Morbid Obesity in Women Is Associated with an Altered Intestinal Expression of Genes Related to Cancer Risk and Immune, Defensive, and Antimicrobial Response.

BACKGROUND: Little is known about the relation between morbid obesity and duodenal transcriptomic changes. We aimed to identify intestinal genes that may be associated with the development of obesity regardless of the degree of insulin resistance (IR) of patients. MATERIAL AND METHODS: Duodenal samples were assessed by microarray in three groups of women: non-obese women and women with morbid obesity with low and high IR. RESULTS: We identified differentially expressed genes (DEGs) associated with morbid obesity, regardless of IR degree, related to digestion and lipid metabolism, defense response and inflammatory processes, maintenance of the gastrointestinal epithelium, wound healing and homeostasis, and the development of gastrointestinal cancer. However, other DEGs depended on the IR degree. We mainly found an upregulation of genes involved in the response to external organisms, hypoxia, and wound healing functions in women with morbid obesity and low IR. CONCLUSIONS: Regardless of the degree of IR, morbid obesity is associated with an altered expression of genes related to intestinal defenses, antimicrobial and immune responses, and gastrointestinal cancer. Our data also suggest a deficient duodenal immune and antimicrobial response in women with high IR.

EVOO Promotes a Less Atherogenic Profile Than Sunflower Oil in Smooth Muscle Cells Through the Extracellular Vesicles Secreted by Endothelial Cells.

Background: Little is known about the effect of extra virgin olive (EVOO) and sunflower oil (SO) on the composition of extracellular vesicles (EVs) secreted by endothelial cells and the effects of these EVs on smooth muscle cells (SMCs). These cells play an important role in the development of atherosclerosis. Methods: We evaluated the effects of endothelial cells-derived EVs incubated with triglyceride-rich lipoproteins obtained after a high-fat meal with EVOO (EVOO-EVs) and SO (SO-EVs), on the transcriptomic profile of SMCs. Results: We found 41 upregulated and 19 downregulated differentially expressed (DE)-miRNAs in EVOO-EVs. Afterwards, SMCs were incubated with EVOO-EVs and SO-EVs. SMCs incubated with SO-EVs showed a greater number of DE-mRNA involved in pathways related to cancer, focal adhesion, regulation of actin cytoskeleton, and MAPK, toll-like receptor, chemokine and Wnt signaling pathways than in SMCs incubated with EVOO-EVs. These DE-mRNAs were involved in biological processes related to the response to endogenous stimulus, cell motility, regulation of intracellular signal transduction and cell population proliferation. Conclusion: EVOO and SO can differently modify the miRNA composition of HUVEC-derived EVs. These EVs can regulate the SMCs transcriptomic profile, with SO-EVs promoting a profile more closely linked to the development of atherosclerosis than EVOO-EVs.

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.

An Isolated Dose of Extra-Virgin Olive Oil Produces a Better Postprandial Gut Hormone Response, Lipidic, and Anti-Inflammatory Profile that Sunflower Oil: Effect of Morbid Obesity.

INTRODUCTION: This study evaluates the effects of 25 mL of three types of oils [extra-virgin olive oil (EVOO), olive oil (OO), and sunflower oil (SO)] on postprandial (3 h) satiety markers and variables related to metabolic status and inflammation in non-obese patients (n = 6) and in those with morbid obesity (n = 6), before and 1 year after Roux-en-Y gastric by-pass (RYGB). METHODS AND RESULTS: After EVOO intake, serum acylated ghrelin decreases and GLP1 increases more than with OO and SO. EVOO causes a higher increase of insulin and lower postprandial hypertriglyceridemia and free fatty acid levels than with OO and SO. EVOO decreases TNFα and IL6 expression in peripheral blood mononuclear cells, with OO inducing intermediate effects and SO inducing an increase of these proinflammatory markers. These results are observed in non-obese patients and in those with morbid obesity after RYGB. However, patients with morbid obesity before RYGB show a profound alteration of this response. CONCLUSION: EVOO produces more beneficial effects than OO, which has lower amounts of minor components, and SO, which has PUFA as its main component. RYGB produces an improvement in the metabolic response to all three types of oils in patients with morbid obesity.

