Rafael Moncada

Increased Cardiometabolic Risk Factors and Inflammation in Adipose Tissue in Obese Subjects ClassifiedasMetabolicallyHealthy

OBJECTIVE It has been suggested that individuals with the condition known as metabolically healthy obesity (MHO) may not have the same increased risk for the development of metabolic abnormalities as their non–metabolically healthy counterparts. However, the validity of this concept has recently been challenged, since it may not translate into lower morbidity and mortality. The aim of the current study was to compare the cardiometabolic/inflammatory profile and the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) in patients categorized as having MHO or metabolically abnormal obesity (MAO). RESEARCH DESIGN AND METHODS We performed a cross-sectional analysis to compare the cardiometabolic/inflammatory profile of 222 MHO and 222 MAO patients (62% women) matched by age, including 255 lean subjects as reference (cohort 1). In a second cohort, we analyzed the adipokine profile and the expression of genes involved in inflammation and extracellular matrix remodeling in visceral adipose tissue (VAT; n = 82) and liver (n = 55). RESULTS The cardiometabolic and inflammatory profiles (CRP, fibrinogen, uric acid, leukocyte count, and hepatic enzymes) were similarly increased in MHO and MAO in both cohorts. Moreover, above < 30% of patients classified as MHO according to fasting plasma glucose exhibited IGT or T2D. The profile of classic (leptin, adiponectin, resistin) as well as novel (serum amyloid A and matrix metallopeptidase 9) adipokines was almost identical in MHO and MAO groups in cohort 2. Expression of genes involved in inflammation and tissue remodeling in VAT and liver showed a similar alteration pattern in MHO and MAO individuals. CONCLUSIONS The current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals.

Activation of Noncanonical Wnt Signaling Through WNT5A in Visceral Adipose Tissue of Obese Subjects Is Related to Inflammation

CONTEXT Wingless-type mouse mammary tumor virus integration site family (WNT)-5A is a glycoprotein involved in the regulation of the inflammatory response by activating the noncanonical Wnt signaling pathway. Secreted frizzled-related protein (SFRP)-5 acts as a decoy receptor that binds and sequesters WNT5A, preventing activation of frizzled receptors and attenuating the noncanonical Wnt signaling. OBJECTIVE The aim of the study was to evaluate the involvement of WNT5A and SFRP5 in obesity and obesity-related comorbidities as well as to explore their effect in visceral adipose tissue inflammation. PATIENTS AND METHODS Samples obtained from 90 subjects were used. Circulating and gene expression levels of WNT5A and SFRP5 were analyzed in different metabolic tissues. The effect of TNF-α and lipopolysaccharide on the transcript levels of WNT5A and SFRP5 in adipocytes was explored. We also investigated whether WNT5A itself can activate an inflammatory response. RESULTS Increased circulating levels of WNT5A in obese patients (P < .05) were decreased (P < .001) after gastric bypass. In this line, WNT5A mRNA in visceral adipose tissue was increased (P < .05) in obese patients with gene expression levels of SFRP5 being down-regulated (P < .05). WNT5A mRNA expression was significantly enhanced (P < .01) by lipopolysaccharide and TNF-α treatment, whereas no effects were found in SFRP5 gene expression levels. Furthermore, exogenous WNT5A induced (P < .05) IL-6, IL1B, MMP2, MMP9, and SSP1 mRNA expression in human adipocyte cultures. CONCLUSIONS Activation of noncanonical Wnt signaling through the up-regulation of WNT5A and down-regulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.

The usefulness of plasma histamine and different tryptase cut‐off points in the diagnosis of peranaesthetic hypersensitivity reactions

Anaesthetic hypersensitivity reactions can be IgE‐ or not IgE‐mediated and are a challenge to find the causal agent. Histamine and tryptase determination are classically considered useful in the diagnosis of these reactions. The aim of our study was to assess the diagnostic usefulness of plasma histamine and different cut‐off points of serum tryptase.

