Adults with excess weight or obesity, but not with overweight, report greater pain intensities than individuals with normal weight: a systematic review and meta-analysis.

Context: Over 1.9 billion adult people have overweight or obesity. Considered as a chronic disease itself, obesity is associated with several comorbidities. Chronic pain affects approximately 60 million people and its connection with obesity has been displayed in several studies. However, controversial results showing both lower and higher pain thresholds in subjects with obesity compared to individuals with normal weight and the different parameters used to define such association (e.g., pain severity, frequency or duration) make it hard to draw straight forward conclusions in the matter. The objective of this article is to examine the relationship between overweight and obesity (classified with BMI as recommended by WHO) and self-perceived pain intensity in adults. Methods: A literature search was conducted following PRISMA guidelines using the databases CINAHL, Cochrane Library, EMBASE, PEDro, PubMed, Scopus and Web of Science to identify original studies that provide BMI values and their associated pain intensity assessed by self-report scales. Self-report pain scores were normalized and pooled within meta-analyses. The Cochrane's Q test and I2 index were used to clarify the amount of heterogeneity; meta-regression was performed to explore the relationship between each outcome and the risk of bias. Results: Of 2194 studies, 31 eligible studies were identified and appraised, 22 of which provided data for a quantitative analysis. The results herein suggested that adults with excess weight (BMI ≥ 25.0) or obesity (BMI ≥ 30.0) but not with overweight (pre-obesity) alone (BMI 25.0-29.9), are more likely to report greater intensities of pain than individuals of normal weight (BMI 18.5-24.9). Subgroup analyses regarding the pathology of the patients showed no statistically significant differences between groups. Also, influence of age in the effect size, evaluated by meta-regression, was only observed in one of the four analyses. Furthermore, the robustness of the findings was supported by two different sensitivity analyses. Conclusion: Subjects with obesity and excess weight, but not overweight, reported greater pain intensities than individuals with normal weight. This finding encourages treatment of obesity as a component of pain management. More research is required to better understand the mechanisms of these differences and the clinical utility of the findings. Systematic Review Registration: https://doi.org/10.17605/OSF.IO/RF2G3, identifier OSF.IO/RF2G3.

Interleukin-16 is increased in obesity and alters adipogenesis and inflammation in vitro.

Introduction: Obesity is a chronic condition associated with low-grade inflammation mainly due to immune cell infiltration of white adipose tissue (WAT). WAT is distributed into two main depots: subcutaneous WAT (sWAT) and visceral WAT (vWAT), each with different biochemical features and metabolic roles. Proinflammatory cytokines including interleukin (IL)-16 are secreted by both adipocytes and infiltrated immune cells to upregulate inflammation. IL-16 has been widely studied in the peripheral proinflammatory immune response; however, little is known about its role in adipocytes in the context of obesity. Aim & Methods: We aimed to study the levels of IL-16 in WAT derived from sWAT and vWAT depots of humans with obesity and the role of this cytokine in palmitate-exposed 3T3-L1 adipocytes. Results: The results demonstrated that IL-16 expression was higher in vWAT compared with sWAT in individuals with obesity. In addition, IL-16 serum levels were higher in patients with obesity compared with normal-weight individuals, increased at 6 months after bariatric surgery, and at 12 months after surgery decreased to levels similar to before the intervention. Our in vitro models showed that IL-16 could modulate markers of adipogenesis (Pref1), lipid metabolism (Plin1, Cd36, and Glut4), fibrosis (Hif1a, Col4a, Col6a, and Vegf), and inflammatory signaling (IL6) during adipogenesis and in mature adipocytes. In addition, lipid accumulation and glycerol release assays suggested lipolysis alteration. Discussion: Our results suggest a potential role of IL-16 in adipogenesis, lipid and glucose homeostasis, fibrosis, and inflammation in an obesity context.

Claudin-1 as a novel target gene induced in obesity and associated to inflammation, fibrosis, and cell differentiation.

