Effects of eicosapentaenoic acid ethyl ester on visfatin and apelin in lean and overweight (cafeteria diet-fed) rats

Previous studies have demonstrated that the n-3 fatty acid EPA improves insulin resistance induced by high-fat diets. The aim of the present study was to investigate the potential role of visfatin and apelin in the insulin-sensitising effects of EPA ethyl ester. The effects of EPA on muscle and adipose GLUT mRNA, as well as on liver glucokinase (GK) and glucose-6-phosphatase (G6Pase) activity, were investigated. Male Wistar rats fed on a standard diet or a high-fat cafeteria diet were daily treated by oral administration with EPA ethyl ester (1 g/kg) for 5 weeks. A significant decrease (P,0·01) in white adipose tissue (WAT) visfatin mRNA levels was found in the cafeteria-fed rats, which was reversed by EPA administration (P,0·05). Moreover, a negative relationship was observed between homeostatic model assessment (HOMA) and the visfatin:total WAT ratio. In contrast, cafeteria-diet feeding caused a significant increase (P,0·01) in apelin mRNA in visceral WAT. EPA increased (P,0·01) apelin gene expression, and a negative relationship between HOMA index with visceral apelin mRNA and serum apelin:total WAT ratio was also observed. EPA treatment did not induce changes in skeletal muscle GLUT1, GLUT4 or insulin receptor mRNA levels. Neither liver GK and G6Pase activity nor the GK:G6Pase ratio was modified by EPA. These data suggest that somehow the insulin-sensitising effects of EPA could be related to its stimulatory action on both visfatin and apelin gene expression in visceral fat, while changes in skeletal muscle GLUT, as well as in hepatic glucose production, are not likely to be the main contributing factors in the improvement in insulin resistance induced by EPA

Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes

Lipoic acid (LA) is an antioxidant with therapeutic potential on several diseases such as diabetes and obesity. Hyperleptinemia and oxidative stress play a major role in the development of obesity-linked diseases. The aim of this study was to examine in vivo and in vitro the effects of LA on leptin production, as well as to elucidate the mechanisms and signalling pathways involved in LA actions. Methods and results: Dietary supplementation with LA decreased both circulating leptin, and adipose tissue leptin mRNA in rats. Treatment of 3T3-L1 adipocytes with LA caused a concentration-dependent inhibition of leptin secretion and gene expression. Moreover, LA stimulated the anaerobic utilization of glucose to lactate, which negatively correlated with leptin secretion. Furthermore, LA enhanced phosphorylation of Sp1 and inhibited Sp1 transcriptional activity in 3T3-L1 adipocytes. Moreover, LA inhibited Akt phosphorylation, a downstream target of phosphatidylinositol 3-kinase (PI3K). Treatment with the PI3K inhibitor LY294002 mimicked LA actions, dramatically inhibiting both leptin secretion and gene expression and stimulating Sp1 phosphorylation. Conclusion: All of these data suggest that the phosphorylation of Sp1 and the accompanying reduced DNA-binding activity are likely to be involved in the inhibition of leptin induced by LA, which could be mediated in part by the abrogation of the PI3K/Akt pathway

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Effects of α-lipoic acid on lipid metabolism and mitochondrial biogenesis in adipocytes: study of the molecular mechanisms involved

α-lipoic acid (5-(1,2-dithiolan-3-yl)-pentanoic acid) is a natural occurring compound which possesses antioxidant properties. Moreover, anti-obesity properties in both rodents and humans have been attributed to α-lipoic acid being adipose tissue a target for this compound. In this context, the present study has demonstrated the ability of α-LA to modulate lipid metabolism in both murine and human white adipocytes. Thus, α-LA: 1) Inhibits fatty acids uptake (through CD36 downregulation); 2) Reduces fatty acids esterification into triglycerides (through DGAT1 reduction); 3) Decreases de novo lipogenesis (induced by inhibition of FAS, SCD1 and ACC mediated by AMPK activation); 4) Stimulates lipolysis (mainly mediated by the phosphorylation of HSL through cAMP-mediated activation of PKA, probably through the inhibition of AdPLA and PGE2; 5) Increases fatty acid oxidation machinery (CPT1 and ACOX) in white adipocytes; 6) Promotes mitochondrial biogenesis by the activation of PGC-1α mediated by SIRT1 and AMPK activation; and 7) Induces a brown-like remodelling in white subcutaneous adipocytes from overweight/obese subjects. Taking together all of these facts suggest that α-LA remodels adipocyte metabolism towards oxidation rather than storage, and this could contribute to the anti-obesity properties of α-LA

