Non-alcoholic fatty liver disease in patients with morbid obesity: the gut microbiota axis as a potential pathophysiology mechanism.

BACKGROUND/AIM: Alterations in gut microbiota are associated with the pathogenesis of metabolic diseases, including metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate gut microbiota composition and functionality in patients with morbid obesity with different degrees of MAFLD, as assessed by biopsy. SUBJECTS/METHODS: 110 patients with morbid obesity were evaluated by biopsy obtained during bariatric surgery for MAFLD. Stool samples were collected prior to surgery for microbiota analysis. RESULTS: Gut microbiota from patients with steatosis and non-alcoholic steatohepatitis (NASH) were characterized by an enrichment in Enterobacteriaceae (an ethanol-producing bacteria), Acidaminococcus and Megasphaera and the depletion of Eggerthellaceae and Ruminococcaceae (SCFA-producing bacteria). MAFLD was also associated with enrichment of pathways related to proteinogenic amino acid degradation, succinate production, menaquinol-7 (K2-vitamin) biosynthesis, and saccharolytic and proteolytic fermentation. Basic histological hepatic alterations (steatosis, necroinflammatory activity, or fibrosis) were associated with specific changes in microbiota patterns. Overall, the core microbiome related to basic histological alterations in MAFLD showed an increase in Enterobacteriaceae and a decrease in Ruminococcaceae. Specifically, Escherichia coli was associated with steatosis and necroinflammatory activity, whilst Escherichia-shigella was associated with fibrosis and necroinflammatory activity. CONCLUSIONS: We established a link between gut microbiota alterations and histological injury in liver diagnosis using biopsy. Harmful products such as ethanol or succinate may be involved in the pathogenesis and progression of MAFLD. Thus, these alterations in gut microbiota patterns and their possible metabolic pathways could add information to the classical predictors of MAFLD severity and suggest novel metabolic targets.

Epigenetic Marks as Predictors of Metabolic Response to Bariatric Surgery: Validation from an Epigenome Wide Association Study.

Little is known about the potential role of epigenetic marks as predictors of the resolution of obesity-related comorbidities after bariatric surgery. In this study, 20 patients were classified according to the metabolic improvement observed 6 months after sleeve gastrectomy, based on the diagnosis of metabolic syndrome, into responders if metabolic syndrome reversed after bariatric surgery (n = 10) and non-responders if they had metabolic syndrome bariatric surgery (n = 10). Blood DNA methylation was analyzed at both study points using the Infinium Methylation EPIC Bead Chip array-based platform. Twenty-six CpG sites and their annotated genes, which were previously described to be associated with metabolic status, were evaluated. Cg11445109 and cg19469447 (annotated to Cytochrome P450 2E1 (CYP2E1) gene) were significantly more hypomethylated in the responder group than in the non-responder group at both study points, whilst cg25828445 (annotated to Nucleolar Protein Interacting With The FHA Domain Of MKI67 Pseudogene 3 (NIFKP3) gene) showed to be significantly more hypermethylated in the non-responder group compared to the responder group at both study points. The analysis of the methylation sites annotated to the associated genes showed that CYP2E1 had 40% of the differentially methylated CpG sites, followed by Major Histocompatibility Complex, Class II, DR Beta 1 (HLA-DRB1) (33.33%) and Zinc Finger Protein, FOG Family Member 2 (ZFPM2) (26.83%). Cg11445109, cg19469447 and cg25828445 could have a role in the prediction of metabolic status and potential value as biomarkers of response to bariatric surgery.

Hypertension and hypercholesterolemia are predictive factors associated with type 2 diabetes persistence after metabolic surgery: A prospective study.

BACKGROUND: Metabolic surgery is the most effective therapeutic strategy for the management of type 2 diabetes (T2DM). Several preoperative clinical factors have been associated with T2DM remission after metabolic surgery. However, other potential predictors remain unexplored. AIM: To assess the role of basal (pre-surgery) clinical and biochemical parameters in T2DM remission after metabolic surgery. METHODS: A prospective study including 98 patients with T2DM undergoing metabolic surgery was performed. Clinical, anthropometric, and biochemical data were collected at baseline and 1 year following metabolic surgery. RESULTS: Patients without T2DM remission 1 year after metabolic surgery presented a longer duration of diabetes and higher glycated hemoglobin (HbA1c) levels; a higher percentage of these subjects were using insulin therapy, antihypertensive drugs, and lipid-lowering therapies before metabolic surgery, compared to those patients with T2DM remission. A lower percentage of T2DM remission after metabolic surgery was observed among patients with hypertension/hypercholesterolemia before surgery, compared to those patients without hypertension/hypercholesterolemia (51.7 % vs 86.8 %, p < 0.001, and 38.5 % vs 75 %, p < 0.001, respectively), and among patients with longer duration of diabetes (≥5 years vs <5 years; 44.4 % vs 83 %, respectively; p < 0.001). In the logistic regression model, diabetes duration, basal HbA1c, and the presence of hypertension and hypercholesterolemia before surgery were inversely related to T2DM remission following metabolic surgery, after adjusting for sex, age, waist circumference, and type of surgery. CONCLUSIONS: In a cohort of patients with obesity and T2DM, preoperative hypertension and hypercholesterolemia, together with a longer diabetes duration and higher HbA1c concentrations, were independent predictors of T2DM persistence after metabolic surgery.

