Very low-density lipoprotein receptor mediates triglyceride-rich lipoprotein-induced oxidative stress and insulin resistance.

Obesity is associated with excess lipid deposition in non-adipose tissues, leading to increased oxidative stress and insulin resistance. Very-low-density lipoprotein receptor (VLDLR), a member of the LDL receptor family, binds and increases the catabolism of triglyceride-rich lipoproteins. Although VLDLR is highly expressed in the heart, its role in obesity-associated oxidative stress and insulin resistance is unclear. Here, we used lean (WT), genetically obese leptin-deficient (ob/ob), and leptin-VLDLR double-null (ob/ob-VLDLR-/-) mice to determine the impact of VLDLR deficiency on obesity-induced oxidative stress and insulin resistance in the heart. While insulin sensitivity and glucose uptake were reduced in the hearts of ob/ob mice, VLDLR expression was upregulated and was associated with increased VLDL uptake and excess lipid deposition. This was accompanied by an upregulation of cardiac NADPH oxidase (Nox) expression and increased production of Nox-dependent superoxides. Silencing the VLDLR in ob/ob mice had reduced VLDL uptake and prevented excess lipid deposition in the heart, in addition to a reduction of superoxide overproduction and the normalization of insulin sensitivity and glucose uptake. In isolated cardiomyocytes, VLDLR deficiency had prevented VLDL-mediated induction of Nox activity and superoxide overproduction while improving insulin sensitivity and glucose uptake. Our findings indicate that VLDLR deficiency prevents excess lipid accumulation and moderates oxidative stress and insulin resistance in the heart of obese mice. This effect is linked to the active role of VLDLR in VLDL uptake, which triggers a cascade of events leading to increased NOX activity, overproduction superoxide and insulin resistance.

Depletion of Omega-3 Fatty Acids in RBCs and Changes of Inflammation Markers in Patients With Morbid Obesity Undergoing Gastric Bypass.

BACKGROUND: Bariatric surgery is considered the most effective treatment for severe obesity. Despite this wide success, bariatric surgery is associated with increased risks of nutritional deficiencies. OBJECTIVES: To examine whether Roux-en-Y-gastric bypass (RYGB) alters essential fatty acid (FA) status and inflammation markers. METHODS: Subjects with obesity (n = 28; BMI > 40 kg/m2; mean age 48 years) were studied before and 1 year after RYGB. We collected blood samples before and 12 months after RYGB, and analyzed FA in RBCs and peripheral blood mononuclear cells (PBMC), and measured inflammation parameters in plasma. The proportion of total n-3 FAs was the primary outcome, while parameters related to other FAs and inflammation factors were the secondary parameters. In addition, PBMCs from 15 of the participants were cultured alone or with 100 and 200 µM DHA, and the production of IL-6, IL-1ß, PGE2, and prostaglandin F2-alpha (PGF2α) was assayed after endotoxin (LPS) stimulation. RESULTS: RYGB induced a significant reduction of BMI (-30%) and improvement of insulin resistance (-49%). While the proportion of arachidonic acid was 15% higher after RYGB, the proportions of total and individual n-3 FAs were 50%-75% lower (P < 0.01). Consequently, the RBC omega-3 index and n-3:n-6 fatty acid ratio were 45% and 50% lower after surgery, respectively. In isolated PBMCs, LPS induced the production of IL-6, IL-1ß, PGE2, and PGF2α in both pre- and post-RYGB cells, but the effects were 34%-65% higher (P < 0.05) after RYGB. This effect was abrogated by DHA supplementation. CONCLUSIONS: This study presents evidence that RBC and PBMC n-3 FAs are severely reduced in patients with obesity after RYGB. DHA supplementation in PBMC moderates the production of inflammation markers, suggesting that n-3 FA supplementation would merit a trial in bariatric patients.

Prevalence of stunting and obesity in Ecuador: a systematic review.