OBJECTIVE: T lymphocytes from visceral and subcutaneous white adipose tissues (vWAT and sWAT, respectively) can have opposing roles in the systemic metabolic changes associated with obesity. However, few studies have focused on this subject. Claudin-1 (CLDN1) is a protein involved canonically in tight junctions and tissue paracellular permeability. We evaluated T-lymphocyte gene expression in vWAT and sWAT and in the whole adipose depots in human samples. METHODS: A Clariom D-based transcriptomic analysis was performed on T lymphocytes magnetically separated from vWAT and sWAT from patients with obesity (Cohort 1; N = 11). Expression of candidate genes resulting from that analysis was determined in whole WAT from individuals with and without obesity (Cohort 2; patients with obesity: N = 13; patients without obesity: N = 14). RESULTS: We observed transcriptional differences between T lymphocytes from sWAT compared with vWAT. Specifically, CLDN1 expression was found to be dramatically induced in vWAT T cells relative to those isolated from sWAT in patients with obesity. CLDN1 was also induced in obesity in vWAT and its expression correlates with genes involved in inflammation, fibrosis, and adipogenesis. CONCLUSION: These results suggest that CLDN1 is a novel marker induced in obesity and differentially expressed in T lymphocytes infiltrated in human vWAT as compared with sWAT. This protein may have a crucial role in the crosstalk between T lymphocytes and other adipose tissue cells and may contribute to inflammation, fibrosis, and alter homeostasis and promote metabolic disease in obesity.

DIDO is necessary for the adipogenesis that promotes diet-induced obesity.

The prevalence of overweight and obesity continues to rise in the population worldwide. Because it is an important predisposing factor for cancer, cardiovascular diseases, diabetes mellitus, and COVID-19, obesity reduces life expectancy. Adipose tissue (AT), the main fat storage organ with endocrine capacity, plays fundamental roles in systemic metabolism and obesity-related diseases. Dysfunctional AT can induce excess or reduced body fat (lipodystrophy). Dido1 is a marker gene for stemness; gene-targeting experiments compromised several functions ranging from cell division to embryonic stem cell differentiation, both in vivo and in vitro. We report that mutant mice lacking the DIDO N terminus show a lean phenotype. This consists of reduced AT and hypolipidemia, even when mice are fed a high-nutrient diet. DIDO mutation caused hypothermia due to lipoatrophy of white adipose tissue (WAT) and dermal fat thinning. Deep sequencing of the epididymal white fat (Epi WAT) transcriptome supported Dido1 control of the cellular lipid metabolic process. We found that, by controlling the expression of transcription factors such as C/EBPα or PPARγ, Dido1 is necessary for adipocyte differentiation, and that restoring their expression reestablished adipogenesis capacity in Dido1 mutants. Our model differs from other lipodystrophic mice and could constitute a new system for the development of therapeutic intervention in obesity.

Lipidome Profiling in Childhood Obesity Compared to Adults: A Pilot Study.

The objective is to assess the circulating lipidome of children with obesity before and after lifestyle intervention and to compare the data to the circulating lipidome of adults with obesity before and after bariatric surgery. Ten pediatric (PE) and thirty adult (AD) patients with obesity were prospectively recruited at a referral single center. The PE cohort received lifestyle recommendations. The AD cohort underwent bariatric surgery. Clinical parameters and lipidome were analyzed in serum before and after six months of metabolic intervention. The abundance of phosphatidylinositols in the PE cohort and phosphatidylcholines in the AD significantly increased, while O-phosphatidylserines in the PE cohort and diacyl/triacylglycerols in the AD decreased. Fifteen lipid species were coincident in both groups after lifestyle intervention and bariatric surgery. Five species of phosphatidylinositols, sphingomyelins, and cholesteryl esters were upregulated. Eight species of diacylglycerols, glycerophosphoglycerols, glycerophosphoethanolamines, and phosphatidylcholines were downregulated. Most matching species were regulated in the same direction except for two phosphatidylinositols: PI(O-36:2) and PI(O-34:0). A specific set of lipid species regulated after bariatric surgery in adult individuals was also modulated in children undergoing lifestyle intervention, suggesting they may constitute a core circulating lipid profile signature indicative of early development of obesity and improvement after clinical interventions regardless of individual age.

microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction.

