistically associated to high blood pressure and FTO (OR = 2.0; CI 95 %  = 1.3-3.1; p = 0.001), GNB3 (OR = 2.69; CI 95 %  = 1.0-7.2; p = 0.04), IFI30 (OR = 2.0; CI 95 %  = 1.16-3.6; p = 0.01), and MC4R (OR = 1.81; CI 95 %  = 1.13-2.9; p = 0.01) to type 2 diabetes (T2D). Based on ANOVA analysis, POMC (rs1042571) was the SNP most significantly associated to a higher weight loss after RYGB., Conclusions: Obese patients have similar SNP frequencies. Several SNP results are statistically associated to high blood pressure and T2D. POMC was significantly associated to a higher surgically induced weight loss.

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.

Background: Analysis of the expression of genes related to the energy metabolism can elucidate the understanding of physiological and genetic factors that contribute to obesity. This study aimed to evaluate the expression of genes and its influence on resting metabolic rate and weight loss in obese patients before and after bariatric surgery., Methods: This study was conducted on 23 women, who were divided into two groups: bariatric surgery (preoperative and 6 months after surgery) and control. Abdominal subcutaneous adipose tissue samples were collected to analyze the gene expression, and the resting metabolic rate (RMR) was measured by indirect calorimetry., Results: Significant differences were observed in weight reduction (22 %, p = 0.01), BMI (22.5 %, p = 0.01), and RMR values (10.5 %, p = 0.01) after the bariatric surgery, while the weight-adjusted RMR increased (15.8 %, p = 0.01). Increased UCP2 expression after 6 months of Roux-en-Y gastric bypass (RYGB) as compared to preoperative period (0.764 to 1.268, p = 0.01) was observed. Analysis with weight-adjusted RMR as dependent variable revealed that UCP2 (r 2  = 0.517, p = 0.01) and PLIN1 (r 2  = 0.420, p = 0.04) expression determine the RMR values in preoperative period. Moreover, UCP2 and PLIN1 expression in preoperative period influenced the percentage of weight loss, even when adjusted for age and BMI., Conclusions: We have demonstrated that after 6 months of bariatric surgery, there is significant increase in the UCP2 expression. Additionally, the expression of UCP2 and PLIN1 genes influences the resting metabolic rate in obese individuals and could predict the weight loss after bariatric surgery.

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.

Background: Weight loss can be influenced by genetic factors and epigenetic mechanisms that participate in the regulation of body weight. This study aimed to investigate whether the weight loss induced by two different obesity treatments (energy restriction or bariatric surgery) may affect global DNA methylation (LINE-1) and hydroxymethylation profile, as well as the methylation patterns in inflammatory genes., Methods: This study encompassed women from three differents groups: 1. control group (n = 9), normal weight individuals; 2. energy restriction group (n = 22), obese patients following an energy-restricted Mediterranean-based dietary treatment (RESMENA); and 3. bariatric surgery group (n = 14), obese patients underwent a hypocaloric diet followed by bariatric surgery. Anthropometric measurements and 12-h fasting blood samples were collected before the interventions and after 6 months. Lipid and glucose biomarkers, global hydroxymethylation (by ELISA), LINE-1, SERPINE-1, and IL-6 (by MS-HRM) methylation levels were assessed in all participants., Results: Baseline LINE-1 methylation was associated with serum glucose levels whereas baseline hydroxymethylation was associated with BMI, waist circumference, total cholesterol, and triglycerides. LINE-1 and SERPINE-1 methylation levels did not change after weight loss, whereas IL-6 methylation increased after energy restriction and decreased in the bariatric surgery group. An association between SERPINE-1 methylation and weight loss responses was found., Conclusions: Global DNA methylation and hydroxymethylation might be biomarkers for obesity and associated comorbidities. Depending on the obesity treatment (diet or surgery), the DNA methylation patterns behave differently. Baseline SERPINE-1 methylation may be a predictor of weight loss values after bariatric surgery.

We examined the association of 34 single nucleotide polymorphisms with weight loss up to 9.5 years after Roux-en-Y surgery. Participants were enrollees in the NUgene biobank with stored DNA and linked electronic health records. Ninety-five self-identified white participants underwent surgery and had follow-up weights obtained between 1 and 9.5 years after surgery. SNP rs4771122 was the variant most significantly associated with long-term weight loss after surgery in a repeated linear mixed model (p = .004) of long-term weight loss. In this model, each additional copy of the minor allele was associated with nearly 5 % greater percentage weight loss. This same SNP was also nominally significantly (p < .05) associated with weight loss trajectories, weight loss nadir, and weight loss 2 years after surgery.

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: Significant variability in weight loss and glycemic control has been observed in obese patients receiving bariatric surgery. Genetic factors may play a role in the different outcomes., Methods: Five hundred and twenty severely obese patients with body mass index (BMI) ≥35 were recruited. Among them, 149 and 371 subjects received laparoscopic adjustable gastric banding (LAGB) and laparoscopic mini-gastric bypass (LMGB), respectively. All individuals were genotyped for five obesity-related single nucleotide polymorphisms on ESR1, FTO, PPARγ, and UCP2 genes to explore how these genes affect weight loss and glycemic control after bariatric surgery at the 6th month., Results: Obese patients with risk genotypes on rs660339-UCP2 had greater decrease in BMI after LAGB compared to patients with non-risk genotypes (-7.5 vs. -6 U, p = 0.02). In contrast, after LMGB, obese patients with risk genotypes on either rs712221-ESR1 or rs9939609-FTO had significant decreases in BMI (risk vs. non-risk genotype, -12.5 vs. -10.0 U on rs712221, p = 0.02 and -12.1 vs. -10.6 U on rs9939609, p = 0.04) and a significant amelioration in HbA1c levels (p = 0.038 for rs712221 and p < 0.0001 for rs9939609). The synergic effect of ESR1 and FTO genes on HbA1c amelioration was greater (-1.54%, p for trend <0.001) than any of these genes alone in obese patients receiving LMGB., Conclusions: The genetic variants in the ESR, FTO, and UCP2 genes may be considered as a screening tool prior to bariatric surgery to help clinicians predict weight loss or glycemic control outcomes for severely obese patients.

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.

Background: Bariatric surgery is the most effective long-term treatment for morbid obesity, reducing obesity-associated comorbidities. The purpose of the present study was to evaluate the UCP3 promotor (-55C-->T) polymorphism outcomes 1 year after biliopancreatic diversion in morbidly obese patients., Methods: A sample of 40 morbidly obese patients (BMI >40 kg/m(2)) were operated. Weight, fat mass, blood pressure, basal glucose, triacylglycerols, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured at basal visit and at each visit. The frequency of patients with diabetes mellitus, hypertension, and hyperlipidemia was recorded at each visit., Results: Twenty-eight patients (70%) had the genotype C/C (wild group) and 12 (30%) patients C/T (mutant group). In wild type group, body mass index, weight, fat mass, systolic blood pressure, glucose, total cholesterol, low-density lipoprotein cholesterol, and triacylglycerols concentrations decreased. In mutant type group, the same parameters improved, without statistical differences with wild group. Initial weight percent loss at 1 year of follow-up was similar in both genotypes (34.1% vs 28.6%; ns)., Conclusion: Polymorphism -55C/T of the UCP3 promotor did not have an effect on weight loss or clinical outcomes after bariatric 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.