Oleic acid restores the rhythmicity of the disrupted circadian rhythm found in gastrointestinal explants from patients with morbid obesity.

BACKGROUND & AIMS: We investigated whether oleic acid (OA), one of the main components of the Mediterranean diet, participates in the regulation of the intestinal circadian rhythm in patients with morbid obesity. METHODS: Stomach and jejunum explants from patients with morbid obesity were incubated with oleic acid to analyze the regulation of clock genes. RESULTS: Stomach explants showed an altered circadian rhythm in CLOCK, BMAL1, REVERBα, CRY1, and CRY2, and an absence in PER1, PER2, PER3 and ghrelin (p > 0.05). OA led to the emergence of rhythmicity in PER1, PER2, PER3 and ghrelin (p < 0.05). Jejunum explants showed an altered circadian rhythm in CLOCK, BMAL1, PER1 and PER3, and an absence in PER2, REVERBα, CRY1, CRY2 and GLP1 (p > 0.05). OA led to the emergence of rhythmicity in PER2, REVERBα, CRY1 and GLP1 (p < 0.05), but not in CRY2 (p > 0.05). OA restored the rhythmicity of acrophase and increased the amplitude for most of the genes studied in stomach and jejunum explants. OA placed PER1, PER2, PER3, REVERBα, CRY1 and CRY2 in antiphase with regard to CLOCK and BMAL1. CONCLUSIONS: There is an alteration in circadian rhythm in stomach and jejunum explants in morbid obesity. OA restored the rhythmicity of the genes related with circadian rhythm, ghrelin and GLP1, although with slight differences between tissues, which could determine a different behaviour of the explants from jejunum and stomach in obesity.

NGS of microRNAs Involved in Cardioprotection Induced by Sevoflurane Compared to Propofol in Myocardial Revascularization Surgery: The ACDHUVV-16 Clinical Trial.

BACKGROUND: Numerous studies have demonstrated that halogenated agents elicit myocardial conditioning effects when administered perioperatively in cardiac surgery. Recent evidence has been published on the benefits of maintaining exposure to halogenated agents during the early postoperative period. The enzymatic mechanisms by which this beneficial effect is exerted were explained recently. OBJECTIVES: Our study was performed to investigate whether this phenomenon is mediated by either the activation or suppression of miRNAs targeted by halogenated anesthetics. METHODS: A double-blind, two-stage trial was conducted. The results of the first stage of the trial are presented in this paper. The sample was composed of patients undergoing off-pump myocardial revascularization surgery. Patients were randomized to receive either sevoflurane [S] or propofol [P] during the intraoperative and early postoperative period (during the first six hours after the intervention). Hemodynamics (heart rate, blood pressure, central venous pressure, cardiac index, systolic volume index, LVEF) and myocardial enzymes (troponin I) were monitored at six hour intervals during the first 48 hours. In the first stage of the trial, blood was drawn for gene sequencing from eight patients (four per group) at baseline and at 24 h. In the second stage of the study, a qPCR analysis was performed of the miRNAs identified as significant by gene sequencing. Levels of cardioprotective enzymes (serine/threonine protein kinase (Akt), tumor necrosis factor alpha (TNFα), extracellular regulated protein kinase (ERK 1/2), and caspase 3) were measured to assess their role in myocardial conditioning pathways. The purpose was to identify the miRNAs that play a major role in myocardial conditioning induced by halogenated agents. Concentrations of cardioprotective enzymes were higher in patients who received sevoflurane than the patients who were administered propofol. RESULTS: NGS differences were observed between baseline and 24-h values in the two study groups. In group P, miRNA 197-3p was overexpressed, whereas miRNAs 4443 and 1294, 708-3p were underexpressed. In group S, miRNAs 615-3p, 4466, 29, 937-3p, 636, 197-3P, 184, 4685, 296-3p, 147b, 3199, 6815, 1294 and 3176 were underexpressed; whereas 708-3p was overexpressed. qPCR showed significant variations in miRNAs 197-3p, 4443, 708-3p and 1294 in the P group, and in miRNAs 937-3p, 636, 197- 3p, 296-3p and 708-3p in the S group. CONCLUSION: In the P Group, changes in the expression of some miRNAs were associated with lower concentrations of the enzymes involved in myocardial pre- and postconditioning. In contrast, in Group S, variations in miRNAs were associated with the activation of mediators of anesthetic-induced pre- and post-conditioning, a reduction in cell apoptosis, and a decrease in caspase and TnBF alpha concentrations. Changes in these miRNAs were associated with better prognosis in patients with ischemic heart disease. The main limitation of this study will be overcome in the second stage of the trial, where the specific role of each miRNA will be determined.

