Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Neutrophil peptidylarginine deiminase 4 plays a systemic role in obesity-induced chronic inflammation in mice.

BACKGROUND: Obesity is an increasing problem in our current society and is expected to keep rising in incidence. With its multiorigin, complex pathophysiology, it is difficult to treat and easy to acquire unnoticeably. During obesity, it has been established that the body is in a constant state of low-grade inflammation, thereby causing changes in immune cell physiology. OBJECTIVES: Here, we investigated the influence of neutrophils, more specifically as a result of peptidylarginine deiminase 4 (PAD4) activity and the release of neutrophil extracellular traps (NETs), during obesity-induced chronic inflammation. METHODS: Wild-type mice were placed on a high-fat diet (HFD) and investigated over a period of 10 weeks for NET formation and its impact on the heart. Neutrophil-selective PAD4 knockout (Ne-PAD4-/-) mice were studied in parallel. RESULTS: As a result of high fat intake, we observed clear alteration in the priming status of isolated neutrophils toward NET release, including early stages of speck formation and histone citrullination of apoptosis-associated speck-like protein containing a CARD. Ne-PAD4-/- mice deficient in NET formation did not increase bodyweight to the same extent as their littermate controls, with Ne-PAD4-/- mice being leaner after 10 weeks of HFD feeding. Interestingly, obesity progression led to cardiac remodeling and diastolic dysfunction in wild-type mice after 10 weeks, while this remodeling and subsequent decrease in function were absent in Ne-PAD4-/- mice. Surprisingly, HFD did not alter NET content or thrombus formation in the inferior vena cava stenosis model. CONCLUSION: Detrimental physiological effects, the result of obesity progression, can in part be attributed to neutrophil PAD4 and NETs in response to chronic inflammation.

Increased acid sphingomyelinase levels in pediatric patients with obesity.

The level of secretory acid sphingomyelinase (S-ASM), a key enzyme in the sphingolipid metabolism, is elevated in a variety of human diseases, including in the serum of obese adults. Alterations in S-ASM were also found to induce morphological changes in erythrocytes. Consequently, the inhibition of S-ASM by functional Inhibitors of ASM (FIASMA) may have broad clinical implications. The purpose of this study was to assess S-ASM activity in pediatric patients with obesity and healthy matched controls, as well as to investigate the erythrocyte morphology using transmission electron microscopy. We recruited 46 obese patients (mean age 11 ± 2.9 years) and 44 controls (mean age 10.8 ± 2.9 years). S-ASM activity was significantly higher (Wilcoxon signed-rank test p-value: 0.004) in obese patients (mean 396.4 ± 49.7 pmol/ml/h) than in controls (mean 373.7 ± 23.1 pmol/ml/h). No evidence of morphological differences in erythrocytes was found between the two populations. We then carried out a case-control study based on the spontaneous reporting system database to compare FIASMAs with NON-FIASMAs in terms of weight gain risk. Children who received FIASMA had a significantly lower frequency of weight gain reports than patients who took NON-FIASMA agents (p < 0.001). Our findings suggest there is an intriguing possibility that S-ASM may play a role in pediatric obesity. This pilot study could serve as the basis for future studies in this interesting field of research.

Emodin inhibits NF-κB signaling pathway to protect obese asthmatic rats from pathological damage via Visfatin.

PURPOSE: Emodin has a protective effect on asthma. Obesity is closely related to asthma. We further explored the role of Emodin in obese asthmatic rats. METHODS: Ovalbumin (OVA) was used to induce asthma model, and high fat diet (HFD) was used to induce obese rat model. Body weight was measured before and after the modeling. Serum lipid levels were evaluated using commercial kits. Then, lung tissue and airway tissue of rat were separated forin vivo. Hematoxylin-eosin staining (HE) analyzed the extent of lung lesions. Quantitative reverse transcription PCR assessed the mRNA expression of Visfatin and Enzyme linked immunosorbent assay measured NF-κB protein expression in airway tissues. MTT, Brdu and Western blot detected cell viability, proliferation and NF-κB level of human bronchial epithelial cells 16HBE, respectively. RESULTS: Asthma and Emodin alone had no effect on the body weight of normal rats, while HFD promoted the body weight of rats and could be reversed by Emodin. Both asthma and obesity promoted the pathological damage of rat lungs, including emphysema, lipid accumulation, edema changes, lymphoid hypertrophy and airway smooth muscle hyperplasia as well as lipid accumulation in surum, and Emodin treatment could reduce the damage. In the airway tissues of asthma and obesity models, up-regulated Visfatin mRNA and NF-κB protein were observed. In 16HBE, Emodin reversed Visfatin's role in promoting cell viability, proliferation and activating NF-κB signaling pathway. CONCLUSION: Emodin inhibited NF-κB expression to relieve the pathological symptoms of obese asthmatic rats by Visfatin.