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

p27Kip1 Deficiency Impairs Brown Adipose Tissue Function Favouring Fat Accumulation in Mice.

The aim of this work was to investigate the effect of the whole-body deletion of p27 on the activity of brown adipose tissue and the susceptibility to develop obesity and glucose homeostasis disturbances in mice, especially when subjected to a high fat diet. p27 knockout (p27-/-) and wild type (WT) mice were fed a normal chow diet or a high fat diet (HFD) for 10-weeks. Body weight and composition were assessed. Insulin and glucose tolerance tests and indirect calorimetry assays were performed. Histological analysis of interscapular BAT (iBAT) was carried out, and expression of key genes/proteins involved in BAT function were characterized by qPCR and Western blot. iBAT activity was estimated by 18F-fluorodeoxyglucose (18FDG) uptake with microPET. p27-/- mice were more prone to develop obesity and insulin resistance, exhibiting increased size of all fat depots. p27-/- mice displayed a higher respiratory exchange ratio. iBAT presented larger adipocytes in p27-/- HFD mice, accompanied by downregulation of both Glut1 and uncoupling protein 1 (UCP1) in parallel with defective insulin signalling. Moreover, p27-/- HFD mice exhibited impaired response to cold exposure, characterized by a reduced iBAT 18FDG uptake and difficulty to maintain body temperature when exposed to cold compared to WT HFD mice, suggesting reduced thermogenic capacity. These data suggest that p27 could play a role in BAT activation and in the susceptibility to develop obesity and insulin resistance.

Potential benefits of egg white hydrolysate in the prevention of Hg-induced dysfunction in adipose tissue.

Aim: To investigate the effects of egg white hydrolysate (EWH) on the lipid and glycemic metabolism disruption in the white adipose tissue (WAT) dysfunction induced by mercury (Hg). Experimental: Wistar rats were treated for 60 days: control (saline, intramuscular - i.m.); hydrolysate (EWH, gavage, 1 g kg-1 day-1); mercury (HgCl2, i.m., 1st dose 4.6 µg kg-1, subsequent doses 0.07 µg kg-1 day-1) and hydrolysate-mercury (EWH-HgCl2). Hg level and histological analyses were performed in epididymal WAT (eWAT), pancreas and liver. GRP78, CHOP, PPARα, PPARγ, leptin, adiponectin, and CD11 mRNA expressions were analyzed in eWAT. The plasma lipid profile, glucose, and insulin levels were measured. Antioxidant status was also evaluated in the plasma and liver. Results: EWH intake prevented the reduced eWAT weight, adipocyte size, insulin levels, and antioxidant defenses and the increased glucose and triglyceride levels induced by Hg exposure; hepatic glutathione levels were higher in rats co-treated with EWH. The increased mRNA expression of CHOP, PPARα, and leptin induced by Hg was reduced in co-treated rats. EWH did not modify the elevated mRNA expression of GRP78, PPARγ and adiponectin in Hg-treated rats. Increased levels of Hg were found in the liver; the co-treatment did not alter this parameter. EWH prevented the morphological and metabolic disorder induced by Hg, by improving antioxidant defenses, inactivating pro-apoptotic pathways and normalizing the mRNA expression of PPARs and adipokines. Its effects enabled an increase in insulin levels and a normal balance between the fat storage and expenditure mechanisms in WAT. Conclusions: EWH may have potential benefits in the prevention and management of Hg-related metabolic disorders.

Tackling the effects of extracellular vesicles in fibrosis.