Renal and Neurologic Benefit of Levosimendan vs Dobutamine in Patients With Low Cardiac Output Syndrome After Cardiac Surgery: Clinical Trial FIM-BGC-2014-01.

BACKGROUND: Low-cardiac output syndrome (LCOS) after cardiac surgery secondary to systemic hypoperfusion is associated with a higher incidence of renal and neurological damage. A range of effective therapies are available for LCOS. The beneficial systemic effects of levosimendan persist even after cardiac output is restored, which suggests an independent cardioprotective effect. METHODS: A double-blind clinical trial was conducted in patients with a confirmed diagnosis of LCOS randomized into two treatment groups (levosimendan vs. dobutamine). Monitoring of hemodynamic (cardiac index, systolic volume index, heart rate, mean arterial pressure, central venous pressure, central venous saturation); biochemical (e.g. creatinine, S100B protein, NT-proBNP, troponin I); and renal parameters was performed using acute kidney injury scale (AKI scale) and renal and brain ultrasound measurements [vascular resistance index (VRI)] at diagnosis and during the first 48 h. RESULTS: Significant differences were observed between groups in terms of cardiac index, systolic volume index, NT-proBNP, and kidney injury stage at diagnosis. In the levosimendan group, there were significant variations in AKI stage after 24 and 48 h. No significant differences were observed in the other parameters studied. CONCLUSION: Levosimendan showed a beneficial effect on renal function in LCOS patients after cardiac surgery that was independent from cardiac output and vascular tone. This effect is probably achieved by pharmacological postconditioning. CLINICAL TRIAL REGISTRATION: EUDRA CT, identifier 2014-001461-27. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001461-27.

Oleic Acid Protects Against Insulin Resistance by Regulating the Genes Related to the PI3K Signaling Pathway.

BACKGROUND: The effects of different types of fatty acids on the gene expression of key players in the IRS1/PI3K signaling pathway have been poorly studied. MATERIAL AND METHODS: We analyzed IRS1, p85α, and p110ß mRNA expression and the fatty acid composition of phospholipids in visceral adipose tissue from patients with morbid obesity and from non-obese patients. Moreover, we analyzed the expression of those genes in visceral adipocytes incubated with oleic, linoleic, palmitic and dosahexaenoic acids. RESULTS: We found a reduced IRS1 expression in patients with morbid obesity, independent of insulin resistance, and a reduced p110ß expression in those with lower insulin resistance. A positive correlation was found between p85α and stearic acid, and between IRS1 and p110ß with palmitic and dosahexaenoic acid. In contrast, a negative correlation was found between p85α and oleic acid, and between IRS1 and p110ß with linoleic, arachidonic and adrenic acid. Incubation with palmitic acid decreased IRS1 expression. p85α was down-regulated after incubation with oleic and dosahexaenoic acid and up-regulated with palmitic acid. p110ß expression was increased and decreased after incubation with oleic and palmitic acid, respectively. The ratio p85α/p110ß was decreased by oleic and dosahexaenoic acid and increased by palmitic acid. CONCLUSIONS: Our in vitro results suggest a detrimental role of palmitic acid on the expression of gene related to insulin signaling pathway, with oleic acid being the one with the higher and more beneficial effects. DHA had a slight beneficial effect. Fatty acid-induced regulation of genes related to the IRS1/PI3K pathway may be a novel mechanism by which fatty acids regulate insulin sensitivity in visceral adipocytes.

Different Expression of Duodenal Genes Related to Insulin Resistance Between Nonobese Women and Those with Severe Obesity.

