Circulating Levels of Sclerostin Predict Glycemic Improvement after Sleeve Gastrectomy.

Among the different effects of bariatric surgery, here we focus on bone-derived inflammatory molecules, and in particular, sclerostin; an osteocyte product potentially associated with cardio-metabolic diseases. In 94 morbidly obese patients undergoing laparoscopic sleeve gastrectomy (SG), over-time changes in anthropometric and biochemical measures-including insulin resistance (IR) indexes-were correlated with serum sclerostin levels. Sclerostin was positively associated with anthropometric indexes of obesity, and inversely with IR, namely homeostatic model assessment for peripheral insulin sensitivity (HOMA2%S) (r = -0.218; p = 0.045). Sclerostin emerged as the only significant predictor of HOMA2-%S normalization, independently of demographic and anthropometric variables (OR 1.01 (95% CI 1.00-1.02); p = 0.024). We also identified two distinct patterns of serum sclerostin change: the higher/lower sclerostin levels at baseline, the greater their post-surgical reduction/increase (p < 0.001 for all subgroups). Among those two patterns, especially the post-surgery increase in serum sclerostin was associated with lean mass reduction, without any association with IR indexes. Although counterintuitive, this change was likely dependent on the post-surgical increase in bone turnover. In conclusion, baseline serum levels of sclerostin correlate with anthropometric measures of obesity and IR, and the ability to predict glycemic improvements after SG. Specifically, serum sclerostin was closely associated with peripheral insulin sensitivity (HOMA2-%S), thus supporting the role of skeletal muscle/bone interactions in metabolic diseases.

Chemerin predicts carotid intima-media thickening in severe obesity.

BACKGROUND AND AIMS: Chemerin is an adipokine with an emerging role in the crosstalk between adipose tissue and immune system. It is overexpressed in severe obesity, affects adipogenesis and glucose homeostasis and it correlates with early vascular damage. The aim of this study is to investigate the correlation between circulating levels of chemerin and early vascular damage in subjects with severe obesity, before and after laparoscopic sleeve gastrectomy (LSG). METHODS: Fifty-six obese subjects eligible for LSG were enrolled in the study. The following parameters were evaluated: body mass index (BMI), glycemia, insulinemia, glycated haemoglobin, lipid profile, plasma chemerin levels and carotid intima-media thickness (cIMT). Fifty-four subjects were evaluated 1 year after the intervention. RESULTS: Univariate analysis showed a direct and significant correlation between chemerin and waist circumference, insulin resistance, glycated haemoglobin and cIMT. Chemerin was a better predictor of intima-media thickening than waist circumference and glycated haemoglobin at the ROC curve analysis, with a cut-off value for chemerin of 140 ng/mL. The reduction of chemerin is independently associated with the reduction of cIMT and the improvement of insulin sensitivity after LSG. CONCLUSION: Chemerin is involved in the development and progression of early vascular damage and insulin resistance in subjects with severe obesity, and in their healing after bariatric surgery. Chemerin could also have a role in the assessment of cardiovascular risk in subjects with severe obesity.

Folate and Vitamin B12 in Morbid Obesity: The Influence of Folate on Anti-Atherogenic Lipid Profile.

Previous studies showed a high prevalence of micronutrient deficiencies in obese subjects, with low folate and vitamin B12 serum levels and intakes. Correlations between vitamins and lipids have been investigated both in animal and human studies. The aim of our study is to evaluate the influence of dietetic and serum levels of folate and vitamin B12 on lipid pattern in morbidly obese subjects. We also analysed the relationship between serum concentrations and dietary intake of these micronutrients, and compared the intakes to the Recommended Levels of Nutrients and Energy Intakes (LARN). In 122 morbidly obese patients, mean BMI 45 ± 7 kg/m2, we evaluated anthropometric parameters, hepatic, glyco/lipid profile, total folate and vitamin B12, blood pressure, and finally nutritional intakes in a subgroup of 68 patients using a food frequency questionnaire about the frequency of food consumption and daily water intake. These values were determined in obese patients before and one year after sleeve gastrectomy. Both before and after surgery, levels of vitamins and minerals remained in normal range compared to LARN. According to univariate analysis, at baseline folate showed a significantly positive correlation with high-density lipoprotein cholesterol (p = 0.028, ρ = 0.204), apolipoprotein A-I (p = 0.006, ρ = 0.268) and vitamin B12 (p = 0.040, ρ = 0.192), and a significantly negative correlation with triglycerides (p = 0.049, ρ = -0.184). Folate and vitamin B12 levels do not correlate with their nutritional intakes, which remain within recommended range after surgery. In conclusion the correlation between folate and anti-atherogenic lipid profile is confirmed also in a large group of morbid obese patients.