Fibrosis is a physiological process of tissue repair that turns into pathological when becomes chronic, damaging the functional structure of the tissue. In this review we outline the current status of extracellular vesicles as modulators of the fibrotic process at different levels. In adipose tissue, extracellular vesicles mediate the intercellular communication not only between adipocytes, but also between adipocytes and other cells of the stromal vascular fraction. Thus, they could be altering essential processes for the functionality of adipose tissue, such as adipocyte hypertrophy/hyperplasia, tissue plasticity, adipogenesis and/or inflammation, and ultimately trigger fibrosis. This process is particularly important in obesity, and may eventually, influence the development of obesity-associated alterations. In this regard, obesity is now recognized as an independent risk factor for the development of chronic kidney disease, although the role of extracellular vesicles in this connection has not been explored so far. Nonetheless, the role of extracellular vesicles in the onset and progression of renal fibrosis has been highlighted due to the critical role of fibrosis as a common feature of kidney diseases. In fact, the content of extracellular vesicles disturbs cellular signaling cascades involved in fibrosis in virtually all types of renal cells. What is certain is that the study of extracellular vesicles is complex, as their isolation and manipulation is still difficult to reproduce, which complicates the overview of their physiopathological effects. Nevertheless, new strategies have been developed to exploit the potential of extracellular vesicles and their cargo, both as biomarkers and as therapeutic tools to prevent the progression of fibrosis towards an irreversible event.

Pleiotrophin Deficiency Induces Browning of Periovarian Adipose Tissue and Protects against High-Fat Diet-Induced Hepatic Steatosis.

(1) Background: Pleiotrophin preserves insulin sensitivity, regulates adipose tissue lipid turnover and plasticity, energy metabolism and thermogenesis. The aim of this study was to determine the role of pleiotrophin in hepatic lipid metabolism and in the metabolic crosstalk between the liver and brown and white adipose tissue (AT) in a high-fat diet-induced (HFD) obesity mice model. (2) Methods: We analyzed circulating variables, lipid metabolism (hepatic lipid content and mRNA expression), brown AT thermogenesis (UCP-1 expression) and periovarian AT browning (brown adipocyte markers mRNA and immunodetection) in Ptn-/- mice either fed with standard-chow diet or with HFD and in their corresponding Ptn+/+ counterparts. (3) Results: HFD-Ptn-/- mice are protected against the development of HFD-induced insulin resistance, had lower liver lipid content and lower expression of the key enzymes involved in triacylglycerides and fatty acid synthesis in liver. HFD-Ptn-/- mice showed higher UCP-1 expression in brown AT. Moreover, Ptn deletion increased the expression of specific markers of brown/beige adipocytes and was associated with the immunodetection of UCP-1 enriched multilocular adipocytes in periovarian AT. (4) Conclusions: Ptn deletion protects against the development of HFD-induced insulin resistance and liver steatosis, by increasing UCP-1 expression in brown AT and promoting periovarian AT browning.

Transforming growth factor ß3 deficiency promotes defective lipid metabolism and fibrosis in murine kidney.

Glomerulosclerosis and tubulointerstitial fibrosis are pathological features of chronic kidney disease. Transforming growth factor ß (TGFß) is a key player in the development of fibrosis. However, of the three known TGFß isoforms, only TGFß1 has an established role in fibrosis, and the pathophysiological relevance of TGFß2 and TGFß3 is unknown. Because Tgfb3 deficiency in mice results in early postnatal lethality, we analyzed the kidney phenotype of heterozygous Tgfb3-knockout mice (Tgfb3+/-) and compared it with that of matched wild-type mice. Four-month-old Tgfb3+/- mice exhibited incipient renal fibrosis with epithelial-mesenchymal transition, in addition to glomerular basement membrane thickening and podocyte foot process effacement associated with albuminuria. Also evident was insulin resistance and oxidative stress at the renal level, together with aberrant renal lipid metabolism and mitochondrial function. Omics analysis revealed toxic species, such as diacylglycerides and ceramides, and dysregulated mitochondrial metabolism in Tgfb3+/- mice. Kidneys of Tgfb3+/- mice showed morphological alterations of mitochondria and overactivation of non-canonical MAPK ERK1/2 and JNK cascades. Our study indicates that renal TGFß3 might have antifibrotic and renoprotective properties, opposing or counteracting the activity of TGFß1. This article has an associated First Person interview with the first author of the paper.