Deletion of PTP1B From Brain Neurons Partly Protects Mice From Diet-Induced Obesity and Minimally Improves Fertility.

Reproductive dysfunction in women has been linked to high caloric diet (HCD)-feeding and obesity. Central resistance to leptin and insulin have been shown to accompany diet-induced infertility in rodent studies, and we have previously shown that deleting suppressor of cytokine signaling 3, which is a negative regulator of leptin signaling, from all forebrain neurons partially protects mice from HCD-induced infertility. In this study, we were interested in exploring the role of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of both leptin and insulin signaling, in the pathophysiology of HCD-induced obesity and infertility. To this end, we generated male and female neuron-specific PTP1B knockout mice and compared their body weight gain, food intake, glucose tolerance, and fertility relative to control littermates under both normal calorie diet and HCD feeding conditions. Both male and female mice with neuronal PTP1B deletion exhibited slower body weight gain in response to HCD feeding, yet only male knockout mice exhibited improved glucose tolerance compared with controls. Neuronal PTP1B deletion improved the time to first litter in HCD-fed mice but did not protect female mice from eventual HCD-induced infertility. While the mice fed a normal caloric diet remained fertile throughout the 150-day period of assessment, HCD-fed females became infertile after producing only a single litter, regardless of their genotype. These data show that neuronal PTP1B deletion is able to partially protect mice from HCD-induced obesity but is not a critical mediator of HCD-induced infertility.

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice.

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Association between pregravid liver enzyme levels and gestational diabetes in twin pregnancies: a secondary analysis of national cohort study.

Multiple pregnancies are prone to gestational diabetes mellitus (GDM). This study investigated the association between pregravid liver enzyme levels and the development of GDM in a twin pregnancy. Women who had the National Health Screening Examination and delivered their twin babies within one year were enrolled. Pregravid liver enzyme levels were divided into high and low level. Risks for developing GDM by high levels of liver enzymes were analyzed, in subgroups by pregravid obesity or metabolic syndrome. Among the 4348 twin pregnancies, 369 women (8.5%) developed GDM not requiring insulin treatment (GDM - IT), and 119 women (2.7%) developed GDM requiring insulin treatment(GDM + IT). High levels of pregravid GGT and ALT were related to risks of GDM + IT not only in women with obesity or metabolic syndrome (odds ratio[OR] 6.348, 95% confidence interval [CI] 2.579-15.624 and OR 6.879, 95% CI 2.232-21.204, respectively), but also in women without obesity (OR 3.05, 95% CI 1.565-5.946) or without metabolic syndrome (OR 3.338, 95% CI 1.86-5.992), compared to in women with low levels of those. However, there were no significant associations in the pregravid ALT and GGT levels and risks for development of GDM - IT, unrelated to pregravid obesity or metabolic syndrome. Therefore, this study suggests that women with high levels of pregravid GGT and ALT need to recognize their increased risk of GDM + IT, regardless of pregravid obesity or MetS, when they get pregnant twin.

Roles of Nicotinamide N-Methyltransferase in Obesity and Type 2 Diabetes.

Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.

Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity.