OBJECTIVE: In low- and middle-income countries, undernutrition remains a major risk factor for child growth retardation. In addition, the emergence of obesity in recent years is adding another public health concern in that both stunting and obesity are associated with serious adverse health consequences. This review was designed to evaluate the prevalence of stunting and obesity in Ecuador. DESIGN: Electronic databases were searched for articles published through February 2018 reporting the prevalence of stunting and/or obesity. Selected data were subjected to meta-analysis and pooled prevalence and their 95 percentiles (95 % CI) were calculated. SETTING: Studies were identified in Medline, Web of Science, CINAHL, Cochrane Database and Ibero-America databases. PARTICIPANTS: Population of Ecuador. RESULTS: Twenty-three articles were selected according to the inclusion/exclusion criteria of the study. The estimate of pooled prevalence of stunting was 23·2 % (95 % CI 23·3, 23·5) in preschoolers (age < 5 years), but was markedly higher in indigenous and rural communities. Pooled prevalence of obesity was 8·1 % (95 % CI 6·9, 9·3), 10·7 % (95 % CI 9·6, 11·7) and 10·5 % (95 % CI 9·2, 11·8) in preschoolers, school-age children (age: 5-11 years) and adolescent (age: 12-18 years), respectively. In adults (age ≥ 19 years), the rate of obesity was remarkably high as indicated by an overall estimate equal to 44·2 % (95 % CI 43·1, 45·4). CONCLUSIONS: This study underlines high levels of stunting among children and obesity among adults in Ecuador, both of which are not equally distributed among the population. The magnitude of this double burden emphasises the need for sustained and targeted interventions.

WITHDRAWN: Very low density lipoprotein receptor deficiency prevents obesity-induced cardiac lipotoxicity.

This article has been withdrawn by the authors. We have become aware of errors in the construction of Figs 1 and 2. In Fig 1D, the tIRS1 immunoblot from untreated cardiomyocytes was inadvertently reused from Fig 2A of PLOS One 2016 May 19;11(5):e0155611. Also in Fig 1D, there were undeclared gel splices with no line indicating the assemblage of two parts in the pIRS1 immunoblot from insulin-stimulated cardiomyocytes. In Fig 2B, lanes 1-3 and lanes 5-7 of the actin immunoblot were mistakenly duplicated. Because some of the original data are no longer available, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper, and will repeat the missing immunoblots to complete the paper.

Very low density lipoprotein receptor (VLDLR) expression is a determinant factor in adipose tissue inflammation and adipocyte-macrophage interaction.

Obesity is associated with adipose tissue remodeling, characterized by adipocyte hypertrophy and macrophage infiltration. Previously, we have shown that very low density lipoprotein receptor (VLDLR) is virtually absent in preadipocytes but is strongly induced during adipogenesis and actively participates in adipocyte hypertrophy. In this study, we investigated the role of VLDLR in adipose tissue inflammation and adipocyte-macrophage interactions in wild type and VLDLR-deficient mice fed a high fat diet. The results show that VLDLR deficiency reduced high fat diet-induced inflammation and endoplasmic reticulum (ER) stress in adipose tissue in conjunction with reduced macrophage infiltration, especially those expressing pro-inflammatory markers. In adipocyte culture, VLDLR deficiency prevented adipocyte hypertrophy and strongly reduced VLDL-induced ER stress and inflammation. Likewise, cultures of primary peritoneal macrophages show that VLDLR deficiency reduced lipid accumulation and inflammation but did not alter chemotactic response of macrophages to adipocyte signals. Moreover, VLDLR deficiency tempered the synergistic inflammatory interactions between adipocytes and macrophages in a co-culture system. Collectively, these results show that VLDLR contributes to adipose tissue inflammation and mediates VLDL-induced lipid accumulation and induction of inflammation and ER stress in adipocytes and macrophages.

Regulation of adiponectin production by insulin: interactions with tumor necrosis factor-α and interleukin-6.

Obesity is often associated with insulin resistance, low-grade systemic inflammation, and reduced plasma adiponectin. Inflammation is also increased in adipose tissue, but it is not clear whether the reductions of adiponectin levels are related to dysregulation of insulin activity and/or increased proinflammatory mediators. In this study, we investigated the interactions of insulin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in the regulation of adiponectin production using in vivo and in vitro approaches. Plasma adiponectin and parameters of insulin resistance and inflammation were assessed in a cohort of lean and obese insulin-resistant subjects. In addition, the effect of insulin was examined in vivo using the hyperinsulinemic-euglycemic clamp, and in adipose tissue (AT) cultures. Compared with lean subjects, the levels of total adiponectin, and especially the high-molecular-weight (HMW) isomer, were abnormally low in obese insulin-resistant subjects. The hyperinsulinemic clamp data confirmed the insulin-resistant state in the obese patients and showed that insulin infusion significantly increased the plasma adiponectin in lean but not obese subjects (P < 0.01). Similarly, insulin increased total adiponectin release from AT explants of lean and not obese subjects. Moreover, expression and secretion of TNF-α and IL-6 increased significantly in AT of obese subjects and were negatively associated with expression and secretion of adiponectin. In 3T3-L1 and human adipocyte cultures, insulin strongly enhanced adiponectin expression (2-fold) and secretion (3-fold). TNF-α, and not IL-6, strongly opposed the stimulatory effects of insulin. Intriguingly, the inhibitory effect of TNF-α was especially directed toward the HMW isomer of adiponectin. In conclusion, these studies show that insulin upregulates adiponectin expression and release, and that TNF-α opposes the stimulatory effects of insulin. A combination of insulin resistance and increased TNF-α production could explain the decline of adiponectin levels and alterations of isomer composition in plasma of obese insulin-resistant subjects.