Cross-sectional associations of persistent organic pollutants measured in adipose tissue and metabolic syndrome in clinically diagnosed middle-aged adults.

INTRODUCTION: Although often overlooked in clinical settings, accumulation of persistent organic pollutants (POPs) in visceral adipose tissue (VAT) is thought to be a relevant risk factor for metabolic syndrome (MetS). METHODS: One hundred and seventeen patients undergoing non-oncological surgery were randomly recruited and classified as MetS + if presented 3 out of the 5 MetS components: waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP, respectively), serum glucose, insulin, triglycerides (TG) and high-density lipoprotein (HDL) cholesterol levels, according International Diabetes Federation (IDF) criteria. Seventeen organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in adipose tissue samples. Linear, logistic and weighted quantile sum (WQS) regression models, adjusted for age and sex, were performed. RESULTS: One third of the participants were males (36.8%) with a median age of 44 years, showing clinical evidences of MetS (35.0%). Adjusted linear regression models showed that WC correlated positively with all OCP concentrations. Higher fasting serum glucose levels were related to higher HCB and γ-HCH concentrations. The remaining OCPs and PCBs were not associated with this MetS component. HCB was inversely associated with HDL cholesterol levels, while PCB-180 was positively associated. HCB and γ-HCH concentrations were also positively correlated with DBP and SBP levels. PCB-138 was also positively associated with SBP. Adjusted logistic models revealed that exposure to HCB and γ-HCH were associated with increased odds of MetS [ORs (95%CI) 1.53 (1.22-1.92) and 1.39 (1.10-1.76) respectively; p < 0.01]. No associations were observed for the remaining POPs. WQS models showed a positive and significant mixture effect of POPs on the odds of MetS (exp [beta] = 2.34; p < 0.001), with γ-HCH (52.9%), o,p'-DDT (26.9%) and HCB (19.7%) driving the association. CONCLUSIONS: Our findings support that POPs accumulated in VAT, specifically HCB and (gamma)-HCH, are associated with both isolated components and clinically diagnosed SMT.

Evaluation of Adipose Tissue Zinc-Alpha 2-Glycoprotein Gene Expression and Its Relationship with Metabolic Status and Bariatric Surgery Outcomes in Patients with Class III Obesity.

Zinc-α2 glycoprotein (ZAG) is an adipokine involved in adipocyte metabolism with potential implications in the pathogenesis of metabolic disorders. Our aim was to evaluate the relationship between visceral (VAT) and subcutaneous adipose tissue (SAT) ZAG expression and metabolic parameters in patients with class III obesity, along with the impact of basal ZAG expression on short- and medium-term outcomes related to bariatric surgery. 41 patients with class III obesity who underwent bariatric surgery were included in this study. ZAG gene expression was quantified in SAT and VAT. Patients were classified into two groups according to SAT and VAT ZAG percentile. Anthropometric and biochemical variables were obtained before and 15 days, 45 days, and 1 year after surgery. The lower basal SAT ZAG expression percentile was associated with higher weight and waist circumference, while the lower basal VAT ZAG expression percentile was associated with higher weight, waist circumference, insulin, insulin resistance, and the presence of metabolic syndrome. Basal SAT ZAG expression was inversely related to weight loss at 45 days after surgery, whereas no associations were found between basal VAT ZAG expression and weight loss after surgery. Additionally, a negative association was observed between basal SAT and VAT ZAG expression and the decrease of gamma-glutamyl transferase after bariatric surgery. Therefore, lower SAT and VAT ZAG expression levels were associated with an adverse metabolic profile. However, this fact did not seem to confer worse bariatric surgery-related outcomes. Further research is needed to assess the clinical significance of the role of ZAG expression levels in the dynamics of hepatic enzymes after bariatric surgery.