OBJECTIVE: The study aim was to identify changes in duodenal gene expression associated with the development of insulin resistance according to the BMI of women. METHODS: Duodenal samples were assessed by microarray in four groups of women, nonobese women and women with severe obesity, with both low and high insulin resistance. RESULTS: There was a group of shared downregulated differentially expressed genes (DEGs) related to tissue homeostasis and antimicrobial humoral response in women with higher insulin resistance both with severe obesity and without obesity. In the exclusive DEGs found in severe obesity, downregulated DEGs related to the regulation of the defense response to bacterium and cell adhesion, involving pathways related to the immune system, inflammation, and xenobiotic metabolism, were observed. In the exclusive DEGs from nonobese women with higher insulin resistance, upregulated DEGs mainly related to the regulation of lipoprotein lipase activity, very low-density lipoprotein particle remodeling, lipid metabolic process, antigen processing, and the presentation of peptide antigen were found. CONCLUSIONS: Independent of BMI, higher insulin resistance was associated with a downregulation of duodenal DEGs mainly related to the immune system, inflammation, and xenobiotic metabolism. Also, intestinal lipoprotein metabolism may have a certain relevance in the regulation of insulin resistance in nonobese women.

miRNA/Target Gene Profile of Endothelial Cells Treated with Human Triglyceride-Rich Lipoproteins Obtained after a High-Fat Meal with Extra-Virgin Olive Oil or Sunflower Oil.

SCOPE: The effects of triglyceride-rich lipoproteins (TRLs) on the miRNA expression of endothelial cells, which are very involved in atherosclerosis, according to the type of diet are not known. METHODS AND RESULTS: The differences between the effects of TRLs isolated from blood of subjects after a high-fat meal with extra-virgin olive oil (EVOO) and sunflower oil (SO) on the microRNA-Seq profile related to atherosclerosis in human umbilical vein endothelial cells are analyzed. 28 upregulated microRNAs with EVOO-derived TRLs, which can regulate 22 genes related to atherosclerosis, are found. 21 upregulated microRNAs with SO-derived TRLs, which can regulate 20 genes related to atherosclerosis, are found. These microRNAs are mainly involved in angiogenesis, with a predominance of an anti-angiogenic effect with EVOO-derived TRLs. Other microRNAs upregulated with SO-derived TRLs are involved in cardiovascular diseases. Pathways for the target genes obtained from the upregulated microRNA with EVOO-derived TRLs are involved in lipid metabolism and inflammatory and defense response, while those with SO-derived TRLs are involved in lipid metabolic process. CONCLUSION: EVOO-derived TRLs seem to produce a more atheroprotective profile than SO-derived TRLs. This study provides alternative mechanisms on the protective role of EVOO against the atherogenic process through microRNA regulation in endothelial cells.

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.

Increased production of functional small extracellular vesicles in senescent endothelial cells.

Small extracellular vesicles (EVs) are novel players in vascular biology. However, a thorough understanding of their production and function remains elusive. Endothelial senescence is a key feature of vascular ageing and thus, is an attractive therapeutic target for the treatment of vascular disease. In this study, we sought to characterize the EV production of senescent endothelial cells. To achieve this, Human Umbilical Vascular Endothelial Cells (HUVECs) were replicated until they reached senescence, as determined by measurement of Senescence-Associated ß-Galactosidase activity via microscopy and flow cytometry. Expression of the endosomal marker Rab7 and the EV marker CD63 was determined by immunofluorescence. Small EVs were isolated by ultracentrifugation and characterized using electron microscopy, nanoparticle tracking analysis and immunoassays to assess morphology, size, concentration and expression of exosome markers CD9 and CD81. Migration of HUVECs in response to EVs was studied using a transwell assay. The results showed that senescent endothelial cells express higher levels of Rab7 and CD63. Moreover, senescent endothelial cells produced higher levels of CD9- and CD81-positive EVs. Additionally, small EVs from both young and senescent endothelial cells promoted HUVEC migration. Overall, senescent endothelial cells produce an increased number of functional small EVs, which may have a role in vascular physiology and disease.

Jejunal Insulin Signalling Is Increased in Morbidly Obese Subjects with High Insulin Resistance and Is Regulated by Insulin and Leptin.

