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

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

Anatomical distribution of primary amine oxidase activity in four adipose depots and plasma of severely obese women with or without a dysmetabolic profile

Semicarbazide-sensitive amine oxidase (SSAO), identical to primary amine oxidase or vascular adhesion protein-1, is a membrane enzyme that generates hydrogen peroxide. SSAO is highly expressed at the adipocyte surface, and its plasma levels increase with type 2 diabetes. Since visceral adipose tissue (AT) is more tightly associated with obesity complications than subcutaneous (SC) abdominal fat, we compared SSAO activity in plasma and 4 distinct AT locations in 48 severely obese women (body mass index (BMI), averaging 54 ± 11 kg/m2), with or without a dysmetabolic profile. Higher glucose and triacylglycerol levels vs lower high-density lipoprotein (HDL)-cholesterol characterized dysmetabolic women (DYS; n = 25) from non-dysmetabolic (NDYS; n = 23), age- and weight-matched subjects. SC, mesenteric (ME), omental (OM), and round ligament (RL) fat locations were collected during bariatric surgery. SSAO capacity to oxidize up to 1 mM benzylamine was determined in AT and plasma with radiometric and fluorimetric methods. Plasma SSAO was higher in the DYS group. SSAO activity was higher in fat than in plasma, when expressed as radiolabeled benzaldehyde per milligram of protein. In ATs from DYS women, protein content was 10 % higher, and basal hydrogen peroxide release lower than in NDYS subjects, except for RL location. The SSAO affinity towards benzylamine did not exhibit regional variation and was not altered by a dysmetabolic profile (K m averaging 184 ± 7 μM; n = 183). Although radiometric and fluorimetric methods gave different estimates of oxidase activity, both indicated that AT SSAO activity did not vary according to anatomical location and/or metabolic status in severely obese women

Pregnancy after Bariatric Surgery: Balancing Risks and Benefits.

The majority of bariatric surgeries in Canada are performed in women of reproductive age. Clinicians encounter more and more often pregnancies that occur after bariatric surgeries. The appropriate management and education of women who want to conceive after bariatric surgery is still unclear due to the lack of consistent data about maternal and neonatal outcomes following bariatric surgery. Maternal obesity during pregnancy confers a higher risk for gestational diabetes, hypertensive disorders, congenital malformations, prematurity and perinatal mortality. Generally, pregnancies in severely obese women who have undergone bariatric surgery are safe, and the women are at significantly lower risk for gestational diabetes, hypertensive disorders and large-for-gestational-age neonates, but the surgery confers a higher risk for small-for-gestational-age infants and prematurity. This review aims to provide evidence from recent publications about the risks and benefits of bariatric surgeries in the context of future pregnancies.

Anatomical distribution of primary amine oxidase activity in four adipose depots and plasma of severely obese women with or without a dysmetabolic profile.

Semicarbazide-sensitive amine oxidase (SSAO), identical to primary amine oxidase or vascular adhesion protein-1, is a membrane enzyme that generates hydrogen peroxide. SSAO is highly expressed at the adipocyte surface, and its plasma levels increase with type 2 diabetes. Since visceral adipose tissue (AT) is more tightly associated with obesity complications than subcutaneous (SC) abdominal fat, we compared SSAO activity in plasma and 4 distinct AT locations in 48 severely obese women (body mass index (BMI), averaging 54 ± 11 kg/m2), with or without a dysmetabolic profile. Higher glucose and triacylglycerol levels vs lower high-density lipoprotein (HDL)-cholesterol characterized dysmetabolic women (DYS; n = 25) from non-dysmetabolic (NDYS; n = 23), age- and weight-matched subjects. SC, mesenteric (ME), omental (OM), and round ligament (RL) fat locations were collected during bariatric surgery. SSAO capacity to oxidize up to 1 mM benzylamine was determined in AT and plasma with radiometric and fluorimetric methods. Plasma SSAO was higher in the DYS group. SSAO activity was higher in fat than in plasma, when expressed as radiolabeled benzaldehyde per milligram of protein. In ATs from DYS women, protein content was 10 % higher, and basal hydrogen peroxide release lower than in NDYS subjects, except for RL location. The SSAO affinity towards benzylamine did not exhibit regional variation and was not altered by a dysmetabolic profile (K m averaging 184 ± 7 µM; n = 183). Although radiometric and fluorimetric methods gave different estimates of oxidase activity, both indicated that AT SSAO activity did not vary according to anatomical location and/or metabolic status in severely obese women.