Predictive Role of Gut Microbiota in Weight Loss Achievement after Bariatric Surgery.

BACKGROUND: Bariatric surgery induces changes in gut microbiota that have been suggested to contribute to weight loss and metabolic improvement. However, whether preoperative gut microbiota composition could predict response to bariatric surgery has not yet been elucidated. STUDY DESIGN: Seventy-six patients who underwent sleeve gastrectomy were classified according to the percentage of excess weight loss (%EWL) 1 year after surgery in the responder group: >50%EWL (n=50) and the nonresponder group: <50%EWL (n=26). Patients were evaluated before surgery, and 3 months and 1 year after surgery. Gut microbiota composition was analyzed before surgery (n=76) and 3 months after bariatric surgery (n=40). RESULTS: Diversity analysis did not show differences between groups before surgery or 3 months after surgery. Before surgery, there were differences in the abundance of members belonging to Bacteroidetes and Firmicutes phyla (nonresponder group: enriched in Bacteroidaceae, Bacteroides, Bacteroides uniformis, Alistipes finegoldii, Alistipes alistipes, Dorea formicigenerans, and Ruminococcus gnavus. Responder group: enriched in Peptostreptococcaceae, Gemmiger, Gemiger formicilis, Barnesiella, Prevotellaceae, and Prevotella; linear discriminant analysis >2; p < 0.05). Prevotella-to-Bacteroides ratio was significantly lower in the nonresponder group compared to the responder group (p = 0.048). After surgery, the responder group showed an enrichment in taxa that have been shown to have beneficial effects on host metabolism. Before surgery, PICRUSt analysis showed an enrichment in pathways involved in the biosynthesis components of the O-antigen polysaccharideunits in lipopolysaccharides in the nonresponder group. CONCLUSIONS: Preoperative gut microbiota could have an impact on bariatric surgery outcomes. Prevotella-to-Bacteroides ratio could be used as a predictive tool for weight loss trajectory. Early after surgery, patients who experienced successful weight loss showed an enrichment in taxa related to beneficial effects on host metabolism.

Gut Microbiota Metabolism of Bile Acids Could Contribute to the Bariatric Surgery Improvements in Extreme Obesity.

Bariatric surgery is the only procedure to obtain and maintain weight loss in the long term, although the mechanisms driving these benefits are not completely understood. In the last years, gut microbiota has emerged as one of the drivers through its metabolites, especially secondary bile acids. In the current study, we have compared the gut microbiota and the bile acid pool, as well as anthropometric and biochemical parameters, of patient with morbid obesity who underwent bariatric surgery by two different techniques, namely Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Gut microbiota populations differed after the respective procedures, particularly with respect to the Enterobacteriaceae family. Both techniques resulted in changes in the bile acids pool, but RYGB was the procedure which suffered the greatest changes, with a reduction in most of their levels. Blautia and Veillonella were the two genera that more relationships showed with secondary bile acids, indicating a possible role in their formation and inhibition, respectively. Correlations with the anthropometric and biochemical variables showed that secondary bile acids could have a role in the amelioration of the glucose and HDL-cholesterol levels. Thus, we have observed a possible relationship between the interaction of the bile acids pool metabolized by the gut microbiota in the metabolic improvements obtained by bariatric surgery in the frame of morbid obesity, deserving further investigation in greater cohorts to decipher the role of each bile acid in the homeostasis of the host for their possible use in the development of microbiota-based therapeutics, such as new drugs, postbiotics or probiotics.

Oxidized LDL Increase the Proinflammatory Profile of Human Visceral Adipocytes Produced by Hypoxia.

BACKGROUND: Little is known about the effects of hypoxia on scavenger receptors (SRs) levels in adipocytes. We analyzed the effect of morbid obesity and hypoxia on SRs and inflammation markers in human visceral adipocytes and whether ox-LDL modify the inflammatory profile produced by hypoxia. METHODS: We studied in 17 non-obese and 20 subjects with morbid obesity (MO) the mRNA expression of HIF-1α, SRs (LOX-1, MSR1, CL-P1 and CXCL16), IL6 and TNFα in visceral adipocytes and the effect of hypoxia with or without ox-LDL on visceral in vitro-differentiated adipocytes (VDA). RESULTS: HIF-1α, TNFα, IL6, LOX-1, MSR1 and CXCL16 expression in adipocytes was increased in MO when compared with those in non-obese subjects (p < 0.05). The expression of most of the inflammatory markers and SRs gene correlated with HIF-1α. In VDA, hypoxia increased TNFα, IL6, MSR1, CXCL16 and CL-P1 (p < 0.05) in non-obese subjects, and TNFα, IL6, MSR1 and CXCL16 (p < 0.05) in MO. Silencing HIF-1α prevented the increase of TNFα, IL6, LOX-1, MSR1, CL-P1 and CXCL16 expression (p < 0.05). The combination of hypoxia and ox-LDL produced higher TNFα expression (p = 0.041). CONCLUSIONS: Morbid obesity and hypoxia increased SRs and inflammatory markers in visceral adipocytes. In a hypoxic state, ox-LDL increased the proinflammatory response of visceral adipocytes to hypoxia.