Increased plasmatic NETs by-products in patients in severe obesity.

Neutrophil extracellular traps (NETs) are DNAs products involved in immune process. Obesity through a low-grade chronic inflammation determines neutrophil activation, but it is still unclear its role in NETs formation. Here we analyzed the NETs levels in healthy and morbid obese, their association with anthropometric and glyco-metabolic parameters and their changes after bariatric surgery. For this study, we enrolled 73 patients with morbid obesity (BMI ≥40 kg/m2 or ≥35 kg/m2 + comorbidity) eligible to sleeve gastrectomy. In parallel, 55 healthy subjects and 21 patients with severe coronary artery disease were studied as controls. We evaluated anthropometric parameters, peripheral blood pressure, biochemical and serum analysis at the enrollment and at twelve months after surgery. Plasmatic levels of MPO-DNA complexes were assessed by ELISA. NETs levels were higher in obese than in control group (p < 0.001) and correlated with the main anthropometric variable (BMI, waist, hip), glyco-metabolic variables and systolic blood pressure. NETs trend after intervention was uneven. The reduction of NETs correlated with the entity of reduction of BMI (ρ = 0.416, p < 0.05), visceral fat area (ρ = 0.351, p < 0.05), and glycemia (ρ = 0.495, p < 0.001). In medical history of patients in whom NETs increased, we observed a higher number of thromboembolic events. Our observations indicate that severe obesity is associated with increased generation of NETs, which in turn could influence the patients' systemic inflammatory state. Weight loss and in particular, loss of adipose tissue after bariatric surgery does not in itself correct NET's dysregulated production. Finally, patients in whom NETs accumulation persists after surgery are probably those at the highest risk of cardiovascular events.

Lysosomal Acid Lipase as a Molecular Target of the Very Low Carbohydrate Ketogenic Diet in Morbidly Obese Patients: The Potential Effects on Liver Steatosis and Cardiovascular Risk Factors.

A very low carbohydrate ketogenic diet (VLCKD) is an emerging technique to induce a significant, well-tolerated, and rapid loss of body weight in morbidly obese patients. The low activity of lysosomal acid lipase (LAL) could be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), which is a common feature in morbidly obese patients. Fifty-two obese patients suitable for a bariatric surgery intervention underwent a 25-day-long VLCKD. The biochemical markers of glucose and lipid metabolism, and flow-mediated dilation (FMD) of the brachial artery were measured before and after VLCKD. LAL activity was measured using the dried blood spot technique in 20 obese patients and in a control group of 20 healthy, normal-weight subjects. After VLCKD, we observed a significant reduction in body mass index, fasting glucose, insulinemia, and lipid profile parameters. No significant variation in FMD was observed. The number of patients with severe liver steatosis significantly decreased. LAL activity significantly increased, although the levels were not significantly different as compared to the control group. In conclusion, VLCKD induces the activity of LAL in morbidly obese subjects and reduces the secretion of all circulating lipoproteins. These effects could be attributed to the peculiar composition of the diet, which is particularly poor in carbohydrates and relatively rich in proteins.

Serum Bile Acid Levels Before and After Sleeve Gastrectomy and Their Correlation with Obesity-Related Comorbidities.

BACKGROUND AND AIMS: The rising prevalence of morbid obesity is increasing the demand for bariatric surgery. The benefits observed after bariatric surgery seems to be not fully explained by surgery-induced weight loss or traditional cardiovascular risk factors regression or improvement. Some evidences suggest that bile acid (BA) levels change after bariatric surgery, thus suggesting that BA concentrations could influence some of the metabolic improvement induced by bariatric surgery. In this report, we have characterized circulating BA patterns and compared them to metabolic and vascular parameters before and after sleeve gastrectomy (SG). PATIENTS AND METHODS: Seventy-nine subjects (27 males, 52 females, aged 45 ± 12 years, mean BMI 45 ± 7 kg/m2) SG candidates were included in the study. Before and about 12 months after SG, all subjects underwent a clinical examination, blood tests (including lipid profile, plasma glucose and insulin, both used for calculating HOMA-IR, and glycated hemoglobin), ultrasound visceral fat area estimation, ultrasound flow-mediated dilation evaluation, and determination of plasma BA concentrations. RESULTS: Before SG, both primary and secondary BA levels were higher in insulin-resistant obese subjects than in non-insulin resistant obese, and BA were positively associated with the markers of insulin-resistance. After SG, total (conjugated and unconjugated) cholic acids significantly decreased (p 0.007), and total lithocholic acids significantly increased (p 0.017). SG-induced total cholic and chenodeoxycholic acid changes were directly associated with surgery-induced glycemia (p 0.011 and 0.033 respectively) and HOMA-IR (p 0.016 and 0.012 respectively) changes. CONCLUSIONS: Serum BA are associated with glucose metabolism and particularly with markers of insulin-resistance. SG modifies circulating BA pool size and composition. SG-induced BA changes are associated with insulin-resistance amelioration. In conclusion, an interplay between glucose metabolism and circulating BA exists but further studies are needed.