BACKGROUND AND AIMS: Oxidative stress plays a key role in the development of metabolic complications associated with obesity, including insulin resistance and the most common chronic liver disease worldwide, nonalcoholic fatty liver disease. We have recently discovered that the microRNA miR-144 regulates protein levels of the master mediator of the antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2). On miR-144 silencing, the expression of NRF2 target genes was significantly upregulated, suggesting that miR-144 controls NRF2 at the level of both protein expression and activity. Here we explored a mechanism whereby hepatic miR-144 inhibited NRF2 activity upon obesity via the regulation of the tricarboxylic acid (TCA) metabolite, fumarate, a potent activator of NRF2. METHODS: We performed transcriptomic analysis in liver macrophages (LMs) of obese mice and identified the immuno-responsive gene 1 (Irg1) as a target of miR-144. IRG1 catalyzes the production of a TCA derivative, itaconate, an inhibitor of succinate dehydrogenase (SDH). TCA enzyme activities and kinetics were analyzed after miR-144 silencing in obese mice and human liver organoids using single-cell activity assays in situ and molecular dynamic simulations. RESULTS: Increased levels of miR-144 in obesity were associated with reduced expression of Irg1, which was restored on miR-144 silencing in vitro and in vivo. Furthermore, miR-144 overexpression reduces Irg1 expression and the production of itaconate in vitro. In alignment with the reduction in IRG1 levels and itaconate production, we observed an upregulation of SDH activity during obesity. Surprisingly, however, fumarate hydratase (FH) activity was also upregulated in obese livers, leading to the depletion of its substrate fumarate. miR-144 silencing selectively reduced the activities of both SDH and FH resulting in the accumulation of their related substrates succinate and fumarate. Moreover, molecular dynamics analyses revealed the potential role of itaconate as a competitive inhibitor of not only SDH but also FH. Combined, these results demonstrate that silencing of miR-144 inhibits the activity of NRF2 through decreased fumarate production in obesity. CONCLUSIONS: Herein we unravel a novel mechanism whereby miR-144 inhibits NRF2 activity through the consumption of fumarate by activation of FH. Our study demonstrates that hepatic miR-144 triggers a hyperactive FH in the TCA cycle leading to an impaired antioxidant response in obesity.

Metformin alleviates monoamine oxidase-related vascular oxidative stress and endothelial dysfunction in rats with diet-induced obesity.

In the past decade, monoamine oxidase (MAO) with 2 isoforms, MAO-A and B, has emerged as an important source of mitochondrial reactive oxygen species (ROS) in cardio-metabolic pathologies. We have previously reported that MAO-related oxidative stress mediates endothelial dysfunction in rodent models of diabetes and diabetic patients; however, the role of MAO in the vascular impairment associated to obesity has not been investigated so far. Metformin (METF), the first-line drug in the therapy of type 2 diabetes mellitus, has been reported to elicit vasculoprotective effects via partially elucidated mechanisms. The present study was purported to assess the effects of METF on MAO expression, ROS production and vasomotor function of aortas isolated from rats with diet-induced obesity. After 24 weeks of high calorie junk food (HCJF) diet, isolated aortic rings were prepared and treated with METF (10 µM, 12 h incubation). Measurements of MAO expression (quantitative PCR and immune histochemistry), ROS production (spectrometry and immune-fluorescence) and vascular reactivity (myograph studies) were performed in rat aortic rings. MAO expression was upregulated in aortic rings isolated from obese rats together with an increase in ROS production and an impairment of vascular reactivity. METF decreased MAO expression and ROS generation, reduced vascular contractility and improved the endothelium-dependent relaxation in the diseased vascular preparations. In conclusion, METF elicited vascular protective effects via the mitigation of MAO-related oxidative stress in the rat model of diet-induced obesity.

Hepatic ADTRP overexpression does not influence lipid and glucose metabolism.

The peroxisome proliferator-activated receptors (PPARs) are a group of transcription factors belonging to the nuclear receptor superfamily. Since most target genes of PPARs are implicated in lipid and glucose metabolism, regulation by PPARs could be used as a screening tool to identify novel genes involved in lipid or glucose metabolism. Here, we identify Adtrp, a serine hydrolase enzyme that was reported to catalyze the hydrolysis of fatty acid esters of hydroxy fatty acids (FAHFAs), as a novel PPAR-regulated gene. Adtrp was significantly upregulated by PPARα activation in mouse primary hepatocytes, liver slices, and whole liver. In addition, Adtrp was upregulated by PPARγ activation in 3L3-L1 adipocytes and in white adipose tissue. ChIP-SEQ identified a strong PPAR-binding site in the immediate upstream promoter of the Adtrp gene. Adenoviral-mediated hepatic overexpression of Adtrp in diet-induced obese mice caused a modest increase in plasma nonesterified fatty acids but did not influence diet-induced obesity, liver triglyceride levels, liver lipidomic profiles, liver transcriptomic profiles, plasma cholesterol, triglyceride, glycerol, and glucose levels. Moreover, hepatic Adtrp overexpression did not lead to significant changes in FAHFA levels in plasma or liver and did not influence glucose and insulin tolerance. Finally, hepatic overexpression of Adtrp did not influence liver triglycerides and levels of plasma metabolites after a 24-h fast. Taken together, our data suggest that despite being a PPAR-regulated gene, hepatic Adtrp does not seem to play a major role in lipid and glucose metabolism and does not regulate FAHFA levels.