Influence of Factors Altering Gastric Microbiota on Bariatric Surgery Metabolic Outcomes.

Little is known about the influence of gastric microbiota on host metabolism, even though the stomach plays an important role in the production of hormones involved in body weight regulation and glucose homeostasis. Proton pump inhibitors (PPIs) and Helicobacter pylori alter gut microbiota, but their impact on gastric microbiota in patients with obesity and the influence of these factors on the metabolic response to bariatric surgery is not fully understood. Forty-one subjects with morbid obesity who underwent sleeve gastrectomy were included in this study. The H. pylori group was established by the detection of H. pylori using a sequencing-based method (n = 16). Individuals in whom H. pylori was not detected were classified according to PPI treatment. Gastric biopsy specimens were obtained during surgery and were analyzed by a high-throughput-sequencing method. Patients were evaluated at baseline and 3, 6, and 12 months after surgery. ß-Diversity measures were able to cluster patients according to their gastric mucosa-associated microbiota composition. H. pylori and PPI treatment are presented as two important factors for gastric mucosa-associated microbiota. H. pylori reduced diversity, while PPIs altered ß-diversity. Both factors induced changes in the gastric mucosa-associated microbiota composition and its predicted functions. PPI users showed lower percentages of change in the body mass index (BMI) in the short term after surgery, while the H. pylori group showed higher glucose levels and lower percentages of reduction in body weight/BMI 1 year after surgery. PPIs and H. pylori colonization could modify the gastric mucosa-associated microbiota, altering its diversity, composition, and predicted functionality. These factors may have a role in the metabolic evolution of patients undergoing bariatric surgery. IMPORTANCE The gut microbiota has been shown to have an impact on host metabolism. In the stomach, factors like proton pump inhibitor treatment and Helicobacter pylori haven been suggested to alter gut microbiota; however, the influence of these factors on the metabolic response to bariatric surgery has not been fully studied. In this study, we highlight the impact of these factors on the gastric microbiota composition. Moreover, proton pump inhibitor treatment and the presence of Helicobacter pylori could have an influence on bariatric surgery outcomes, mainly on body weight loss and glucose homeostasis. Deciphering the relationship between gastric hormones and gastric microbiota and their contributions to bariatric surgery outcomes paves the way to develop gut manipulation strategies to improve the metabolic success of bariatric surgery.

Genome Profiling of H3k4me3 Histone Modification in Human Adipose Tissue during Obesity and Insulin Resistance.

BACKGROUND: Adipose tissue (AT) dysfunction is involved in obesity-related comorbidities. Epigenetic alterations have been recently associated with AT deterioration in obesity conditions. In this work, we profiled the H3K4me3 histone mark in human AT, with special emphasis on the changes in the pattern of histone modification in obesity and insulin resistance (IR). Visceral AT (VAT) was collected and subjected to chromatin immunoprecipitation (ChIP) using anti-H3K4me3 antibody and then sequenced to obtain the H3K4me3 genome profile. RESULTS: We found that most of the H3K4me3 enriched regions were located in gene promoters of pathways related to AT biology and function. H3K4me3 enrichment at gene promoters was strongly related to higher mRNA levels. Differentially expressed genes in AT of patients classified as non-obese, obese with low IR, and obese with high IR could be regulated by differentially enriched H3K4me3; these genes encoded for pathways that could in part explain AT functioning during obesity and insulin resistance (e.g., extracellular matrix organization, PPARG signaling or inflammation). CONCLUSIONS: In conclusion, we emphasize the importance of the epigenetic mark H3K4me3 in VAT dysfunction in obesity and IR. The understanding of such mechanisms could give rise to the development of new epigenetic-based pharmacological strategies to ameliorate obesity-related comorbidities.