Sleeve Gastrectomy Reduces Hepatic Steatosis by Improving the Coordinated Regulation of Aquaglyceroporins in Adipose Tissue and Liver in Obese Rats

BackgroundGlycerol constitutes an important metabolite for the control of lipid accumulation and glucose homeostasis. Our aim was to investigate the potential role of aquaglyceroporins, which are glycerol channels mediating glycerol efflux in adipocytes (AQP3 and AQP7) and glycerol influx (AQP9) in hepatocytes, in the improvement of adiposity and hepatic steatosis after sleeve gastrectomy in an experimental model of diet-induced obesity (DIO).MethodsMale Wistar DIO rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal diet (ND) or a high-fat diet (HFD) or pair-fed to the amount of food eaten by sleeve-gastrectomized animals]. The tissue distribution and expression of AQPs in biopsies of epididymal (EWAT) and subcutaneous (SCWAT) white adipose tissue and liver were analyzed by real-time PCR, Western blot, and immunohistochemistry.ResultsFour weeks after surgery, DIO rats undergoing sleeve gastrectomy showed a reduction in body weight, whole-body adiposity, and hepatic steatosis. DIO was associated with a tendency towards an increase in EWAT AQP3 and SCWAT AQP7 and a decrease in hepatic AQP9. Sleeve gastrectomy downregulated AQP7 in both fat depots and upregulated AQP3 in EWAT, without changing hepatic AQP9. Aqp7 transcript levels in EWAT and SCWAT were positively associated with adiposity and glycemia, while Aqp9 mRNA was negatively correlated with markers of hepatic steatosis and insulin resistance.ConclusionOur results show, for the first time, that sleeve gastrectomy, a widely applied bariatric surgery procedure, restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, thereby improving whole-body adiposity and hepatic steatosis.

Early skin testing is effective for diagnosis of hypersensitivity reactions occurring during anesthesia.

Allergic skin tests have to be performed 4–6 weeks after an allergic anesthetic reaction. Patients with allergic reactions during anesthesia were prospectively included (n = 44). Skin tests were performed in two stages: (i) Stage 1 (S1), 0–4 days after the reaction; and (ii) Stage 2 (S2), 4–8 weeks after. Five (11.5%) surgical procedures were suspended due to the reaction. Positive skin tests were obtained in 25/44 patients (57%). Allergic diagnosis was carried out at S1 in 15/25 (60%) and at S2 in 10/25 (40%). Three patients resulted positive only in S1. Overall agreement among S1 and S2 skin tests was 70.45%. The kappa statistic was 0.41 (P‐value = 0.002). Odds ratio of obtaining a false negative in S1 (compared with S2) was 3.33. Early allergological study is useful, could minimize false negatives, but should be considered as a complement to late skin tests.

Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats.

Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA β-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA β-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA β-oxidation and autophagy in obese rats, thereby ameliorating NAFLD.

Increased IL-32 Levels in Obesity Promote Adipose Tissue Inflammation and Extracellular Matrix Remodeling. Effect of Weight Loss.

Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral blood mononuclear cells. IL32 was mainly expressed by stromovascular fraction cells, and its expression was significantly enhanced by inflammatory stimuli and hypoxia, whereas no changes were found after the incubation with anti-inflammatory cytokines. The addition of exogenous IL-32 induced the expression of inflammation and extracellular matrix–related genes in human adipocyte cultures, and IL32-silenced adipocytes showed a downregulation of inflammatory genes. Furthermore, adipocyte-conditioned media obtained from obese patients increased IL32 gene expression in human monocyte cultures, whereas the adipocyte-conditioned media from lean volunteers had no effect on IL32 mRNA levels. These findings provide evidence, for the first time, about the inflammatory and remodeling properties of IL-32 in AT, implicating this cytokine in obesity-associated comorbidities.

Effect of sleeve gastrectomy on osteopontin circulating levels and expression in adipose tissue and liver in rats.