Obesity and pregnancy, the perfect metabolic storm.

Pregnancy is a physiological stress that requires dynamic, regulated changes affecting maternal and fetal adiposity. Excessive accumulation of dysfunctional adipose tissue defined by metabolic and molecular alterations cause severe health consequences for mother and fetus. When subjected to sustained overnutrition, the cellular and lipid composition of the adipose tissue changes predisposing to insulin resistance, diabetes, and other metabolic disorders compromising the outcome of the pregnancy. Moreover, excessive maternal weight gain, usually in the context of obesity, predisposes to an increased flux of nutrients from mother to fetus throughout the placenta. The fetus of an obese mother will accumulate more adiposity and may increase the risk of future metabolic disorder later in life. Thus, further understanding of the interaction between maternal metabolism, epigenetic regulation of the adipose tissue, and their transgenerational transfer are required to mitigate the adverse health outcomes for the mother and the fetus associated with maternal obesity.

Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity.

Age-related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle-aged (12 months), and old (20 months) mice fed al libitum and middle-aged and old mice subjected to early-onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle-aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle-aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordingly, CR attenuated the age-related decline in scWAT function and decreased the extent of fibro-inflammation. Furthermore, CR promoted scWAT browning. In brief, our study identifies the contribution of scWAT impairment to age-associated metabolic dysfunction and identifies browning in response to food restriction, as a potential therapeutic strategy to prevent the adverse metabolic effects in middle-aged animals.

Chronic mercury at low doses impairs white adipose tissue plasticity.

INTRODUCTION: The toxic effects of mercury (Hg) are involved in homeostasis of energy systems such as lipid and glucose metabolism, and white adipose tissue dysfunction is considered as a central mechanism leading to metabolic disorders. OBJECTIVE: The aim of this study was to determine the effects of chronic inorganic Hg exposure at low doses on the lipid and glycemic metabolism. METHODS: Male Wistar rats were divided into two groups and treated for 60 days with: saline solution, i.m. (Untreated) and mercury chloride, i.m. - 1st dose 4.6 µg/kg, subsequent doses 0.07 µg/kg/day - (Mercury). Histological analyses, Hg levels measurement and GRP78, CHOP, PPARα, PPARγ, leptin, adiponectin and CD11 mRNA expressions were performed in epididymal white adipose tissue (eWAT). Glucose, triglycerides, total cholesterol and insulin plasma levels were also measured. RESULTS: Hg exposure reduced the absolute and relative eWAT weights, adipocyte size, plasma insulin levels, glucose tolerance, antioxidant defenses and increased plasma glucose and triglyceride levels. In addition, CHOP, GRP78, PPARα, PPARγ, leptin and adiponectin mRNA expressions were increased in Hg-treated animals. No differences in Hg concentration were found in eWAT between the untreated and Hg groups. These results suggest that the reduction in adipocyte size is related to the impaired antioxidant defenses, endoplasmic reticulum (ER) stress, the disrupted PPARs and adipokines mRNA expression induced by the metal in eWAT. These disturbances possibly induced a decrease in circulating insulin levels, an imbalance between lipolysis and lipogenesis mechanisms in eWAT, with an increase in fatty acids mobilization, a reduction in glucose uptake and an activation of pro-apoptotic pathways, leading to hyperglycemia and hyperlipidemia. CONCLUSIONS: Hg is a powerful environmental WAT disruptor that influences signaling events and impairs metabolic activity and hormonal balance of adipocytes.

Transforming Growth Factor-ß3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue.