Variables Associated with Short-Term Weight Loss in a Cohort of Patients with Morbid Obesity According to Age and Three Types of Bariatric Surgery.

Background The percentage of excess weight lost (%EWL) after bariatric surgery (BS) shows great discrepancies from one individual to another. Objective To evaluate the %EWL one year after BS and to determine the existence of baseline biomarkers associated with weight loss. Methods We studied 329 patients with morbid obesity undergoing three types of BS (biliopancreatic diversion (BPD), Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG)), depending on the %EWL one year after surgery: good responders (GR) (%EWL≥50%) and non-responders (NR) (%EWL <50%). Results The GR presented a higher percentage of change in anthropometric and biochemical variables compared to the NR group, even within each type of BS. There was a greater percentage of GR among those who underwent RYGB. The patients who underwent SG showed the lowest decrease in biochemical variables, both in GR and NR. Within the GR group, those with a lower age showed greater improvement compared to the other age groups. A %EWL ≥50% was negatively associated with the age and atherogenic index of plasma (AIP), and positively with the type of BS (RYGB). Conclusions The GR group was associated with lower age and AIP and undergoing RYGB. Additionally, those patients who underwent SG showed a lower metabolic improvement.

Incidental Prophylactic Appendectomy Is Associated with a Profound Microbial Dysbiosis in the Long-Term.

Incidental prophylactic surgeries are performed in certain situations. Incidental prophylactic appendectomies were common practice within opened bariatric surgeries. The gut microbiota has emerged as an important actor within the homeostasis of the host. A new hypothesis has been formulated about the appendix function in relation to gut microbiota. Our objective was to study the gut microbiota profiles of patients that had suffered from an incidental prophylactic appendectomy during their bariatric surgeries, while comparing them to patients whose appendixes had remained intact. A case-control observational prospective study of 40 patients who underwent bariatric surgery, with or without an incidental prophylactic appendectomy, during 2004-2008 with an evaluation of their gut microbiota populations at the end of 2016 was conducted by sequencing the 16 S rRNA gene by Next Generation Sequencing of patients' stools and appendix tissues. Patients with their appendix removed showed lower levels of richness and diversity of their gut microbiota populations. Odoribacter, Bilophila, Butyricimonas, and Faecalibacterium levels were increased in the Intact group, while Lachnobacterium suffered an expansion in the group without the appendix. Moreover, a linear regression model introduced the concept that Butyricimonas and Odoribacter may be implicated in insulin regulation. Thus, gut microbiota should be considered in the decisions of practical surgery, regarding the appendix as a mediator of homeostasis in the host. Butyricimonas and Odoribacter require further investigation as key bacteria implicated in insulin regulation.

Oxidized LDL Modify the Human Adipocyte Phenotype to an Insulin Resistant, Proinflamatory and Proapoptotic Profile.

Little information exists in humans on the regulation that oxidized low-density lipoprotein (oxLDL) exerts on adipocyte metabolism, which is associated with obesity and type 2 diabetes. The aim was to analyze the oxLDL effects on adipocytokine secretion and scavenger receptors (SRs) and cell death markers in human visceral adipocytes. Human differentiated adipocytes from visceral adipose tissue from non-obese and morbidly obese subjects were incubated with increasing oxLDL concentrations. mRNA expression of SRs, markers of apoptosis and autophagy, secretion of adipocytokines, and glucose uptake were analyzed. In non-obese and in morbidly obese subjects, oxLDL produced a decrease in insulin-induced glucose uptake, a significant dose-dependent increase in tumor necrosis factor-α (TNF-α), IL-6, and adiponectin secretion, and a decrease in leptin secretion. OxLDL produced a significant increase of Lox-1 and a decrease in Cxcl16 and Cl-p1 expression. The expression of Bnip3 (marker of apoptosis, necrosis and autophagy) was significantly increased and Bcl2 (antiapoptotic marker) was decreased. OxLDL could sensitize adipocytes to a lower insulin-induced glucose uptake, a more proinflammatory phenotype, and could modify the gene expression involved in apoptosis, autophagy, necrosis, and mitophagy. OxLDL can upregulate Lox-1, and this could lead to a possible amplification of proinflammatory and proapoptotic effects of oxLDL.

Change in serum polyamine metabolome pattern after bariatric surgery in obese patients with metabolic syndrome.