BackgroundSleeve gastrectomy (SG) constitutes an effective procedure for the treatment of morbid obesity. The aim of the present study was to establish in rats the effects of surgically induced weight loss on circulating concentrations and mRNA expression in adipose tissue and liver of osteopontin (OPN), a proinflammatory protein involved in the development of obesity.MethodsEighty male diet-induced obese Wistar rats were subjected to surgical interventions [sham operation (SH), SG, or pair-fed to the amount of food eaten by SG animals] and dietary interventions [fed ad libitum with a normal chow diet (ND) or a high-fat diet (HFD)]. Body, epididymal adipose tissue (EWAT), and liver weights were determined. Circulating OPN concentrations and the transcript levels of Spp1 (OPN) in EWAT and liver were analyzed.ResultsRats undergoing SG showed decreased body weight (P < 0.001) and fat mass (P < 0.001) and greater excess weight loss (P < 0.001). The HFD significantly decreased serum OPN levels (P < 0.001). However, SG did not change serum OPN concentrations. OPN expression was dramatically increased in animals fed HFD (P < 0.001) in EWAT, but was unaffected by SG. The expression of OPN in the liver was not affected by HFD or SG.ConclusionsCirculating OPN levels decreased with HFD feeding remaining unaltered after SG. The expression of Spp1 in EWAT and liver was not modified by SG. The global improvement of metabolism after SG appears not to involve changes in serum OPN concentrations as well as in EWAT and liver expression in rats.

The incidence of perioperative hypersensitivity reactions: a single-center, prospective, cohort study.

BACKGROUND:The incidence of perioperative hypersensitivity reactions, which can be life-threatening, ranges from 1 in 20,000 to 1 in 1361. These reactions are usually classified as IgE or non-IgE mediated. The aim of this study was to determine the incidence of allergic reactions during general anesthesia in our hospital, to establish the incidence of the allergic reactions for each drug used, to assess the frequency of IgE-mediated reactions in even mild reactions, and to compare the degree of agreement between anesthesiologist suspicion and allergy diagnosis. METHODS:We included patients diagnosed with a clinical hypersensitivity reaction during a procedure under general anesthesia over a 30-month period (February 2008 to August 2010). Plasma histamine and serum tryptase concentrations were determined in these patients. We performed skin tests to diagnose the causative agent. Data from the hospital electronic prescribing system were collected to determine the ratio of reactions for each drug. RESULTS:During the study period, 16,946 anesthetic procedures were performed (53% involved males; mean age, 51.6 years). Forty-four perianesthetic reactions were recorded, and the ratio of reactions was 1 in 385 operations (95% confidence interval, 1/529–1/287). Twenty-five reactions (25/44; 57%) occurred during the induction of anesthesia. Twenty-one reactions (21/44; 48%) were mild, involving only skin, and 23 of 44 (52%) were anaphylactic reactions. Four of 10 patients who had only a rash experienced IgE-mediated reactions. Five surgeries (11%) were suspended because of the severity of the reactions. Fifteen reactions (15/30; 50%) were IgE mediated, and, in 2 of 30 (7%), a non-IgE agent was found (cold urticaria and nonsteroidal anti-inflammatory drug intolerance). The ratio of reactions for each drug was as follows: protamine, 1 in 468; cisatracurium, 1 in 1388; amoxicillin-clavulanate, 1 in 1968; atracurium, 1 in 2039; and dipyrone, 1 in 3159. CONCLUSIONS:Perioperative reactions are more common than previously reported. Mild hypersensitivity perioperative reactions—involving only skin—should be considered in evaluating patients because a substantial number of these reactions are IgE mediated.

Metabolic Surgery Enters the T2DM Treatment Algorithm

A Joint Statement endorsed by 45 international organizations, clinicians, and researchers indicating when to recommend or consider metabolic surgery in type 2 diabetes mellitus (T2DM) treatment has been recently published. These new guidelines, resulting from the Second Diabetes Surgery Summit (DSS-II), represent the most radical change in T2DM management of the past few decades.