Methylation quantitative trait loci within the TOMM20 gene are associated with metabolic syndrome-related lipid alterations in severely obese subjects.

BACKGROUND: The TOMM20 gene was previously identified as differentially expressed and methylated between severely obese subjects with and without metabolic syndrome (MS). Since metabolic complications do not affect all obese patients to the same extent, the aim of this study was to identify methylation quantitative trait loci (meQTL) potentially associated with MS-related complications within the TOMM20 locus. METHODS: Methylation profiling, SNP genotyping and meQTL association tests (general linear models) were performed in a population of 48 severely obese subjects. Genotyping was extended to a larger population of 1720 severely obese subjects with or without MS, where genotype- and diplotype-based association tests were assessed by logistic regression. In silico analyses were performed using TRAP. RESULTS: Four SNPs were identified as significant meQTLs for the differentially methylated site cg16490124. Individuals carrying rare alleles of rs4567344 (A > G) (P = 4.9 × 10(-2)) and rs11301 (T > C) (P = 5.9 × 10(-3)) showed decreased methylation levels at this site, whereas those carrying rare alleles of rs4551650 (T > C) (P = 3.5 × 10(-15)) and rs17523127 (C > G) (P = 3.5 × 10(-15)) exhibited a significant increase in methylation. rs4567344 and rs11301 were associated with increased susceptibility to exhibit high plasma triglycerides (TG ≥ 1.69 mmol/L), while rare alleles of rs4551650 and rs17523127 were significantly more represented in the low plasma total-C group (total-C ≤ 6.2 mmol/L). Haplotype reconstruction with the four meQTLs (rs4567344, rs11301, rs4551650, rs17523127) led to the identification of ten different diplotypes, with H1/H2 (GCGG/ACGG) exhibiting a nearly absence of methylation at cg16490124, and showing the highest risk of elevated plasma TG levels [OR = 2.03 (1.59-3.59)], a novel association with elevated LDL-cholesterol [OR = 1.86 (1.06-3.27)] and the complete inversion of the protective effect on total-C levels [OR = 2.03 (1.59-3.59)], especially in men. In silico analyses revealed that rs17523127 overlapped the CpG site cg16490124 and encompassed the core binding sites of the transcription factors Egr 1, 2 and 3, located within the TOMM20 promoter region. CONCLUSION: This study demonstrates that TOMM20 SNPs associated with MS-related lipid alterations are meQTLs potentially exerting their action through a CpG methylation-dependent effect. The strength of the diplotype-based associations may denote a novel meQTL additive action and point to this locus as particularly relevant in the inter-individual variability observed in the metabolic profiles of obese subjects.

Piceatannol and resveratrol share inhibitory effects on hydrogen peroxide release, monoamine oxidase and lipogenic activities in adipose tissue, but differ in their antilipolytic properties.

Piceatannol is a hydroxylated derivative of resveratrol. While both dietary polyphenols coexist in edible plants and fruits, and share equivalent concentrations in several wines, the influence of piceatannol on adiposity has been less studied than that of resveratrol. Though resveratrol is now recognized to limit fat deposition in various obesity models, the benefit of its dietary supplementation remains under debate regarding human obesity treatment or prevention. The research for more potent resveratrol analogs is therefore still undergoing. This prompted us to compare various effects of piceatannol and resveratrol directly on human adipose tissue (hAT). Hydrogen peroxide release was measured by Amplex Red-based fluorescence in subcutaneous hAT samples from obese patients. Interactions of stilbenes with human amine oxidases and quinone reductase were assessed by radiometric methods, computational docking and electron paramagnetic resonance. Influences on lipogenic and lipolytic activities were compared in mouse adipocytes. Resveratrol and piceatannol inhibited monoamine oxidase (MAO) with respective IC50 of 18.5 and 133.7 µM, but not semicarbazide-sensitive amine oxidase (SSAO) in hAT. For both stilbenes, the docking scores were better for MAO than for SSAO. Piceatannol and resveratrol similarly hampered hydrogen peroxide detection in assays with and without hAT, while they shared pro-oxidant activities when incubated with purified quinone reductase. They exhibited similar dose-dependent inhibition of adipocyte lipogenic activity. Only piceatannol inhibited basal and stimulated lipolysis when incubated at a dose ≥100 µM. Thus, piceatannol exerted on fat cells dose-dependent effects similar to those of resveratrol, except for a stronger antilipolytic action. In this regard, piceatannol should be useful in limiting the lipotoxicity related to obesity when ingested or administered alone - or might hamper the fat mobilization induced by resveratrol when simultaneously administered with it.