BACKGROUND: Recent works have reported that bariatric surgery has remarkable effects on the metabolome, which might be potentially associated to the metabolic improvement of this procedure in patients with obesity. Serum polyamines, metabolites derived from amino acid metabolism, have been recently related to the metabolic status in obese individuals. However, the impact of bariatric surgery on the circulating levels of polyamines remains elusive. OBJECTIVE: To evaluate the effect of bariatric surgery on serum polyamine levels and to evaluate the association of changes in these molecules with metabolic improvement in patients with morbid obesity. SETTING: Virgen de la Victoria University Hospital, Malaga, Spain. METHODS: This study included 32 morbidly obese patients (weight index ≥40 kg/m2) with metabolic syndrome, who underwent sleeve gastrectomy. Serum levels of polyamines (putrescine, spermidine, and spermine), acetylpolyamines, and polyamine-related amino acids (arginine and ornithine) were assessed at baseline and 6 months after bariatric surgery, and were analyzed in an ultraperformance liquid chromatography-mass spectrometry platform. RESULTS: Our metabolomic analysis revealed a significant rise in several metabolites related to the polyamine metabolism, such as putrescine and acetyl derivatives of spermidine and spermine in serum samples from morbidly obese patients after bariatric surgery. Changes in serum levels of both putrescine and acetylputrescine were associated to the resolution of metabolic syndrome after surgery. CONCLUSION: Our study indicates that bariatric surgery affects the serum polyamine pattern and the resolution of metabolic syndrome after bariatric surgery is associated to specific changes in the serum polyamine metabolome.

Altered Adipose Tissue DNA Methylation Status in Metabolic Syndrome: Relationships Between Global DNA Methylation and Specific Methylation at Adipogenic, Lipid Metabolism and Inflammatory Candidate Genes and Metabolic Variables.

Metabolic syndrome (MetS) has been postulated to increase the risk for type 2 diabetes, cardiovascular disease and cancer. Adipose tissue (AT) plays an important role in metabolic homeostasis, and AT dysfunction has an active role in metabolic diseases. MetS is closely related to lifestyle and environmental factors. Epigenetics has emerged as an interesting landscape to evaluate the possible interconnection between AT and metabolic disease, since it can be modulated by environmental factors and metabolic status. The aim of this study was to determine whether MetS has an impact on the global DNA methylation pattern and the DNA methylation of several genes related to adipogenesis (PPARG, PPARA), lipid metabolism (RXRA, SREBF2, SREBF1, SCD, LPL, LXRb), and inflammation (LRP1 C3, LEP and TNF) in visceral adipose tissue. LPL and TNF DNA methylation values were significantly different in the control-case comparisons, with higher and lower methylation respectively in the MetS group. Negative correlations were found between global DNA methylation (measured by LINE-1 methylation levels) and the metabolic deterioration and glucose levels. There were associations among variables of MetS, BMI, and HOMA-IR with DNA methylation at several CpG positions for the studied genes. In particular, there was a strong positive association between serum triglyceride levels (TG) with PPARA and LPL methylation levels. TNF methylation was negatively associated with the metabolic worsening and could be an important factor in preventing MetS occurrence according to logistic regression analysis. Therefore, global DNA methylation and methylation at specific genes related to adipogenesis, lipid metabolism and inflammation are related to the etiology of MetS and might explain in part some of the features associated to metabolic disorders.

A Pilot Study of Serum Sphingomyelin Dynamics in Subjects with Severe Obesity and Non-alcoholic Steatohepatitis after Sleeve Gastrectomy.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is present in a high percentage of obese patients undergoing bariatric surgery. A significant proportion of patients still present NASH even after considerable weight loss and metabolic improvements after surgery. OBJECTIVE: To determine whether the changes in the serum lipidome after sleeve gastrectomy could be used to discriminate obese patients with NASH patients to those with non-alcoholic fatty liver (NAFL). METHODS: This study involved 24 patients with grade 3 obesity diagnosed with either NAFL (n = 8) or NASH (n = 16) using the non-invasive OWLiver assay. All patients suffering from NASH were re-evaluated 6 months after bariatric surgery using the OWLiver test to confirm NASH resolution. Serum lipid extracts were assessed at baseline and 6 months post surgery and were analyzed in an ultra-performance liquid chromatography/time-of-flight mass spectrometry (UPLC-TOF-MS)-based platform. RESULTS: Lipidomic analysis revealed a differential sphingomyelin profile in patients with NASH resolution after sleeve gastrectomy. Certain serum sphingomyelin species were significantly higher at baseline in NASH patients in comparison to those with NAFL. Sphingomyelin profile of subjects with NASH resolution was similar to that for obese subjects with NAFL before bariatric surgery. CONCLUSION: Our study indicates that the serum sphingomyelin levels could be related to the status of non-alcoholic fatty liver disease and that certain sphingomyelin species may be used for the follow-up of obese patients with NASH after sleeve gastrectomy.