Vascular effects of disrupting endothelial mTORC1 signaling in obesity.

The mechanistic target of rapamycin complex 1 (mTORC1) signaling complex is emerging as a critical regulator of cardiovascular function with alterations in this pathway implicated in cardiovascular diseases. In this study, we used animal models and human tissues to examine the role of vascular mTORC1 signaling in the endothelial dysfunction associated with obesity. In mice, obesity induced by high-fat/high-sucrose diet feeding for ∼2 mo resulted in aortic endothelial dysfunction without appreciable changes in vascular mTORC1 signaling. On the other hand, chronic high-fat diet feeding (45% or 60% kcal: ∼9 mo) in mice resulted in endothelial dysfunction associated with elevated vascular mTORC1 signaling. Endothelial cells and visceral adipose vessels isolated from obese humans display a trend toward elevated mTORC1 signaling. Surprisingly, genetic disruption of endothelial mTORC1 signaling through constitutive or tamoxifen inducible deletion of endothelial Raptor (critical subunit of mTORC1) did not prevent or rescue the endothelial dysfunction associated with high-fat diet feeding in mice. Endothelial mTORC1 deficiency also failed to reverse the endothelial dysfunction evoked by a high-fat/high-sucrose diet in mice. Taken together, these data show increased vascular mTORC1 signaling in obesity, but this vascular mTORC1 activation appears not to be required for the development of endothelial impairment in obesity.

Social inequalities and trends in pre-pregnancy body mass index in Swedish women.

Obesity rates in adolescence and young adulthood have increased in Sweden, reflecting global trends. To which extent this occurs across different socioeconomic strata has not been clarified. The aim of the present study was to investigate trends in social inequalities in body mass index (BMI) in young/mid-adulthood Swedish women. We obtained weight and height for all women aged 20-45 years, at their first registered pregnancy (< 12 weeks of gestation) in the Swedish Medical Birth Register 1982-2013 (1,022,330, mean age = 28.8 years), documenting education and county of residence. Trends in mean BMI and in the prevalence of BMI categories between 1982 and 2013 were estimated across education levels and geographical location. Overall, mean BMI increased from 22.7 kg/m2 (SD 3.2) to 24.3 kg/m2 (SD 4.4) between 1982 and 2013. Simultaneously, the prevalence of overweight and obesity (BMI ≥ 25 kg/m2) increased from 18.1 to 33.4% while that of moderate obesity (BMI ≥ 30 to < 35 kg/m2) and severe obesity (BMI ≥ 35 kg/m2) increased markedly from 3.4 and 0.4% to 7.4 and 3.1%, respectively. The prevalence of moderate and severe obesity more than doubled during the study period across all educational levels. In conclusion, BMI and moderate and severe obesity increased markedly among young/mid-adulthood Swedish women regardless of education with a widening gap between those with lower and higher education. These growing social inequalities in BMI are likely to cause a rising divide in serious health problems following early and long-lasting obesity.

AMPK in the gut-liver-brain axis and its influence on OP rats in an HSHF intake and WTD rat model.