Characterization of dedifferentiating human mature adipocytes from the visceral and subcutaneous fat compartments: fibroblast-activation protein alpha and dipeptidyl peptidase 4 as major components of matrix remodeling.

Mature adipocytes can reverse their phenotype to become fibroblast-like cells. This is achieved by ceiling culture and the resulting cells, called dedifferentiated fat (DFAT) cells, are multipotent. Beyond the potential value of these cells for regenerative medicine, the dedifferentiation process itself raises many questions about cellular plasticity and the pathways implicated in cell behavior. This work has been performed with the objective of obtaining new information on adipocyte dedifferentiation, especially pertaining to new targets that may be involved in cellular fate changes. To do so, omental and subcutaneous mature adipocytes sampled from severely obese subjects have been dedifferentiated by ceiling culture. An experimental design with various time points along the dedifferentiation process has been utilized to better understand this process. Cell size, gene and protein expression as well as cytokine secretion were investigated. Il-6, IL-8, SerpinE1 and VEGF secretion were increased during dedifferentiation, whereas MIF-1 secretion was transiently increased. A marked decrease in expression of mature adipocyte transcripts (PPARγ2, C/EBPα, LPL and Adiponectin) was detected early in the process. In addition, some matrix remodeling transcripts (FAP, DPP4, MMP1 and TGFß1) were rapidly and strongly up-regulated. FAP and DPP4 proteins were simultaneously induced in dedifferentiating mature adipocytes supporting a potential role for these enzymes in adipose tissue remodeling and cell plasticity.

Long-Term Metabolic Outcomes 5 to 20 Years After Biliopancreatic Diversion.

BACKGROUND: Biliopancreatic diversion (BPD) is a complex bariatric operation requiring meticulous surveillance which has impeded its broad adoption. Improvements in surgical care and technique, better teaching programs, and stringent norms for follow-up have contributed to increased safety of BPD for patients with BMI <50, achieving better long-term results than other bariatric operations. Here we report 20-year outcomes of 2615 consecutive patients (median 8) having open BPD with duodenal switch (DS) between 1992 and 2010. METHODS: Chart of 92 % of patients with complete clinical, biochemical, and physical examinations completed before 2013 was reviewed. The research was conducted at Academic Medical Center, Quebec City. RESULTS: There was total mortality of 4.7 %, equivalent to that of the general population of Quebec. Incident diabetes (38.8 %) was cured in 93.4 % (blood glucose <6 mmol/l; HbA1c <6.5 %) with 4 % relapse rate after mean 9.6 years with no new cases. Dyslipidemia (24.2 %) was cured in 80 %. Hypertension (60 %) was cured in 64 % and improved in 31 %. Mean weight loss of 55.3 kg (71 % excess weight loss (EWL); 20 BMI units) was maintained for 5 to 20 years. Operative mortality was reduced from 1.3 % in 1992 to 0.2 % during 2005-2010, with cumulated rate surgical mortality of 0.5, revision rate 3, and reoperations in 13 %. Nutritional deficiencies were present in 2 % for calcium, iron, and vitamin A. Side effects were considered minor by the great majority of patients, rating global satisfaction as 4.5/5 (91 % "satisfied"). CONCLUSIONS: BPD deserves more consideration as a primary procedure for eligible patients in experienced centers with sufficient resources for delivering high-quality care and long-term follow-up.