Little is known about the jejunal insulin signalling pathways in insulin resistance/diabetes states and their possible regulation by insulin/leptin. We study in jejunum the relation between insulin signalling and insulin resistance in morbidly obese subjects with low (MO-low-IR) or with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM)), and the effect of insulin/leptin on intestinal epithelial cells (IEC). Insulin receptor substrate-1 (IRS1) and the catalytic p110ß subunit (p110ß) of phosphatidylinositol 3-kinase (PI3K) were higher in MO-high-IR than in MO-low-IR. The regulatory p85α subunit of PI3K (p85α)/p110ß ratio was lower in MO-high-IR and MO-metf-T2DM than in MO-low-IR. Akt-phosphorylation in Ser473 was reduced in MO-high-IR compared with MO-low-IR. IRS1 and p110-ß were associated with insulin and leptin levels. The improvement of body mass index (BMI) and HOMA-IR (homeostasis model assessment of insulin resistance index) after bariatric surgery was associated with a higher IRS1 and a lower p85α/p110ß ratio. IEC (intestinal epithelial cells) incubation with a high glucose + insulin dose produced an increase of p85α and p110ß. High dose of leptin produced an increase of IRS1, p85α and p110ß. In conclusion, despite the existence of insulin resistance, the jejunal expression of genes involved in insulin signalling was increased in MO-high-IR. Their expressions were regulated mainly by leptin. IRS1 and p85α/p110ß ratio was associated with the evolution of insulin resistance after bariatric surgery.

A lower duodenal immune response is associated with an increase of insulin resistance in patients with morbid obesity.

OBJECTIVE: The intestinal immune response could play an important role in obesity-related comorbidities. We aim to study the profile of duodenal cytokines and chemokines in patients with morbid obesity (MO), its relation with insulin resistance (IR) and the intake of metformin, and with the evolution of MO after sleeve gastrectomy (SG). RESEARCH DESIGN AND METHODS: Duodenal levels of 24 cytokines and 9 chemokines were analyzed in 14 nonobese and in 54 MO who underwent SG: with lower IR (MO-lower-IR), with higher IR (MO-higher-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM). RESULTS: MO-lower-IR had higher levels of cytokines related to Th1, Th2, Th9, Th17, Th22, M1 macrophages, and chemokines involved in the recruitment of macrophages and T-lymphocytes (p < 0.05), and total (CD68 expression) and M1 macrophages (ITGAX expression) (p < 0.05) when compared with nonobese patients, but with a decrease in M2 macrophages (MRC1 expression) (p < 0.05). In MO-higher-IR, these chemokines and cytokines decreased and were similar to those found in nonobese patients. In MO-metf-T2DM, only IL-4 (Th2) and IL-22 (Th22) increased their levels with regard to MO-higher-IR (p < 0.05). In MO-higher-IR and MO-metf-T2DM, there was a decrease of CD68 expression (p < 0.05) while ITGAX and MRC1 were similar with regard to MO-lower-IR. We found an association between CXCL8, TNFß and IL-2 with the evolution of body mass index (BMI) after SG (p < 0.05). CONCLUSIONS: There is an association between a higher IR and a lower duodenal immune response in MO, with a slight increase in those patients with metformin treatment. Intestinal immune response could be involved in the evolution of BMI after SG.

Overexpression of scavenger receptor and infiltration of macrophage in epicardial adipose tissue of patients with ischemic heart disease and diabetes.