Obesogenic diets (ODs) can affect AMPK activation in several sites as the colon, liver, and hypothalamus. OD intake can impair the hypothalamic AMPK regulation of energy homeostasis. Despite consuming ODs, not all subjects have the propensity to develop or progress to obesity. The obesity propensity is more associated with energy intake than expenditure dysregulations and may have a link with AMPK activity. While the effects of ODs are studied widely, few evaluate the short-term effects of terminating OD intake. Withdrawing from OD (WTD) is thought to improve or reverse the damages caused by the intake. Therefore, here we applied an OD intake and WTD protocol aiming to evaluate AMPK protein content and phosphorylation in the colon, liver, and hypothalamus and their relationship with obesity propensity. To this end, male Wistar rats (60 days) received control or high-sugar/high-fat (HSHF) OD for 30 days. Half of the animals were OD-withdrawn and fed the control diet for 48 h. After intake, we found a reduction in AMPK phosphorylation in the hypothalamus and colon, and after WTD, we found an increase in its hepatic and hypothalamic phosphorylation. The decrease in colon pAMPK/AMPK could be linked with hypothalamic pAMPK/AMPK after HSHF intake, while the increase in hepatic pAMPK/AMPK could have prevented the increase in hypothalamic pAMPK/AMPK. In the obesity-prone rats, we found higher levels of hypothalamic and colon pAMPK/AMPK despite the higher body mass gain. Our results highlight the relevance in multi-organ investigations and animal phenotype evaluation when studying the energy metabolism regulations.

Effects of exercise type and intensity on visfatin and the metabolic syndrome in obesity / Efectos del tipo de ejercicio y de la intensidad en la visfatina y el síndrome metabólico en la obesidad / Efeitos do tipo de exercício e da intensidade na visfatina e a síndrome metabólica na obesidade

ABSTRACT Objective: Visfatin may regulate a variety of physiological functions and it has great potential to significantly enhance our knowledge of the treatment of metabolic syndrome. Metabolic syndrome (MS) refers to metabolic abnormalities, such as abdominal obesity, dyslipidemia, high low-density cholesterol, high blood pressure and diabetes, and physical activity is an important factor for the management of MS. Therefore, the purpose of this study is to investigate the effects of visfatin on MS and MS risk factors through differences in aerobic exercise intensity and exercise type based on the premise of the same amount of exercise (energy expenditure of 400 kcal per day). Method: Thirty two obese, middle-aged women were randomly assigned to exercise intensity groups VO2max 50% (MAE, n=8) and VO2max 80% (VAE, n=8) and to type of exercise groups VO2max 50% + TRX (MARE, n=8) and VO2max 80% + TRX (VARE, n=8). The exercise program was performed 5 times a week. The data was analyzed using two-way repeated measures ANOVA and post-hoc tests within groups with LSD. Results: Body weight (p<.01 and p<.001) and % body fat (p<.05 and p<.01) significantly decreased in all groups and visfatin only increased significantly after exercise in the VARE group (p<.05). TG, glucose, and waist circumstance (p<.05, p<.01, and p<.001) significantly decreased in all groups and HDL-C (p<.05) only increased significantly after exercise only in the MARE group. Conclusion: These results suggest that, in spite of differences in exercise intensity and exercise type, exercise is effective in improving obesity and MS risk factors, but further research is needed on the exact mechanisms of visfatin. Level of evidence I; Therapeutic Studies Investigating the Results of Treatment .

RESUMEN Objetivo: La visfatina puede regular diversas funciones fisiológicas y tiene gran potencial para mejorar significativamente nuestro conocimiento sobre el tratamiento del síndrome metabólico. El síndrome metabólico (SM) se refiere a anormalidades metabólicas, como obesidad abdominal, dislipidemia, colesterol de baja densidad elevado, hipertensión y diabetes, siendo la actividad física un factor importante para el manejo del SM. Siendo así, el objetivo de este estudio es investigar los efectos de la visfatina sobre los factores de riesgo de SM por medio de diferencias de la intensidad de ejercicios aeróbicos y del tipo de ejercicio, con base en la premisa de misma cantidad de ejercicio (gasto energético de 400 kcal por día). Método: Treinta y dos mujeres obesas de media edad fueron aleatoriamente designadas para grupos de intensidad de ejercicio con VO2máx de 50% (EAM, n = 8) y VO2máx de 80% (EAV, n = 8) y grupos con VO2máx de 50% + ERC (EARM, n = 8) y VO2máx de 80% + ERC (EARV, n = 8). El programa de ejercicios fue realizado cinco veces por semana. Los datos fueron analizados con ANOVA de dos vías con medidas repetidas y tests post-hoc en los grupos con DMS. Resultados: El peso corporal (p < 0,01 y p < 0,001) y porcentual de grasa corporal (p < 0,05 y p < 0,01) disminuyeron significativamente en todos los grupos y la visfatina sólo aumentó significativamente después del ejercicio en el grupo EARV (p < 0,05). Los triglicéridos, la glucosa y la circunferencia de la cintura (p < 0,05, p < 0,01 e p < 0,001) disminuyeron significativamente en todos los grupos y el HDL-C (p < 0,05) sólo aumentó significativamente después del ejercicio sólo en el grupo EARM. Conclusión: Esos resultados sugieren que, a pesar de las diferencias de intensidad y tipo de los ejercicios, los mismos son eficaces para mejorar la obesidad y los factores de riesgo del SM, por ende, son necesarias más investigaciones sobre los mecanismos exactos de la visfatina. Nivel de Evidencia I; Estudios terapéuticos - Investigación de los resultados del tratamiento .