Morbid obesity and hypertension: The role of perirenal fat.

Accumulation of fat in renal sinus and hilum is associated with hypertension development. We evaluated the relationship between perirenal fat and hypertension in a population of morbidly obese patients and the potential variations after sleeve-gastrectomy. Two hundred and eighty-four morbidly obese patients were included in the study, and 126 underwent sleeve-gastrectomy. At baseline and 10-12 months after surgery, we evaluated anthropometric parameters, blood pressure, glycometabolic, and lipidic assessment, and performed an ultrasonographic evaluation of visceral fat area and perirenal fat thickness. The perirenal fat thickness in hypertensive obese was higher than in nonhypertensive (13.6 ± 4.8 vs 11.6 ± 4.1, P = 0.001). It showed a significant direct correlation with age, waist circumference, BMI, systolic blood pressure (SBP), insulinemia, HOMA-IR, glycated hemoglobin, and creatinine. The independent predictors (R2  = 0.129) of SBP were perirenal fat thickness (ß = 0.160, P = 0.022) and age (ß = 0.175, P = 0.011). After surgery, perirenal fat thickness significantly decreased (from 13 ± 4 to 9 ± 4 mm, P <0.001). In the 89 hypertensive obese patients who underwent sleeve-gastrectomy, we observed a significant decrease in antihypertensive medications needed. Sixteen patients suspended therapy. The perirenal fat thickness in obese patients could be a valuable tool to define the risk of developing hypertension, providing the clinician with an additional parameter to define those who need a more aggressive treatment and could benefit most from bariatric surgery.

Microcirculatory Improvement Induced by Laparoscopic Sleeve Gastrectomy Is Related to Insulin Sensitivity Retrieval.

AIMS: Microvascular dysfunction is a potential factor explaining the association of obesity, insulin resistance, and vascular damage in morbidly obese subjects. The purpose of the study was to evaluate possible determinants of microcirculatory improvement 1 year after laparoscopic sleeve gastrectomy (LSG) intervention. METHODS: Thirty-seven morbidly obese subjects eligible for bariatric surgery were included in the study. Post-occlusive reactive hyperemia (PORH) of the forearm skin was measured as area of hyperemia (AH) by laser-Doppler flowmetry before LSG and after a 1-year follow-up. RESULTS: After intervention, we observed a significant reduction in BMI, HOMA index, HbA1c, and a significant increase of AH in all patients after surgery; this variation was significant only in those patients having insulin resistance or prediabetes/diabetes. Although significant correlation between the increase of AH and the reduction of both BMI, HOMA index, and HbA1c was observed, BMI was the only independent predictor of AH variation after LSG at the linear regression analysis. CONCLUSIONS: Our study shows that LSG intervention is correlated with a significant improvement in the microvascular function of morbidly obese subjects; this improvement seems to be related to the baseline degree of insulin-resistance and to the retrieval of insulin-sensitivity post-intervention.

Sleeve Gastrectomy Efficacy on Metabolic and Cardiovascular Dysfunction With a Focus on the Role of Comorbidities.