Suplementación de la dieta con ácido lipoico como medida para combatir la obesidad y la insulina-resistencia: Estudio de los mecanismos implicados

La hipótesis del presente trabajo es que el LA pudiera ejercer sus efectos antiobesidad y antidiabetes a través de la regulación de la producción de adipoquinas por el tejido adiposo así como mediante la regulación del transporte intestinal de azúcares. Por ello, el objetivo general del presente trabajo fue investigar el papel preventivo de la suplementación de la dieta con LA sobre el desarrollo de la obesidad en un modelo animal de obesidad inducido por una dieta alta en grasa, así como los potenciales mecanismos implicados fundamentalmente a nivel de tejido adiposo y del intestino utilizando también para ello diversos modelos experimentales ex vivo e in vitro. Por todo ello, los objetivos específicos del presente trabajo fueron: 1.-Determinar los efectos del tratamiento con LA sobre la ganancia de peso, la composición corporal y diferentes parámetros del metabolismo glucídico, tanto enratas alimentadas con una dieta estándar como en ratas a las que se induce obesidad por una dieta alta en grasa. 2.-Investigar el efecto del LA sobre la absorción intestinal de azúcares. 3.-Analizar si los efectos del LA in vivo están mediados por cambios en la expresión y secreción de tres adipoquinas relacionadas con el control del peso corporal, la sensibilidad a la insulina y la inflamación: leptina, adiponectina, y chemerina. 4.-Identificar los posibles mecanismos moleculares que subyacen a las acciones del LA sobre la secreción de dichas adipoquinas en cultivos de adipocitos

Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-a[alfa]

n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P¼0·09), a decrease in food intake (P,0·01) and an increase in leptin production (P,0·05). EPA administration reduced retroperitoneal adipose tissue weight (P,0·05) which could be secondary to the inhibition of the adipogenic transcription factor PPARg gene expression (P,0·001), and also to the increase in apoptosis (P,0·05) found in rats fed with a control diet. TNFa gene expression was significantly increased (P,0·05) by the cafeteria diet, while EPA treatment was able to prevent (P,0·01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFa and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet

Efectos del AL sobre la función mitocondrial y el estrés oxidativo en la NAFLD asociada a obesidad

Non-alcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. In this context, the sirtuin family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant dfenses. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. In this thesis, the potential protective effect of LA supplementation against the development of non-alcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanisms involved in these effects were analyzed. Particularly, I researched the effects of LA on the modulation of mitochondrial defenses through the situin pathway. To achieved these objectives, male Wistar rats were fed a standard diet (C, n=10) and a high-fat diet supplemented with LA (OLIP, n=10). A group pair-fed to the latter group (PFO, n=6) was also included. LA prevents hepatic triglyceride accumulation and liver damage in rats fed on a high-fat diet, through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation, and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities and ATP synthesis, and reduced significantly energy efficiency. By contrast, LA induces an increase in mitochondrial copy number and in Ucp2 gene expression. Moreover, LA prevents liver oxidative damage through the inhibition of hydroperoxide production and the simulation of mitochondrial antioxidant defenses. LA treatment up-regulated manganese superoxide dismutase and glutathione peroxidase activities, and increased the GSH: GSSG ratio and UCP2 mRNA levels. Moreover, this molecule reduced oxidative damage in mitochondrial DNA and increased mitochondrial copy number. LA treatment decreased the acetylation levels of Foxo3a and PGC1β through the stimulation of SIRT3 and SIRT1. In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis coud be mediated by its ability to restore the oxidative balance by increasing antioxidant defenses through the deacetylation of Foxo3a and PGC1β by SIRT1 and SIRT3. Finally, the novelty and importance of this study is the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain

Efectos del AL sobre la función mitocondrial y el estrés oxidativo en la NAFLD asociada a obesidad