Ghrelin levels could be involved in the improvement of insulin resistance after bariatric surgery / Los niveles de Ghrelina podrían estar implicados en la mejora de la resistencia a la insulina después de la cirugía bariátrica

Background and objective: Ghrelin is a gastrointestinal peptide involved in regulation of body weight and energy balance. However, its behavior after bariatric surgery and its relationship to insulin resistance are still controversial. A simultaneous assessment was made of the association between changes in ghrelin levels and different variables after three types of bariatric surgery. Patients and methods: Ghrelin levels were measured in 103 morbidly obese subjects before and 6 months after bariatric surgery (Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion of Scopinaro (BPD), and sleeve gastrectomy (SG)), and in 21 non-obese subjects. Results: Ghrelin levels increased after RYGB (p<0.05), were unchanged after BPD, and decreased after SG (p<0.05). The percent change in ghrelin levels (Δ-ghrelin) was associated to the type of surgery in a multiple linear regression model (p=0.017). When the same analysis was only performed in subjects in whom the gastric fundus was maintained (RYGB and BPD), Δ-ghrelin was negatively associated to Δ-HOMA-IR (p=0.001). In morbidly obese subjects who underwent RYGB and BPD, the odds ratio of a lower Δ-HOMA-IR in patients with Δ-ghrelin in the Q1 quartile versus those with Δ-ghrelin in the Q4 quartile was 8.74 (1.73-44.06) (p=0.009). Conclusions: Changes in ghrelin levels after bariatric surgery are associated to the presence or absence of the gastric fundus. After bariatric surgery, the decrease in insulin resistance was associated to increased ghrelin levels in procedures in which the fundus is not excluded (AU)

Antecedentes y objetivo: La ghrelina es un péptido gastrointestinal que interviene en la regulación del peso corporal y del equilibrio energético. Sin embargo, su comportamiento después de la cirugía bariátrica y su relación con la resistencia a la insulina todavía está en discusión. Nosotros hemos realizado una evaluación simultánea de la asociación entre los cambios en los niveles de ghrelina y diferentes variables después de tres tipos de cirugía bariátrica. Pacientes y métodos: Se analizaron los niveles de ghrelina en 103 obesos mórbidos, antes y 6 meses después de la cirugía bariátrica (baipás gástrico en Y de Roux [RYGB], derivación biliopancreática de Scopinaro [BPD] y gastrectomía tubular), y en 21 sujetos no obesos. Resultados: La ghrelina sérica aumentó tras el RYGB (p<0,05), no se modificó tras la BPD y disminuyó tras gastrectomía tubular (p<0,05). El porcentaje de cambio en los niveles de ghrelina (Δ-ghrelina) se asoció con el tipo de cirugía en un modelo de regresión lineal múltiple (p=0,017). Cuando se realizó el mismo análisis solo con aquellos sujetos en los que se mantiene el fundus gástrico (RYGB y BPD), Δ-ghrelina se asoció negativamente con el Δ-HOMA-IR (p=0,001). En los sujetos obesos mórbidos sometidos a RYGB y BPD, la odss ratio de tener un Δ-HOMA-IR más bajo de las personas con Δ-ghrelina en el cuartil Q1 frente a aquellos con Δ-ghrelina en el cuartil Q4 fue de 8,74 (1,73-44,06) (p=0,009). Conclusiones: Los cambios en los niveles de ghrelina después de la cirugía bariátrica están asociados con la presencia/ausencia del fundus gástrico. Después de la cirugía bariátrica, la disminución de la resistencia a la insulina se asoció con el aumento de los niveles de ghrelina en aquellas técnicas en las que el fundus no está excluido (AU)

Ghrelin levels could be involved in the improvement of insulin resistance after bariatric surgery.