The burden of hypertension in Ecuador: a systematic review and meta-analysis.

Hypertension is a major risk factor of cardiovascular diseases, which occurrence has increased consistently worldwide. With this in mind, this review was designed to evaluate the prevalence of hypertension in Ecuador. We systematically searched publications in Medline, Cumulative Index of Nursing and Allied Health Literature, Cochrane Database, and Ibero-America electronic databases for articles published through September 2019 and reporting the prevalence of hypertension in Ecuador. Selected data were subjected to meta-analysis, and pooled prevalence and their 95% (95% CI) were calculated. Seventeen articles have been selected according to the inclusion/exclusion criteria of the study. The overall estimate of the pooled prevalence of hypertension was 35.8% (CI: 31.3-38.4). Most importantly, the prevalence of hypertension increased markedly with age and obesity. Pooled estimates for the four age subdivisions (<30 years), (≥30 and ≤50 years), (>50 and ≤60 years) and (>60 years) were 9.4% (CI: 7.3-11.5), 22.0% (CI: 19.0-25.0), 26.1% (22.2-30.0) and 48.7% (CI: 45.4-52.0), respectively. Moreover, the pooled estimate of subjects with BMI ≥ 30 kg/m2 (57.7%, CIs: 45.6-69.8) was markedly higher than those with BMI < 30 kg/m2 (30.4%, CI: 23.3-38.4). Although limited, available data reported higher rates of hypertension in Afro-Ecuadorians than other ethnicities. This study underlines a high prevalence of hypertension in adults nationwide, but mostly in elderly and obese individuals. The magnitude of this burden emphasizes the need for robust and targeted interventions to control hypertension, and ultimately reverse the trend of cardiovascular diseases.

Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) refers to the pathologic buildup of extra fat in the form of triglycerides in liver cells without excessive alcohol intake. NAFLD became the most common cause of chronic liver disease that is tightly associated with key aspects of metabolic disorders, including insulin resistance, obesity, diabetes, and metabolic syndrome. It is generally accepted that multiple mechanisms and pathways are involved in the pathogenesis of NAFLD. Heredity, sedentary lifestyle, westernized high sugar saturated fat diet, metabolic derangements, and gut microbiota, all may interact on a on genetically susceptible individual to cause the disease initiation and progression. While there is an unquestionable role for gene-diet interaction in the etiopathogenesis of NAFLD, it is increasingly apparent that epigenetic processes can orchestrate many aspects of this interaction and provide additional mechanistic insight. Exciting research demonstrated that epigenetic alterations in chromatin can influence gene expression chiefly at the transcriptional level in response to unbalanced diet, and therefore predispose an individual to NAFLD. Thus, further discoveries into molecular epigenetic mechanisms underlying the link between nutrition and aberrant hepatic gene expression can yield new insights into the pathogenesis of NAFLD, and allow innovative epigenetic-based strategies for its early prevention and targeted therapies. Herein, we outline the current knowledge of the interactive role of a high-fat high-calories diet and gene expression through DNA methylation and histone modifications on the pathogenesis of NAFLD. We also provide perspectives on the advancement of the epigenomics in the field and possible shortcomings and limitations ahead.