Non-alcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. In this context, the sirtuin family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant dfenses. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. In this thesis, the potential protective effect of LA supplementation against the development of non-alcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanisms involved in these effects were analyzed. Particularly, I researched the effects of LA on the modulation of mitochondrial defenses through the situin pathway. To achieved these objectives, male Wistar rats were fed a standard diet (C, n=10) and a high-fat diet supplemented with LA (OLIP, n=10). A group pair-fed to the latter group (PFO, n=6) was also included. LA prevents hepatic triglyceride accumulation and liver damage in rats fed on a high-fat diet, through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation, and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities and ATP synthesis, and reduced significantly energy efficiency. By contrast, LA induces an increase in mitochondrial copy number and in Ucp2 gene expression. Moreover, LA prevents liver oxidative damage through the inhibition of hydroperoxide production and the simulation of mitochondrial antioxidant defenses. LA treatment up-regulated manganese superoxide dismutase and glutathione peroxidase activities, and increased the GSH: GSSG ratio and UCP2 mRNA levels. Moreover, this molecule reduced oxidative damage in mitochondrial DNA and increased mitochondrial copy number. LA treatment decreased the acetylation levels of Foxo3a and PGC1β through the stimulation of SIRT3 and SIRT1. In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis coud be mediated by its ability to restore the oxidative balance by increasing antioxidant defenses through the deacetylation of Foxo3a and PGC1β by SIRT1 and SIRT3. Finally, the novelty and importance of this study is the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain

Effects of α-lipoic acid on lipid metabolism and mitochondrial biogenesis in adipocytes: study of the molecular mechanisms involved

α-lipoic acid (5-(1,2-dithiolan-3-yl)-pentanoic acid) is a natural occurring compound which possesses antioxidant properties. Moreover, anti-obesity properties in both rodents and humans have been attributed to α-lipoic acid being adipose tissue a target for this compound. In this context, the present study has demonstrated the ability of α-LA to modulate lipid metabolism in both murine and human white adipocytes. Thus, α-LA: 1) Inhibits fatty acids uptake (through CD36 downregulation); 2) Reduces fatty acids esterification into triglycerides (through DGAT1 reduction); 3) Decreases de novo lipogenesis (induced by inhibition of FAS, SCD1 and ACC mediated by AMPK activation); 4) Stimulates lipolysis (mainly mediated by the phosphorylation of HSL through cAMP-mediated activation of PKA, probably through the inhibition of AdPLA and PGE2; 5) Increases fatty acid oxidation machinery (CPT1 and ACOX) in white adipocytes; 6) Promotes mitochondrial biogenesis by the activation of PGC-1α mediated by SIRT1 and AMPK activation; and 7) Induces a brown-like remodelling in white subcutaneous adipocytes from overweight/obese subjects. Taking together all of these facts suggest that α-LA remodels adipocyte metabolism towards oxidation rather than storage, and this could contribute to the anti-obesity properties of α-LA

Effects of eicosapentaenoic acid ethyl ester on visfatin and apelin in lean and overweight (cafeteria diet-fed) rats

Previous studies have demonstrated that the n-3 fatty acid EPA improves insulin resistance induced by high-fat diets. The aim of the present study was to investigate the potential role of visfatin and apelin in the insulin-sensitising effects of EPA ethyl ester. The effects of EPA on muscle and adipose GLUT mRNA, as well as on liver glucokinase (GK) and glucose-6-phosphatase (G6Pase) activity, were investigated. Male Wistar rats fed on a standard diet or a high-fat cafeteria diet were daily treated by oral administration with EPA ethyl ester (1 g/kg) for 5 weeks. A significant decrease (P,0·01) in white adipose tissue (WAT) visfatin mRNA levels was found in the cafeteria-fed rats, which was reversed by EPA administration (P,0·05). Moreover, a negative relationship was observed between homeostatic model assessment (HOMA) and the visfatin:total WAT ratio. In contrast, cafeteria-diet feeding caused a significant increase (P,0·01) in apelin mRNA in visceral WAT. EPA increased (P,0·01) apelin gene expression, and a negative relationship between HOMA index with visceral apelin mRNA and serum apelin:total WAT ratio was also observed. EPA treatment did not induce changes in skeletal muscle GLUT1, GLUT4 or insulin receptor mRNA levels. Neither liver GK and G6Pase activity nor the GK:G6Pase ratio was modified by EPA. These data suggest that somehow the insulin-sensitising effects of EPA could be related to its stimulatory action on both visfatin and apelin gene expression in visceral fat, while changes in skeletal muscle GLUT, as well as in hepatic glucose production, are not likely to be the main contributing factors in the improvement in insulin resistance induced by EPA