We evaluated the effects of sleeve gastrectomy (SG) on metabolic/cardiovascular parameters according to weight loss, visceral fat area (VFA), and homeostasis model assessment (HOMA)-insulin resistance index; we also assessed the influence of SG on comorbidities (diabetes/hypertension). At baseline and 10 to 12 months after SG, we assessed anthropometric and biochemical parameters, bioimpedentiometry, ultrasonographic VFA, liver steatosis, flow-mediated dilation, and echocardiography in 110 patients with obesity. We found that 23 (21%) patients had diabetes. Diabetic patients who normalized their glycated hemoglobin A1C (HbA1C) level experienced greater total weight loss (TWL), and the probability of normalizing HbA1C levels directly correlated with TWL. Diabetic patients experienced a greater improvement in systolic blood pressure, VFA, and high-density lipoprotein cholesterol than nondiabetics, while patients with hypertension experienced a greater improvement in VFA, triglycerides, HOMA, and HbA1C than nonhypertensive patients. The most important determinant of glucose control in diabetic patients was weight loss. Patients with diabetes and hypertension experienced a greater improvement in vascular and metabolic status after SG.

Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction.

Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction.

Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients.

The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor-in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR-C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects.

Determinants of low levels of brain natriuretic peptide in morbid obesity.

BACKGROUND & AIMS: morbid obesity is associated with cardiovascular comorbidity. A noteworthy feature of this relationship could regard low levels of brain natriuretic peptide (BNP). The study investigates the relationship between BNP and obesity-related markers in a morbid obese population, along with echocardiographic and vascular parameters. METHODS: in 154 morbid obese patients we evaluated anthropometric parameters, glycometabolic/lipid profile, bioimpedentiometry, echocardiography, visceral fat area and flow-mediated dilation (FMD) by ultrasonography. RESULTS: we divided population in two groups on the basis of median BMI levels; patients with higher BMI had significantly lower BNP (p = .008), FMD (p = .014) and HDL-C (p = .001) and showed a more impaired heart function. A similar trend emerged subdividing patients on the basis of median visceral fat area. BNP showed a significant inverse correlation with BMI (p < .001), left ventricular mass (p = .026) and inter-ventricular septum thickness (p = .007) and a significant positive correlation with FMD (p = .008), HDL-C (p = .022), and ejection fraction (p = .013). BMI and triglycerides were independent predictors of BNP levels. CONCLUSIONS: patients with higher BMI show lower BNP levels associated with greater total body fat amount. The correlation of BNP with endothelium-dependent vasodilation and cardiac impairment could represent another link between obesity and cardiovascular damage.

Non-alcoholic fatty liver disease fibrosis score and preclinical vascular damage in morbidly obese patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is strongly related with enhanced morbidity and mortality from cardiovascular disease. In obese patients with both NAFLD and features of the metabolic syndrome, the cardiovascular risk is further increased. AIM: The aim of this study is to investigate the relationship between severity of liver fibrosis evaluated by NAFLD fibrosis score (NAFLD-FS), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), other obesity-related markers and preclinical atherosclerosis in morbidly obese patients with previously diagnosed NAFLD. METHODS: Laboratory parameters, visceral fat area (VFA), flow-mediated dilatation (FMD), intima-media thickness (IMT), HOMA-IR and NAFLD-FS were determined in 196 morbidly obese patients. RESULTS: Patients with higher NAFLD-FS or HOMA-IR show higher left max-IMT and lower FMD (p<0.001). VFA and NAFLD-FS, but not HOMA-IR, were independent predictors of reduced FMD (respectively ß -0.268, p=0.001 and ß -0.165, p=0.039, p of the model<0.001) and increased left max-IMT (respectively ß 0.165, p=0.031 and ß 0.301, p<0.001, p of the model<0.001). CONCLUSIONS: In morbidly obese patients, NAFLD-FS correlates with markers of early vascular damage. NAFLD-FS, easier to obtain than VFA, seems to be a better score than HOMA-IR to categorize such subjects who are potentially at risk of future cardiovascular events.

Facing Morbid Obesity: How to Approach It.

Obesity is a major public health problem, with a prevalence of 10% to 20% in Western Europe. Morbid obesity, characterized by body mass index >40 kg/m(2), showed an increased prevalence in the last 30 years. Obesity is associated with reduced economic and social opportunities, reduced quality of life, and is a determinant of several "intermediate risk factors," leading to an increased mortality and a loss in life expectancy. The rising prevalence of morbid obesity increased the demand for bariatric surgery, also called "metabolic surgery": after these interventions, there is a decrease in metabolic comorbidities, cardiovascular (CV) risk, and total mortality. In this review, we update the evaluation of morbid obese patients from the physical examination to the metabolic, CV and respiratory assessments in order to correctly stratify the CV risk and provide the best treatment. To obtain these achievements, multidisciplinary work has to be carried out with a team involving several experts with different skills.