Epigenetic Regulation of Peroxisome Proliferator-Activated Receptor Gamma Mediates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in Western countries and has become a serious public health concern. Although Western-style dietary patterns, characterized by a high intake of saturated fat, is considered a risk factor for NAFLD, the molecular mechanisms leading to hepatic fat accumulation are still unclear. In this study, we assessed epigenetic regulation of peroxisome proliferator-activated receptor γ (PPARγ), modifications of gene expression, and lipid uptake in the liver of mice fed a high-fat diet (HFD), and in hepatocyte culture challenged with palmitic acid. Bisulfate pyrosequencing revealed that HFD reduced the level of cytosine methylation in the pparγ DNA promoter. This was associated with increased expression of the hepatic PPARγ, very low-density lipoprotein receptor (VLDLR) and cluster differentiating 36 (CD36), and enhanced uptake of fatty acids and very low-density lipoprotein, leading to excess hepatic lipid accumulation. Furthermore, palmitic acid overload engendered comparable modifications in hepatocytes, suggesting that dietary fatty acids contribute to the pathogenesis of NAFLD through epigenetic upregulation of PPARγ and its target genes. The significance of epigenetic regulation was further demonstrated in hepatocytes treated with DNA methylation inhibitor, showing marked upregulation of PPARγ and its target genes, leading to enhanced fatty acid uptake and storage. This study demonstrated that HFD-induction of pparγ DNA promoter demethylation increased the expression of PPARγ and its target genes, vldlr and cd36, leading to excess lipid accumulation, an important initiating mechanism by which HFD increased PPARγ and lipid accumulation. These findings provide strong evidence that modification of the pparγ promoter methylation is a crucial mechanism of regulation in NAFLD pathogenesis.

Peroxisome proliferator-activated receptor-gamma regulates the expression and function of very-low-density lipoprotein receptor.

Very-low-density lipoprotein receptor (VLDLR) is a member of the low-density receptor family, highly expressed in adipose tissue, heart, and skeletal muscle. It binds apolipoprotein E-triglyceride-rich lipoproteins and plays a significant role in triglyceride metabolism. PPARgamma is a primary regulator of lipid metabolism in adipocytes and controls the expression of an array of genes involved in lipid trafficking in adipocytes. However, it is not known whether VLDLR is also under the control of PPARgamma. In this study, we investigated the role of PPARgamma in the regulation of VLDLR expression and function in vivo and in vitro. During the differentiation of 3T3-L1 preadipocytes, the levels of VLDLR protein and mRNA increased in parallel with the induction of PPARgamma expression and reached maximum in mature adipocytes. Treatment of differentiated adipocytes with PPARgamma agonist pioglitazone upregulated VLDLR expression in dose- and time-dependent manners. In contrast, specific inhibition of PPARgamma significantly downregulated the protein level of VLDLR. Induction of VLDLR is also demonstrated in vivo in adipose tissue of wild-type (WT) mice treated with pioglitazone. In addition, pioglitazone increased plasma triglyceride-rich lipoprotein clearance and increased epididymal fat mass in WT mice but failed to induce similar effects in vldlr(-/-) mice. These results were further corroborated by the finding that pioglitazone treatment enhanced adipogenesis and lipid deposition in preadipocytes of WT mice, while its effect in VLDLR-null preadipocytes was significantly blunted. These findings provide direct evidence that VLDLR expression is regulated by PPARgamma and contributes in lipid uptake and adipogenesis.

Effects of oxidized lipids and lipoproteins on cardiac function.

Oxidative modifications of lipids and lipoproteins have long been linked to the pathogenesis of cardiovascular diseases including atherosclerosis and coronary disease. Furthermore, overwhelming evidence indicate that oxidized lipids are also associated with myocardial dysfunction and cardiomyopathy. Oxidized lipid derivatives are generated by enzymatic and non-enzymatic reactions with unsaturated lipids in the cell and foods. In addition, blood LDL particles are prone to oxidation leading to the formation of oxidized LDL (oxLDL), which is often associated with obesity, diabetes and metabolic disease. Whether produced endogenously or delivered by the diet, oxidized lipid derivatives induce multiple metabolic and functional disturbances in the cell leading eventually to cell injury and death. As obesity is already associated with increased oxidative stress and excess lipid deposition in the heart, the cytotoxic effects of oxidized lipids in cardiomyocytes are more pronounced in obese subjects. The overall objective of this review is to provide a synthesis of recent findings about the effects oxidized lipids in the heart. First, the origin of oxidized lipids and lipoproteins is reported. Then, the effects of oxidized lipids in cardiomyocytes are reviewed and discussed. Finally, potential preventive interventions are highlighted and discussed.

Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice.