Influences of gestational obesity on associations between genotypes and gene expression levels in offspring following maternal gastrointestinal bypass surgery for obesity.

METHODS: Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis. RESULTS: Significant interactions (p ≤ 1.22 x 10(-12)) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways. CONCLUSION: We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism.

Cross-sectional associations of acylation stimulating protein (ASP) and adipose tissue gene expression with estradiol and progesterone in pre- and postmenopausal women.

OBJECTIVE: Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP). DESIGN, PATIENTS AND MEASUREMENTS: In 392 women with wide age (18-69 years) and body size (BMI: 17 to 90 kg/m(2) ) ranges, fasting plasma levels of ASP, ovarian hormones, glucose, adiponectin and lipids/apolipoproteins were assessed, along with determination of metabolic syndrome (MS) features. Gene expression of C3 (ASP precursor) and related receptors C5L2, C3aR and C5aR in subcutaneous and omental adipose tissues was measured in a subset. RESULTS: Acylation stimulating protein correlated negatively with concentrations of estradiol (P < 0·0001), adiponectin (P < 0·001) and apolipoprotein A1 (P < 0·001) and positively with apolipoprotein B levels (P < 0·001), systolic blood pressure (P < 0·001), waist circumference (P < 0·001), and triglyceride concentrations (P < 0·01). In age-matched groups of lean, overweight, metabolically healthy obese (MHO) and obese with metabolic syndrome (MSO), there was a stepwise increase in ASP levels (P < 0·001) while concentrations of adiponectin (P < 0·0001) and estradiol (P < 0·001) but not those of progesterone decreased. Progesterone but not estradiol levels correlated positively with C3 gene expression in omental adipose tissue (P < 0·05) and negatively with C5L2 expression in both omental (P < 0·01) and subcutaneous (P < 0·05) adipose tissues. CONCLUSION: Our results are consistent with the concept that sex hormones differentially influence circulating ASP and adipose tissue gene expression of its related proteins in a depot-specific manner. ASP may play a role in the regulation of regional fat metabolism through interactions with sex hormones in women.

Biliopancreatic diversion-duodenal switch: independent contributions of sleeve resection and duodenal exclusion.

BACKGROUND: The choice of first-stage operation in bilio-pancreatic diversion with duodenal switch (BPD-DS) is controversial. There are no published long-term comparisons of one- and two-stage BPD-DS outcomes. METHODS: During 2001-2009, among 1,762 patients scheduled for BPD-DS 48 had duodenal switch (DS) and 53 sleeve gastrectomy (SG) as first-stage procedures. We compared prospectively updated outcomes of 42 DS (100 % open) and 49 SG (88 % laparoscopic), 13 of whom completed their second stage, to a control group of 91 patients with open one-stage BPD-DS. RESULTS: One-year mean percent excess weight loss (%EWL) was greater after SG than DS (47 ± 19 vs. 39 ± 13 SD; p = 0.01) with earlier nadir (16 ± 10 vs. 45 ± 30 months; p < 0.0001) but more rapid significant weight regain. After 5 years, %EWL was 12 ± 35 for 9 SG, 45 ± 19 for 30 DS (p < 0.0006), and 70 ± 18 for the first-stage BPD-DS (p < 0.0001). Weight loss was less after two- than one-stage procedures (p < 0.02). Comorbidities improved progressively between SG, DS and BPD-DS (p < 0.001 for trend). HbA1C decreased by 10, 19, and 31 %, respectively (p < 0.0001). Dyslipidemia was cured in 41, 82, and 100 %, respectively. Systolic and diastolic blood pressure decreased only after DS (12 %; p < 0.0002). Patient satisfaction was similar for SG and DS but greater after BPD-DS overall (p = 0.04). CONCLUSIONS: SG and DS independently contribute to beneficial metabolic outcomes after BPD-DS. Long-term weight loss and correction of metabolic abnormalities were better after DS favoring its use as first stage in BPD-DS; one-stage BPD-DS outcomes were superior to two-staged.

Complement receptors C5aR and C5L2 are associated with metabolic profile, sex hormones, and liver enzymes in obese women pre- and postbariatric surgery.