White adipose tissue (WAT) mass is determined by adipocyte size and number. While adipocytes are continuously turned over, the mechanisms controlling fat cell number in WAT upon weight changes are unclear. Herein, prospective studies of human subcutaneous WAT demonstrate that weight gain increases both adipocyte size and number, but the latter remains unaltered after weight loss. Transcriptome analyses associate changes in adipocyte number with the expression of 79 genes. This gene set is enriched for growth factors, out of which one, transforming growth factor-ß3 (TGFß3), stimulates adipocyte progenitor proliferation, resulting in a higher number of cells undergoing differentiation in vitro. The relevance of these observations was corroborated in vivo where Tgfb3+/- mice, in comparison with wild-type littermates, display lower subcutaneous adipocyte progenitor proliferation, WAT hypertrophy, and glucose intolerance. TGFß3 is therefore a regulator of subcutaneous adipocyte number and may link WAT morphology to glucose metabolism.

Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARγ expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPARγ in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPARγ is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPARγ have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPARγ in renal metabolism as a likely key factor in the maintenance of systemic homeostasis.

PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity.

Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions.

Egg white-derived peptides prevent cardiovascular disorders induced by mercury in rats: Role of angiotensin-converting enzyme (ACE) and NADPH oxidase.

The study aimed to investigate the effects of egg white hydrolysate (EWH) on vascular disorders induced by mercury (Hg). For this, male Wistar rats were treated for 60days: Untreated (saline, i.m.); Mercury (HgCl2, i.m., 1st dose 4.6µg/kg, subsequent doses 0.07µg/kg/day); Hydrolysate (EWH, gavage, 1g/kg/day); Hydrolysate-Mercury. Systolic (SBP) and diastolic (DBP) blood pressure measurement and vascular reactivity experiments in aorta were performed. We analyzed endothelial dependent and independent vasodilator responses and vasoconstrictor response to phenylephrine (Phe) in absence and presence of endothelium, a NOS inhibitor, a NADPH oxidase inhibitor, the superoxide dismutase, a non-selective COX inhibitor, a selective COX-2 inhibitor, an AT-1 receptors blocker. In situ superoxide anion production, SOD-1, NOX-4, p22phox, COX-2 and AT-1 mRNA levels and NOX-1 protein expression were performed in aorta while the determination of angiotensin converting enzyme (ACE) activity was measured in plasma. As results, EWH prevented the increase in SBP and Phe responses and the endothelial dysfunction elicited by Hg, which was related to decreased ACE activity and NOX activation by EWH and, subsequently, alleviated ROS production and improved NO bioavailability in aorta. In conclusion, EWH could be considered as alternative or complementary treatment tools for Hg-induced cardiovascular damage.

Peroxisome proliferator activated receptor gamma 2 modulates late pregnancy homeostatic metabolic adaptations.

Pregnancy requires the adaptation of maternal energy metabolism including expansion and functional modifications of adipose tissue. Insulin resistance (IR), predominantly during late gestation, is a physiological metabolic adaptation that serves to support the metabolic demands of fetal growth. The molecular mechanisms underlying these adaptations are not fully understood and may contribute to gestational diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPARγ) controls adipogenesis, glucose and lipid metabolism and insulin sensitivity. The PPARγ2 isoform is mainly expressed in adipocytes and is thus likely to contribute to adipose tissue adaptation during late pregnancy. In the present study, we investigated the contribution of PPARγ2 to the metabolic adaptations occurring during the late phase of pregnancy in the context of IR. Using a model of late pregnancy in PPARγ2 knockout (KO) mice, we found that deletion of PPARγ2 exacerbated IR in association with lower serum adiponectin levels, increased body weight and enhanced lipid accumulation in liver. Lack of PPARγ2 provoked changes in the distribution of fat mass and preferentially prevented the expansion of the perigonadal depot while at the same time exacerbating inflammation. PPARγ2KO pregnant mice presented adipose tissue depot-dependent decreased expression of genes involved in lipid metabolism. Collectively, these data indicate that PPARγ2 is essential to promote healthy adipose tissue expansion and immune and metabolic functionality during pregnancy, contributing to the physiological adaptations that lead gestation to term.