RESUMO Objetivo: A visfatina pode regular diversas funções fisiológicas e tem grande potencial para aprimorar significativamente nosso conhecimento sobre o tratamento da síndrome metabólica. A síndrome metabólica (SM) refere-se a anormalidades metabólicas, como obesidade abdominal, dislipidemia, colesterol de baixa densidade elevado, hipertensão e diabetes, sendo a atividade física um fator importante para o manejo da SM. Assim sendo, o objetivo deste estudo é investigar os efeitos da visfatina sobre os fatores de risco de SM por meio de diferenças da intensidade de exercícios aeróbicos e do tipo de exercício, com base na premissa de mesma quantidade de exercício (gasto energético de 400 kcal por dia). Método: Trinta e duas mulheres obesas de meia-idade foram randomicamente designadas para grupos de intensidade de exercício com VO2máxde 50% (EAM, n = 8) e VO2máxde 80% (EAV, n = 8) e grupos com VO2máxde 50% + ERC (EARM, n = 8) e VO2máxde 80% + ERC (EARV, n = 8). O programa de exercícios foi realizado 5 vezes por semana. Os dados foram analisados com ANOVA de duas vias com medidas repetidas e testes post-hoc nos grupos com DMS. Resultados: O peso corporal (p < 0,01 e p < 0,001) e percentual de gordura corporal (p < 0,05 e p < 0,01) diminuíram significativamente em todos os grupos e a visfatina só aumentou significativamente depois do exercício no grupo EARV (p < 0,05). Triglicérides, glicose e circunferência da cintura (p < 0,05, p < 0,01 e p < 0,001) diminuíram significativamente em todos os grupos e o HDL-C (p < 0,05) só aumentou significativamente depois o exercício apenas no grupo EARM. Conclusão: Esses resultados sugerem que, apesar das diferenças de intensidade e tipo dos exercícios, eles são eficazes para melhorar a obesidade e os fatores de risco da SM, porém, são necessárias mais pesquisas sobre os mecanismos exatos da visfatina. Nível de Evidência I; Estudos terapêuticos - Investigação dos resultados do tratamento .

Inhibitory effects of xanthine oxidase inhibitor, topiroxostat, on development of neuropathy in db/db mice.

Inflammation and oxidative stress contribute to the pathophysiology of diabetic neuropathy. According to recent evidence, the modulation of macrophage polarization in peripheral nerves represents a potential therapeutic target for diabetic neuropathy. Xanthine oxidase, which is a form of xanthin oxidoreductase, is the rate-limiting enzyme that catalyzes the degradation of hypoxanthine and xanthine into uric acid. Activation of xanthine oxidase promotes oxidative stress and macrophage activation. A preclinical study reported the beneficial effects of xanthine oxidase inhibitors on peripheral nerve dysfunction in experimental models of diabetes. However, the detailed mechanisms remain unknown. In this study, we examined the effect of the xanthine oxidase inhibitor topiroxostat on macrophage polarization and peripheral neuropathy in an obese diabetic model, db/db mice. First, the effects of xanthine oxidase inhibitors on cultured macrophages and dorsal root ganglion neurons exposed to xanthine oxidase were assessed. Furthermore, five-week-old db/db mice were administered the xanthine oxidase inhibitors topiroxostat [1 mg/kg/day (dbT1) or 2 mg/kg/day (dbT2)] or febuxostat [1 mg/kg (dbF)]. Glucose metabolism and body weight were evaluated during the experimental period. At 4 and 8 weeks of treatment, peripheral nerve functions such as nerve conduction velocities, thermal thresholds and pathology of skin and sciatic nerves were evaluated. The mRNA expression of molecules related to inflammation and oxidative stress was also measured in sciatic nerves. Untreated db/db mice and the nondiabetic db strain (db/m) were studied for comparison. An in vitro study showed that topiroxostat suppressed macrophage activation and proinflammatory but not anti-inflammatory polarization, and prevented the reduction in neurite outgrowth from neurons exposed to xanthine oxidase. Neuropathic changes exemplified by delayed nerve conduction and reduced intraepidermal nerve fiber density developed in db/db mice. These deficits were significantly prevented in the treated group, most potently in dbT2. Protective effects were associated with the suppression of macrophage infiltration, cytokine expression, and oxidative stress in the sciatic nerve and decreased plasma xanthine oxidoreductase activity. Our results revealed the beneficial effects of the xanthine oxidase inhibitor topiroxostat on neuropathy development in a mouse model of type 2 diabetes. The suppression of proinflammatory macrophage activation and oxidative stress-induced damage were suggested to be involved in this process.

Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, obesity, and activation of the renin angiotensin system.

BACKGROUND: Diabetic and obese patients are at higher risk of severe disease and cardiac injury in corona virus 2 (SARS-CoV-2) infections. Cellular entry of SARS-CoV-2 is mainly via the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in normal hearts. There is a disagreement regarding the effect of factors such as obesity and diabetes on ACE2 expression in the human heart and whether treatment with renin-angiotensin system inhibitors or anti-diabetic medications increases ACE2 expression and subsequently the susceptibility to infection. We designed this study to elucidate factors that control ACE2 expression in human serum, human heart biopsies, and mice. METHODS: Right atrial appendage biopsies were collected from 79 patients that underwent coronary artery bypass graft (CABG) surgery. We investigated the alteration in ACE2 mRNA and protein expression in heart tissue and serum. ACE2 expression was compared with clinical risk factors: diabetes, obesity and different anti-hypertensive or anti-diabetic therapies. WT or db/db mice were infused with Angiotensin II (ATII), treated with different anti-diabetic drugs (Metformin, GLP1A and SGLT2i) were also tested. RESULTS: ACE2 gene expression was increased in diabetic hearts compared to non-diabetic hearts and was positively correlated with glycosylated hemoglobin (HbA1c), body mass index (BMI), and activation of the renin angiotensin system (RAS), and negatively correlated with ejection fraction. ACE2 was not differentially expressed in patients who were on angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prior to the operation. We found no correlation between plasma free ACE2 and cardiac tissue ACE2 expression. Transmembrane serine protease 2 (TMPRSS2), metalloprotease ADAM10 and ADAM17 that facilitate viral-ACE2 complex entry and degradation were increased in diabetic hearts. ACE2 expression in mice was increased with ATII infusion and attenuated following anti-diabetic drugs treatment. CONCLUSION: Patients with uncontrolled diabetes or obesity with RAS activation have higher ACE2 expressions therefore are at higher risk for severe infection. Since ACEi or ARBs show no effect on ACE2 expression in the heart further support their safety.

Assessing the In Vitro Inhibitory Effects on Key Enzymes Linked to Type-2 Diabetes and Obesity and Protein Glycation by Phenolic Compounds of Lauraceae Plant Species Endemic to the Laurisilva Forest.

Methanolic leaf extracts of four Lauraceae species endemic to Laurisilva forest (Apollonias barbujana, Laurus novocanariensis, Ocotea foetens and Persea indica) were investigated for the first time for their potential to inhibit key enzymes linked to type-2 diabetes (α-amylase, α-glucosidase, aldose reductase) and obesity (pancreatic lipase), and protein glycation. Lauraceae extracts revealed significant inhibitory activities in all assays, altough with different ability between species. In general, P. indica showed the most promissing results. In the protein glycation assay, all analysed extracts displayed a stronger effect than a reference compound: aminoguanidine (AMG). The in vitro anti-diabetic, anti-obesity and anti-glycation activities of analysed extracts showed correlation with their flavonols and flavan-3-ols (in particular, proanthocyanins) contents. These Lauraceae species have the capacity to assist in adjuvant therapy of type-2 diabetes and associated complications, through modulation of the activity of key metabolic enzymes and prevention of advanced glycation end-products (AGEs) formation.