BACKGROUND: Oxidized low-density lipoproteins and scavenger receptors (SRs) play an important role in the formation and development of atherosclerotic plaques. However, little is known about their presence in epicardial adipose tissue (EAT). The objective of the study was to evaluate the mRNA expression of different SRs in EAT of patients with ischemic heart disease (IHD), stratifying by diabetes status and its association with clinical and biochemical variables. METHODS: We analyzed the mRNA expression of SRs (LOX-1, MSR1, CXCL16, CD36 and CL-P1) and macrophage markers (CD68, CD11c and CD206) in EAT from 45 patients with IHD (23 with type 2 diabetes mellitus (T2DM) and 22 without T2DM) and 23 controls without IHD or T2DM. RESULTS: LOX-1, CL-P1, CD68 and CD11c mRNA expression were significantly higher in diabetic patients with IHD when compared with those without T2DM and control patients. MSR1, CXCL16, CD36 and CD206 showed no significant differences. In IHD patients, LOX-1 (OR 2.9; 95% CI 1.6-6.7; P = 0.019) and CD68 mRNA expression (OR 1.7; 95% CI 0.98-4.5; P = 0.049) were identified as independent risk factors associated with T2DM. Glucose and glycated hemoglobin were also shown to be risk factors. CONCLUSIONS: SRs mRNA expression is found in EAT. LOX-1 and CD68 and were higher in IHD patients with T2DM and were identified as a cardiovascular risk factor of T2DM. This study suggests the importance of EAT in coronary atherosclerosis among patients with T2DM.

Increased PON lactonase activity in morbidly obese patients is associated with impaired lipid profile.

AIMS: The paraoxonase-1 (PON1) enzyme could play an important role in the anti-oxidant capacity of high-density lipoprotein. However, there are no studies which analyse the evolution of the three activities of PON1 (PON arylesterase, PON paraoxonase and PON lactonase) after Roux-en-Y Gastric Bypass (RYGB) in morbidly obese subjects. We analysed the association of PON concentration and activities with the evolution of morbidly obese subjects who underwent RYGB, and its relationship with biochemical variables and different atherogenic indices. METHODS: Twenty-seven non-obese and 82 morbidly obese subjects were studied before and 6 months after RYGB. RESULTS: Before RYGB, morbidly obese subjects had a lower PON1 concentration (P < 0.05) and higher PON lactonase activity (P < 0.001) than non-obese subjects, with no differences in PON arylesterase and PON paraoxonase activities. After RYGB, PON1 concentration (P < 0.05) and PON lactonase activity (P < 0.001) decreased with regard to the presurgery state. PON lactonase activity correlated with the atherogenic index of plasma before (r = 0.19, P = 0.047) and after RYGB (r = 0.27, P = 0.035). In different multiple lineal regression analysis models, presurgery PON lactonase activity was associated with total cholesterol (ß = 0.909, P < 0.001), LDL (ß = 0.632, P = 0.006) and DBP (ß = 0.230, P = 0.030) (R2  = 0.295), postsurgery PON lactonase activity was associated with esterified cholesterol (ß = 0.362, P = 0.011) (R2  = 0.131), and the change (Δ) in PON lactonase activity after RYGB was associated with Δesterified cholesterol (ß = 0.304, P = 0.030) (R2  = 0.093). CONCLUSIONS: PON lactonase activity is associated with the presence of morbid obesity and with an impaired lipid profile. All associations found could indicate the relationship between PON lactonase activity and the development of atherosclerosis.

The changes in the transcriptomic profiling of subcutaneous adipose tissue after bariatric surgery depend on the insulin resistance state.

BACKGROUND: The changes that are produced in the gene expression of subcutaneous adipose tissue after Roux-en-Y gastric bypass are not yet fully known. OBJECTIVE: To identify the changes in the subcutaneous adipose tissue gene expression of morbidly obese women with low insulin resistance (MO-low-IR) and high insulin resistance (MO-high-IR) to find a relationship with measured obesity-related co-morbidities. SETTING: A university hospital. METHODS: Subcutaneous adipose tissue samples were assessed by microarray analysis before and 2 years after Roux-en-Y gastric bypass in MO-low-IR and MO-high-IR patients. RESULTS: There is a group of shared differentially expressed genes (DEG) in both MO-low-IR and MO-high-IR, also there is a group of exclusive DEG in MO-low-IR and another group in MO-high-IR. In MO-high-IR, the downexpressed DEG are related to the regulation of transcription and are involved in the pathways related to cytokine-cytokine receptor interaction, cancer, phosphatidylinositol 3-kinase-protein kinase B signaling, human T-lymphotropic virus I infection, chemokine signaling, and Janus kinase/signal transducers and activators of transcription signaling. In MO-low-IR, the overexpressed DEG are related to carbohydrate metabolic processes, the downexpressed DEG to the glycosaminoglycan metabolic process and regulation of translation, and the pathways are related to phosphatidylinositol 3-kinase-protein kinase B signaling and metabolic pathways. The fold change of DEG mainly correlates with the percentage of change (Δ) of waist, Δhip, Δglucose, and Δtriglycerides. These DEG were mainly related to cancer, inflammation/immune regulation, metabolic pathways, ribonucleic acid/deoxyribonucleic acid regulation, virus infection, and regulation of cellular proliferation. CONCLUSIONS: This study suggests a potential association between high insulin resistance and the expression of genes related to cancer and chronic immune activation/inflammation.