OBJECTIVE: Obesity is associated with metabolic dysfunction with sex differences and chronic, low-grade inflammation.We proposed that hepatic expression of immune complement C3 related receptors (C3aR, C5aR, and C5L2) would be associated with pre- or postmenopausal status and metabolic profile in severely obese women. We hypothesized that C5L2/C5aR ratio, potentially influencing the ASP/C5L2 metabolic versus C5a/C5aR immune response, would predict metabolic profiles after weight loss surgery. MATERIALS AND METHODS: Fasting plasma (hormone, lipid, and enzyme analysis) and liver biopsies (RT-PCR gene expression) were obtained from 91 women during surgery. RESULTS: Hepatic C5L2 mRNA expression was elevated in pre- versus postmenopausal women (P < 0.01) and correlated positively with circulating estradiol, estrone, ApoB, ApoA1, ApoA1/B, waist circumference, age, and LDL-C (all P < 0.05).While plasma ASP was lower in pre- versus postmenopausal women (P < 0.01), the hepatic C5L2/C5aR mRNA ratio was increased (P < 0.001) and correlated positively with estrone (P < 0.01) and estradiol (P < 0.001) and negatively with circulating ApoB and liver enzymes ALT, AST, and GGT (all P < 0.05). Over 12 months postoperatively, liver enzymes in low C5L2/C5aR mRNA ratio group remained higher (ALP and ALT, P < 0.05, AST and GGT, P < 0.001 2-way-ANOVA). CONCLUSION: C5L2-C5aR association with other mediators including estrogens may contribute to hepatic metabolic and inflammatory function.

Cross-tissue comparisons of leptin and adiponectin: DNA methylation profiles.

DNA methylation has been mostly studied in circulating blood cells. Although being readily accessible, metabolically active tissues such as adipose tissue would be more informative for the study of metabolic disorders. However, whether or not the blood DNA methylation profile correlates with that of adipose tissue remains unknown. In this study, DNA methylation patterns of variation at LEP and ADIPOQ gene loci were similar between individual CpGs across the different tissues. We also report that DNA methylation levels at biologically relevant CpGs are correlated between blood, subcutaneous, and visceral adipose tissue, and that these nearby CpGs are associated with LEP and ADIPOQ gene expression in adipose tissues. These results will be highly relevant for future epigenetic studies in metabolic disorders.

Downregulation of complement C3 and C3aR expression in subcutaneous adipose tissue in obese women.

BACKGROUND: The central component of the complement system, C3, is associated with obesity, metabolic syndrome and cardiovascular disease however the underlying reasons are unknown. In the present study we evaluated gene expression of C3, the cleavage product C3a/C3adesArg and its cognate receptor C3aR in subcutaneous and omental adipose tissue in women. METHODS: Women (n = 140, 21-69 years, BMI 19.5-79 kg/m2) were evaluated for anthropometric and blood parameters, and adipose tissue gene expression. RESULTS: Subjects were separated into groups (n = 34-36) according to obesity: normal/overweight (≤30 kg/m2), obese I (≤45 kg/m2), obese II (≤51 kg/m2), and obese III (≤80 kg/m2). Overall, while omental expression remained unchanged, subcutaneous C3 and C3aR gene expression decreased with increasing adiposity (2-way ANOVA, p<0.01), with a concomitant decrease in SC/OM ratio (p<0.001). In subcutaneous adipose, both C3 and C3aR expression correlated with apoB, and apoA1 and inversely with waist circumference and blood pressure, while C3aR also correlated with glucose (p<0.05-0.0001). While omental C3aR expression did not correlate with any factor, omental C3 correlated with waist circumference, glucose and apoB (all p<0.05). Further, while plasma C3a/C3adesArg increased and adiponectin decreased with increasing BMI, both correlated (C3a negatively and adiponectin positively) with subcutaneous C3 and C3aR expression (p<0.05-0.001) or less). CONCLUSIONS: The obesity-induced down-regulation of complement C3 and C3aR which is specific to subcutaneous adipose tissue, coupled to the strong correlations with multiple anthropometric, plasma and adipokine variables support a potential role for complement in immunometabolism.