Deficiency of the membrane protein FAT/CD36 causes a marked defect in fatty acid uptake by various tissues and is genetically linked to insulin resistance in rats and humans. Here, we examined insulin responsiveness of CD36-/- mice. When fed a diet high in complex carbohydrates and low (5%) in fat, these animals cleared glucose faster than the wild-type. In vivo, uptake of 2-fluorodeoxyglucose by muscle was increased severalfold, and in vitro, insulin responsiveness of glycogenesis by the soleus was enhanced. Null mice had lower glycogen levels in muscle and liver, lower muscle triglyceride levels, and increased liver triglyceride content--all findings consistent with increased insulin-sensitivity. However, when the chow diet was switched to one high in fructose, CD36-/- mice but not wild-type mice developed marked glucose intolerance, hyperinsulinemia, and decreased muscle glucose uptake. High-fat diets impaired glucose tolerance equally in both groups, although CD36 deficiency helped moderate insulin-responsive muscle glucose oxidation. In conclusion, CD36 deficiency enhances insulin responsiveness on a high-starch, low-fat diet. It predisposes to insulin resistance induced by high fructose and partially protects from that induced by high-fat diets. In humans, CD36 deficiency may be an important factor in the metabolic adaptation to diet and in susceptibility to some forms of diet-induced pathology.

Association between adipokines and critical illness outcomes.

BACKGROUND: Adipose tissue is an endocrine organ that plays a critical role in immunity and metabolism by virtue of a large number of hormones and cytokines, collectively termed adipokines. Dysregulation of adipokines has been linked to the pathogenesis of multiple diseases, but some questions have arisen concerning the value of adipokines in critical illness setting. The objective of this review was to evaluate the associations between blood adipokines and critical illness outcomes. METHODS: PubMed, CINAHL, Scopus, and the Cochrane Library databases were searched from inception through July 2016 without language restriction. Studies reporting the associations of adipokines, leptin, adiponectin, resistin, and/or visfatin with critical illness outcomes mortality, organ dysfunction, and/or inflammation were included. RESULTS: A total of 38 articles were selected according to the inclusion/exclusion criteria of the study. Significant alterations of circulating adipokines have been reported in critically ill patients, some of which were indicative of patient outcomes. The associations of leptin and adiponectin with critical illness outcomes were not conclusive in that blood levels of both adipokines did not always correlate with the illness severity scores or risks of organ failure and mortality. By contrast, studies consistently reported striking increase of blood resistin and visfatin, independently of the critical illness etiology. More interestingly, increased levels of these adipokines were systematically associated with severe inflammation, and high incidence of organ failure and mortality. CONCLUSIONS: There is strong evidence to indicate that increased levels of blood resistin and visfatin are associated with poor outcomes of critically ill patients, including higher inflammation, and greater risk of organ dysfunction and mortality. LEVEL OF EVIDENCE: Systematic review, level III.

Cluster Differentiating 36 (CD36) Deficiency Attenuates Obesity-Associated Oxidative Stress in the Heart.

RATIONALE: Obesity is often associated with a state of oxidative stress and increased lipid deposition in the heart. More importantly, obesity increases lipid influx into the heart and induces excessive production of reactive oxygen species (ROS) leading to cell toxicity and metabolic dysfunction. Cluster differentiating 36 (CD36) protein is highly expressed in the heart and regulates lipid utilization but its role in obesity-associated oxidative stress is still not clear. OBJECTIVE: The aim of this study was to determine the impact of CD36 deficiency on cardiac steatosis, oxidative stress and lipotoxicity associated with obesity. METHODS AND RESULTS: Studies were conducted in control (Lean), obese leptin-deficient (Lepob/ob) and leptin-CD36 double null (Lepob/obCD36-/-) mice. Compared to lean mice, cardiac steatosis, and fatty acid (FA) uptake and oxidation were increased in Lepob/ob mice, while glucose uptake and oxidation was reduced. Moreover, insulin resistance, oxidative stress markers and NADPH oxidase-dependent ROS production were markedly enhanced. This was associated with the induction of NADPH oxidase expression, and increased membrane-associated p47phox, p67phox and protein kinase C. Silencing CD36 in Lepob/ob mice prevented cardiac steatosis, increased insulin sensitivity and glucose utilization, but reduced FA uptake and oxidation. Moreover, CD36 deficiency reduced NADPH oxidase activity and decreased NADPH oxidase-dependent ROS production. In isolated cardiomyocytes, CD36 deficiency reduced palmitate-induced ROS production and normalized NADPH oxidase activity. CONCLUSIONS: CD36 deficiency prevented obesity-associated cardiac steatosis and insulin resistance, and reduced NADPH oxidase-dependent ROS production. The study demonstrates that CD36 regulates NADPH oxidase activity and mediates FA-induced oxidative stress.

CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness.

High levels of intramyocellular triglycerides are linked to insulin resistance and reflect conditions in which fatty acid uptake exceeds the myocyte oxidative capacity. CD36 facilitates fatty acid uptake by myocytes, and its level is increased in diabetic muscle. We examined whether high CD36 levels would increase lipid content and susceptibility of myocytes to fatty acid-induced insulin resistance. C2C12 myoblasts with stable fivefold overexpression of CD36 (+CD36) were generated and differentiated into myotubes. CD36 expression increased palmitate uptake, oxidation, and lipid incorporation but had no effect on cell triglyceride content. Importantly, glycerol release increased fourfold, indicating enhanced triglyceride turnover and suggesting that CD36 promotes futile cycling of fatty acids into triglyceride. When +CD36 myotubes were incubated with excess palmitate, CD36 enhancement of glycerol release was blunted, triglyceride content increased above wild-type cells, and insulin resistance of glucose metabolism was observed. In contrast to palmitate, oleate-treated +CD36 cells exhibited enhanced glycerol release and no alteration in triglyceride content or insulin responsiveness. Furthermore, increased expression of hormone-sensitive lipase was measured with CD36 expression and with oleate treatment. In conclusion, high futile cycling of fatty acids is important for maintaining low triglyceride content and insulin responsiveness of myocytes. The findings provide a new perspective related to the etiology of lipid accumulation and insulin resistance in myocytes.

Predicting dedifferentiation in liposarcoma: a proteomic approach.

There are no known morphologic characteristics, cytogenetic aberrations, or molecular alterations predictive of dedifferentiation in liposarcomas. Identification of such a prognostic marker could potentially affect surgical and adjuvant therapy and/or follow-up surveillance for these patients. Two-dimensional difference gel electrophoresis was utilized to characterize protein expression patterns in lipoma, atypical lipomatous tumor (ALT), and the well-differentiated components of dedifferentiated liposarcoma (DDL). Protein spots were identified by peptide mapping/fingerprinting using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. No significant differences in protein expression were identified between lipoma and ALT or DDL. Proteins that were significantly down-regulated in the well-differentiated component of DDL compared to ALT included mitochondrial aldehyde dehydrogenase 2 (ALDH2, >3-fold reduction) and selenium-binding protein-1 (SELENBP1, >4-fold reduction). Subsequent validation studies were performed by immunohistochemistry (IHC) on a separate series of ALT (n = 30) and the well-differentiated components of DDL (n = 28). IHC stains were evaluated in a semi-quantitative manner, and the results were analyzed using the Mann-Whitney test and receiver-operator curve analysis. Decreased IHC staining for SELENBP1 in the well-differentiated component of DDL was confirmed. Cytoplasmic ALDH2 levels determined by IHC were not significantly different in ALT and DDL; no nuclear staining for ALDH2 was observed. Expression of SELENBP1 is decreased in the well-differentiated component of DDL compared to ALT. However, variability in the staining patterns in liposarcoma precludes its use as a predictive marker for dedifferentiation.

Effect of Body Mass Index on the sensitivity of Magnetogastrogram and Electrogastrogram.

AIM: Gastric disorders affect the gastric slow wave. The cutaneous electrogastrogram (EGG) evaluates the electrical potential of the slow wave but is limited by the volume conduction properties of the abdominal wall. The magnetogastrogram (MGG) evaluates the gastric magnetic field activity and is not affected as much by the volume conductor properties of the abdominal wall. We hypothesized that MGG would not be as sensitive to body mass index as EGG. METHODS: We simultaneously recorded gastric slow wave signals with mucosal electrodes, a Superconducting Quantum Interference Device magnetometer (SQUID) and cutaneous electrodes before and after a test meal. Data were recorded from representative pools of human volunteers. The sensitivity of EGG and MGG was compared to the body mass index and waist circumference of volunteers. RESULTS: The study population had good linear regression of their Waist circumference (Wc) and Body Mass Index (BMI) (regression coefficient, R=0.9). The mean BMI of the study population was 29.2 ±1.8 kgm-2 and mean Wc 35.7±1.4 inch. We found that while subjects with BMI≥25 showed significant reduction in post-prandial EGG sensitivity, only subjects with BMI≥30 showed similar reduction in post-prandial MGG sensitivity. Sensitivity of SOBI "EGG and MGG" was not affected by the anthropometric measurements. CONCLUSIONS: Compared to electrogastrogram, the sensitivity of the magnetogastrogram is less affected by changes in body mass index and waist circumference. The use of Second Order Blind Identification (SOBI) increased the sensitivity of EGG and MGG recordings and was not affected by BMI or waist circumference.