Tissue-Specific Phenotype and Activation of iNKT Cells in Morbidly Obese Subjects: Interaction with Adipocytes and Effect of Bariatric Surgery.

BACKGROUND: The immune response of visceral adipose tissue (VAT) in obesity, in particular the role of invariant natural killer T (iNKT) cells, has not yet been fully elucidated. OBJECTIVE: To characterize iNKT cells and its activation status in VAT and peripheral blood mononuclear cells (PBMC) in morbidly obese subjects (MO), and to analyze their association with metabolic parameters. SUBJECTS AND METHODS: Twenty non-obese and 20 MO subjects underwent Roux-en-Y gastric bypass (RYGB) and were studied before and 6 months after RYGB. VAT and PBMC were obtained. RESULTS: A decrease in VAT iNKT cells from MO was found, however, not in PBMC. Visceral adipocytes from MO presented increased CD1d expression (p = 0.032). MO presented an increase in early activated CD69+ iNKT cells in PBMC before RYGB (p < 0.001), but not after RYGB nor in VAT, and an increase in later activated CD25+ iNKT in VAT (p = 0.046), without differences in PBMC. The co-expression of early and later markers (CD69+CD25+) in iNKT cells was increased in MO in VAT (p = 0.050) and PBMC (p = 0.006), decreasing after RYGB (p = 0.050). CD69+ iNKT and CD69+CD25+ iNKT cells in PBMC after RYGB correlated negatively with glucose, insulin, and insulin resistance levels. CONCLUSIONS: There is a tissue-specific phenotype and activation of iNKT cells in VAT in morbid obesity, which could be involved in VAT immunometabolism dysregulation. Also, the increase in CD1d expression could be to offset the lack of VAT iNKT cells.

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)

Expression of epicardial adipose tissue thermogenic genes in patients with reduced and preserved ejection fraction heart failure.

Epicardial adipose tissue has been proposed to participate in the pathogenesis of heart failure. The aim of our study was to assess the expression of thermogenic genes (Uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), and PR-domain-missing 16 (PRDM16) in epicardial adipose tissue in patients with heart failure, stablishing the difference according to left ventricular ejection fraction (reduced or preserved). Among the 75 patients in our study, 42.7% (n=32) had reduced left ventricular ejection fraction. UCP1, PGC1α and PRDM16 mRNA in EAT were significantly lower in patients with reduced left ventricular ejection fraction. Multiple regression analysis showed that age, male gender, body max index, presence of obesity, type-2-diabetes mellitus, hypertension and coronary artery disease and left ventricular ejection fraction were associated with the expression levels of UCP1, PGC1α and PRDM16 mRNA. Thermogenic genes expressions in epicardial adipose tissue (UCP1: OR 0.617, 95%CI 0.103-0.989, p=0.042; PGC1α: OR 0.416, 95%CI 0.171-0.912, p=0.031; PRDM16: OR 0.643, 95%CI 0.116-0.997, p=0.044) were showed as protective factors against the presence of heart failure with reduced left ventricular ejection fraction, and age (OR 1.643, 95%CI 1.001-3.143, p=0.026), presence of coronary artery disease (OR 6.743, 95%CI 1.932-15.301, p<0.001) and type-2-diabetes mellitus (OR 4.031, 95%CI 1.099-7.231, p<0.001) were associated as risk factors. The adequate expression of thermogenic genes has been shown as possible protective factors against heart failure with reduced ejection fraction, suggesting that a loss of functional epicardial adipose tissue brown-like features would participate in a deleterious manner on heart metabolism. Thermogenic genes could represent a future novel therapeutic target in heart failure.