BACKGROUND AND OBJECTIVE: Ghrelin is a gastrointestinal peptide involved in regulation of body weight and energy balance. However, its behavior after bariatric surgery and its relationship to insulin resistance are still controversial. A simultaneous assessment was made of the association between changes in ghrelin levels and different variables after three types of bariatric surgery. PATIENTS AND METHODS: Ghrelin levels were measured in 103 morbidly obese subjects before and 6 months after bariatric surgery (Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion of Scopinaro (BPD), and sleeve gastrectomy (SG)), and in 21 non-obese subjects. RESULTS: Ghrelin levels increased after RYGB (p<0.05), were unchanged after BPD, and decreased after SG (p<0.05). The percent change in ghrelin levels (Δ-ghrelin) was associated to the type of surgery in a multiple linear regression model (p=0.017). When the same analysis was only performed in subjects in whom the gastric fundus was maintained (RYGB and BPD), Δ-ghrelin was negatively associated to Δ-HOMA-IR (p=0.001). In morbidly obese subjects who underwent RYGB and BPD, the odds ratio of a lower Δ-HOMA-IR in patients with Δ-ghrelin in the Q1 quartile versus those with Δ-ghrelin in the Q4 quartile was 8.74 (1.73-44.06) (p=0.009). CONCLUSIONS: Changes in ghrelin levels after bariatric surgery are associated to the presence or absence of the gastric fundus. After bariatric surgery, the decrease in insulin resistance was associated to increased ghrelin levels in procedures in which the fundus is not excluded.

Hypoxia is associated with a lower expression of genes involved in lipogenesis in visceral adipose tissue.

BACKGROUND: A key role for HIF-1α in the promotion and maintenance of dietary obesity has been proposed. We analyzed the association between hypoxia and de novo lipogenesis in human adipose tissue. METHODS: We studied HIF-1α mRNA and protein expression in fasting status in visceral adipose tissue (VAT) from non-obese and morbidly obese subjects, and in VAT from wild-type and ob/ob C57BL6J mice in both fasting and feeding status. We also analyzed the effect of hypoxia on the VAT mRNA expression of genes involved in lipogenesis. RESULTS: HIF-1α was increased in VAT from morbidly obese subjects. In fasting status, C57BL6J ob/ob mice had a higher VAT HIF-1α mRNA expression than C57BL6J wild-type mice. In feeding status, VAT HIF-1α mRNA expression significantly increased in C57BL6J wild-type, but not in C57BL6J ob/ob mice. In humans, HIF-1α mRNA expression correlated positively with body mass index and insulin resistance. VAT HIF-1α mRNA expression correlated negatively with ACC1, PDHB and SIRT3 mRNA expression, and positively with PPAR-γ. VAT explants incubated in hypoxia showed reduced SIRT3 and increased PPAR-γ, SREBP-1c, ACLY, ACC1 and FASN mRNA expression. CONCLUSIONS: Morbidly obese subjects have a higher level of VAT HIF-1α. Postprandial status is associated with an increase in HIF-1α mRNA expression in C57BL6J wild-type mice. Hypoxia alters the mRNA expression of genes involved in de novo lipogenesis in human VAT.

Lipopolysaccharide and lipopolysaccharide-binding protein levels and their relationship to early metabolic improvement after bariatric surgery.

BACKGROUND: Bariatric surgery usually results in metabolic improvements within a few days from intervention, but the underlying mechanism is not completely understood and may vary depending on the bariatric procedure. Lipopolysaccharides (LPS) from gut microbiota have been proposed as a triggering factor for the inflammatory state in obesity. Roux-en-Y Gastric Bypass (RYGB) leads to a LPS decrease in the medium-term. OBJECTIVE: To analyze LPS and LPS-binding protein (LBP) in normoglycemic (NG) and diabetic morbidly obese patients in the short-term after 2 different bariatric surgery procedures. SETTING: University Hospital, Spain. METHODS: Fifty morbidly obese patients underwent bariatric surgery: 24 with sleeve gastrectomy (SG) and 26 with biliopancreatic diversion (BPD). Patients were classified according to their glycemic status as NG or prediabetic/diabetic. LPS and LBP levels and biochemical and anthropometric variables were determined before and at days 15 and 90 after surgery. RESULTS: A significant LPS reduction was seen only in the prediabetic/diabetic patients at 90 days after SG. LBP levels rose at 15 days after BPD but at 90 days returned to baseline in both NG and prediabetic/diabetic patients. At 90 days after SG, LBP levels significantly decreased compared to baseline in NG and prediabetic/diabetic patients. After multivariate analysis only the change in BMI was independently associated with the change in LBP levels at 90 days. None of the changes in biochemical or anthropometrical variables were significantly associated with the changes in LPS levels at 15 days or 90 days. CONCLUSION: This is the first study showing that the short-term LPS decrease after bariatric surgery depends on the surgical procedure used as well as on the previous glycemic status of the patient, with SG having the greatest short-term effect on LPS and LBP levels. LBP is closely related to anthropometric variables and may be an inflammatory marker in bariatric surgery patients.