Very low density lipoprotein receptor promotes adipocyte differentiation and mediates the proadipogenic effect of peroxisome proliferator-activated receptor gamma agonists.

Very low density lipoprotein receptor (VLDLR) is a member of the low density receptor family, expressed mostly in adipose tissue, heart, and skeletal muscles. VLDLR binds apolipoprotein-E-triglyceride-rich lipoproteins and plays a key role in lipid metabolism. In adipocytes, VLDLR expression increases with differentiation but it is not known whether it plays a role in the adipogenesis. Here we report that VLDLR expression in 3T3-L1 adipocytes is upregulated by PPARγ agonist 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) in dose- and time-dependant manners. Knockdown of peroxisome proliferator-activated receptor-γ (PPARγ) with siRNA abolished pioglitazone- and 15d-PGJ(2)-induced VLDLR expression and simultaneously reduced VLDL uptake in adipocytes. In addition, PPARγ-agonist treatment of control mouse adipocytes (vldlr(+/+)) enhanced adipogenesis and VLDL uptake concurrently with the induction of VLDLR expression. However, vldlr deficiency (vldlr(-/-)) significantly blunted the proadipogenic effects of PPARγ agonists. Sequence analysis revealed the presence of a putative PPARγ responsive sequence (PPRE) within the vldlr promoter, which is responsive to natural (15d-PGJ(2)) and synthetic (pioglitazone) PPARγ agonists. Reporter gene assays using serial deletion of the 5'-flanking region showed that this putative PPRE site induced promoter transactivation, while a site-targeted mutation abolished transactivation. Moreover, electrophoresis mobility shift assay (EMSA) and chromatic immunoprecipitation (ChIP) assays showed the specific binding of PPARγ to the PPRE sequence. Together, these results support a crucial function for VLDLR in adipocyte differentiation and mediation of the proadipogenic effect of PPARγ.

Reduction of 8-iso-prostaglandin F2α in the first week after Roux-en-Y gastric bypass surgery.

Obesity is associated with increased markers of oxidative stress. We examined whether oxidative stress is reduced within the first week after Roux-en-Y gastric bypass (RYGB) surgery and could be related to changes in adipose tissue depots. The reactive oxygen species (ROS) marker 8-iso-prostaglandin F2α (8-iso-PGF2α) and activity of antioxidant glutathione peroxidases (GPX) in plasma were compared before and ~1 week after RYGB. The effects of RYGB on subcutaneous adipose tissue and interstitial fluid 8-iso-PGF2α levels and subcutaneous adipose tissue expression of GPX-3 were also assessed. Levels of 8-iso-PGF2α in subcutaneous and visceral adipose tissue were determined. Plasma 8-iso-PGF2α levels decreased (122 ± 75 to 56 ± 15 pg/ml, P = 0.001) and GPX activity increased (84 ± 18 to 108 ± 25 nmol/min/ml, P = 0.003) in the first week post-RYGB. RYGB also resulted in reductions of 8-iso-PGF2α in subcutaneous adipose tissue (1,742 ± 931 to 1,132 ± 420 pg/g fat, P = 0.046) and interstitial fluid (348 ± 118 to 221 ± 83 pg/ml, P = 0.046) that were comparable to plasma (26-33%, P = 0.74). Adipose GPX-3 expression was increased (6.7 ± 4.7-fold, P = 0.004) in the first postoperative week. The improvements in oxidative stress occurred with minimal weight loss (2.4 ± 3.4%, P = 0.031) and elevations in plasma interleukin-6 (18.0 ± 46.8 to 28.0 ± 58.9 pg/ml, P = 0.004). Subcutaneous and visceral adipose tissues express comparable 8-iso-PGF2α levels (1,204 ± 470 and 1,331 ± 264 pg/g fat, respectively; P = 0.34). These data suggest that RYGB affects adipose tissue leading to the restoration of adipose redox balance within the first postoperative week and that plasma 8-iso-PGF2α is primarily derived from subcutaneous adipose tissue.