Prostaglandin (PG) F2 alpha synthesis in human subcutaneous and omental adipose tissue: modulation by inflammatory cytokines and role of the human aldose reductase AKR1B1.

INTRODUCTION: PGF2α may be involved in the regulation of adipose tissue function. OBJECTIVES: 1) To examine PGF2α release by primary preadipocytes, mature adipocytes and whole tissue explants from the subcutaneous and omental fat compartments; 2) To assess which PGF synthase is the most relevant in human adipose tissue. METHODS: Fat samples were obtained by surgery in women. PGF2α release by preadipocytes, adipocytes and explants under stimulation by TNF-α, IL-1ß or both was measured. Messenger RNA expression levels of AKR1B1 and AKR1C3 were measured by RT-PCR in whole adipose tissue and cytokine-treated preadipocytes. The effect of AKR1B1 inhibitor ponalrestat on PGF2α synthesis was investigated. RESULTS: PGF2α release was significantly induced in response to cytokines compared to control in omental (p = 0.01) and to a lesser extent in subcutaneous preadipocytes (p = 0.02). Messenger RNA of COX-2 was significantly higher in omental compared to subcutaneous preadipocytes in response to combined TNF-α and IL-1ß (p = 0.01). Inflammatory cytokines increased AKR1B1 mRNA expression and protein levels (p≤0.05), but failed to increase expression levels of AKR1C3 in cultured preadipocytes. Accordingly, ponalrestat blunted PGF2α synthesis by preadipocytes in basal and stimulated conditions (p≤0.05). Women with the highest PGF2α release by omental adipocytes had a higher BMI (p = 0.05), waist circumference (p≤0.05) and HOMAir index (p≤0.005) as well as higher mRNA expression of AKR1B1 in omental (p<0.10) and subcutaneous (p≤0.05) adipose tissue compared to women with low omental adipocytes PGF2α release. Positive correlations were observed between mRNA expression of AKR1B1 in both compartments and BMI, waist circumference as well as HOMAir index (p≤0.05 for all). CONCLUSION: PGF2α release by omental mature adipocytes is increased in abdominally obese women. Moreover, COX-2 expression and PGF2α release is particularly responsive to inflammatory stimulation in omental preadipocytes. Yet, blockade of PGF synthase AKR1B1 inhibits most of the PGF2α release.

Association of immune and metabolic receptors C5aR and C5L2 with adiposity in women.

Adipose tissue receptors C5aR and C5L2 and their heterodimerization/functionality and interaction with ligands C5a and acylation stimulating protein (ASP) have been evaluated in cell and rodent studies. Their contribution to obesity factors in humans remains unclear. We hypothesized that C5a receptors, classically required for host defense, are also associated with adiposity. Anthropometry and fasting blood parameters were measured in 136 women divided by body mass index (BMI): normal/overweight (≤30 kg/m(2); n = 34), obese I (≤45 kg/m(2); n = 33), obese II (≤51 kg/m(2); n = 33), and obese III (≤80 kg/m(2); n = 36). Subcutaneous and omental adipose tissue C5aR and C5L2 expression were analysed. C5L2 expression was comparable between subcutaneous and omental across all BMI groups. Plasma ASP and ASP/omental C5L2 expression increased with BMI (P < 0.001 and P < 0.01, resp.). While plasma C5a was unchanged, C5aR expression decreased with increasing BMI in subcutaneous and omental tissues (P < 0.01 and P < 0.05, resp.), with subcutaneous omental depots. Omental C5L2/C5aR ratio increased with BMI (P < 0.01) with correlations between C5L2/C5aR and waist circumference, HDL-C, and adiponectin. Tissue and BMI differences in receptors and ligands, particularly in omental, suggest relationship to metabolic disturbances and highlight adipose-immune interactions.

Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.

OBJECTIVE: Animal models have evidenced the role of intestinal triglyceride-rich lipoprotein overproduction in dyslipidemia. However, few studies have confronted this issue in humans and disclosed the intrinsic mechanisms. This work aimed to establish whether intestinal insulin resistance modifies lipid and lipoprotein homeostasis in the intestine of obese subjects. APPROACH AND RESULTS: Duodenal specimens obtained from 20 obese subjects undergoing bariatric surgery were paired for age, sex, and body mass index with or without insulin resistance, as defined by the homeostasis model assessment of insulin resistance. Insulin signaling, biomarkers of inflammation and oxidative stress, and lipoprotein assembly were assessed. The intestine of insulin-resistant subjects showed defects in insulin signaling as demonstrated by reduced protein kinase B phosphorylation and increased p38 mitogen-activated protein kinase phosphorylation, likely as the result of high oxidative stress (evidenced by malondialdehyde and conjugated dienes) and inflammation (highlighted by nuclear factor-κB, tumor necrosis factor-α, interleukin-6, intercellular adhesion molecule-1, and cyclooxygenase-2). Enhanced de novo lipogenesis rate and apolipoprotein B-48 biogenesis along with exaggerated triglyceride-rich lipoprotein production were observed, concomitantly with the high expression levels of liver and intestinal fatty acid-binding proteins and microsomal transfer protein. The presence of an aberrant intracellular cholesterol transport/metabolism was also suggested by the reduced expression of ATP-binding cassette A1 transporter and proprotein convertase subtilisin/kexin type 9. CONCLUSIONS: According to the present data, the small intestine may be classified as an insulin-sensitive tissue. Dysregulation of intestinal insulin signaling, possibly triggered by oxidative stress and inflammation, was associated with exaggerated lipogenesis and lipoprotein synthesis, which may represent a key mechanism for atherogenic dyslipidemia in patients with metabolic syndrome.

Methylation and expression of immune and inflammatory genes in the offspring of bariatric bypass surgery patients.

BACKGROUND: Maternal obesity, excess weight gain and overnutrition during pregnancy increase risks of obesity, type 2 diabetes mellitus, and cardiovascular disease in the offspring. Maternal biliopancreatic diversion is an effective treatment for severe obesity and is beneficial for offspring born after maternal surgery (AMS). These offspring exhibit lower severe obesity prevalence and improved cardiometabolic risk factors including inflammatory marker compared to siblings born before maternal surgery (BMS). OBJECTIVE: To assess relationships between maternal bariatric surgery and the methylation/expression of genes involved in the immune and inflammatory pathways. METHODS: A differential gene methylation analysis was conducted in a sibling cohort of 25 BMS and 25 AMS offspring from 20 mothers. Following differential gene expression analysis (23 BMS and 23 AMS), pathway analysis was conducted. Correlations between gene methylation/expression and circulating inflammatory markers were computed. RESULTS: Five immune and inflammatory pathways with significant overrepresentation of both differential gene methylation and expression were identified. In the IL-8 pathway, gene methylation correlated with both gene expression and plasma C-reactive protein levels. CONCLUSION: These results suggest that improvements in cardiometabolic risk markers in AMS compared to BMS offspring may be mediated through differential methylation of genes involved in immune and inflammatory pathways.

Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery.

Obesity and overnutrition during pregnancy affect fetal programming of adult disease. Children born after maternal bariatric gastrointestinal bypass surgery (AMS) are less obese and exhibit improved cardiometabolic risk profiles carried into adulthood compared with siblings born before maternal surgery (BMS). This study was designed to analyze the impact of maternal weight loss surgery on methylation levels of genes involved in cardiometabolic pathways in BMS and AMS offspring. Differential methylation analysis between a sibling cohort of 25 BMS and 25 AMS (2-25 y-old) offspring from 20 mothers was conducted to identify biological functions and pathways potentially involved in the improved cardiometabolic profile found in AMS compared with BMS offspring. Links between gene methylation and expression levels were assessed by correlating genomic findings with plasma markers of insulin resistance (fasting insulin and homeostatic model of insulin resistance). A total of 5,698 genes were differentially methylated between BMS and AMS siblings, exhibiting a preponderance of glucoregulatory, inflammatory, and vascular disease genes. Statistically significant correlations between gene methylation levels and gene expression and plasma markers of insulin resistance were consistent with metabolic improvements in AMS offspring, reflected in genes involved in diabetes-related cardiometabolic pathways. This unique clinical study demonstrates that effective treatment of a maternal phenotype is durably detectable in the methylome and transcriptome of subsequent offspring.