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Prieto-Hontoria P.L.,University of Navarra | Perez-Matute P.,University of Navarra | Perez-Matute P.,HIV and Associated Metabolic Alterations Unit | Fernandez-Galilea M.,University of Navarra | And 2 more authors.
European Journal of Nutrition | Year: 2013

Background: Lipoic acid (LA) is an antioxidant with antiobesity and antidiabetic properties. Adiponectin is an adipokine with potent anti-inflammatory and insulin-sensitizing properties. AMP-activated protein kinase (AMPK) is a key enzyme involved in cellular energy homeostasis. Activation of AMPK has been considered as a target to reverse the metabolic abnormalities associated with obesity and type 2 diabetes. Aim of the study: The aim of this study was to determine the effects of LA on AMPK phosphorylation and adiponectin production in adipose tissue of low-fat (control diet) and high-fat diet-fed rats. Results: Dietary supplementation with LA reduced body weight and adiposity in control and high-fat-fed rats. LA also reduced basal hyperinsulinemia as well as the homeostasis model assessment (HOMA) levels, an index of insulin resistance, in high-fat-fed rats, which was in part independent of their food intake lowering actions. Furthermore, AMPK phosphorylation was increased in white adipose tissue (WAT) from LA-treated rats as compared with pair-fed animals. Dietary supplementation with LA also upregulated adiponectin gene expression in WAT, while a negative correlation between adiposity-corrected adiponectin levels and HOMA index was found. Our present data suggest that the ability of LA supplementation to prevent insulin resistance in high-fat diet-fed rats might be related in part to the stimulation of AMPK and adiponectin in WAT. © 2012 Springer-Verlag. Source


Valdecantos M.P.,University of Navarra | Perez-Matute P.,HIV and Associated Metabolic Alterations Unit | Gonzalez-Muniesa P.,University of Navarra | Prieto-Hontoria P.L.,University of Navarra | And 2 more authors.
Obesity | Year: 2012

Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. The sirtuin (SIRT) family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant defenses. In this study, we analyzed the potential protective effect of LA supplementation, via the modulation of mitochondrial defenses through the SIRT pathway, against oxidative stress associated with high-fat feeding. Wistar rats were fed a standard diet (control group (C), n = 10), a high-fat diet (obese group (OB), n = 10) and a high-fat diet supplemented with LA (OLIP, n = 10). A group pair-fed to the latter group (pair-fed OLIP group (PFO), n = 6) was also included. LA prevented hepatic triglyceride (TG) accumulation (68.2%) and liver oxidative damage (P < 0.01) through the inhibition of hydroperoxide (H2O2) production (P < 0.001) and the stimulation of mitochondrial antioxidant defenses. LA treatment upregulated manganese superoxide dismutase (SOD2) (60.6%) and glutathione peroxidase (GPx) (100.2%) activities, and increased the reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and UCP2 mRNA levels (P < 0.001-P < 0.01). Moreover, this molecule reduced oxidative damage in mitochondrial DNA (mtDNA) and increased mitochondrial copy number (P < 0.001- P < 0.01). LA treatment decreased the acetylation levels of Forkhead transcription factor 3a (Foxo3a) and PGC1Β (P < 0.001- P < 0.01) through the stimulation of SIRT3 and SIRT1 (P < 0.001). In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis could 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. Source


Prieto-Hontoria P.L.,University of Navarra | Perez-Matute P.,University of Navarra | Perez-Matute P.,HIV and Associated Metabolic Alterations Unit | Fernandez-Galilea M.,University of Navarra | And 2 more authors.
Molecular Nutrition and Food Research | Year: 2011

Scope: 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. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Fernandez-Galilea M.,University of Navarra | Perez-Matute P.,HIV and Associated Metabolic Alterations Unit | Prieto-Hontoria P.L.,University of Navarra | Prieto-Hontoria P.L.,University of Santiago de Chile | And 10 more authors.
Obesity | Year: 2014

Objective: α-Lipoic acid (α-LA) is a natural occurring antioxidant with beneficial effects on obesity. The aim of this study was to investigate the putative effects of α-LA on triglyceride accumulation and lipogenesis in subcutaneous adipocytes from overweight/obese subjects and to determine the potential mechanisms involved. Methods: Fully differentiated human subcutaneous adipocytes were treated with α-LA (100 and 250 μM) during 24 h for studying triglyceride content, de novo lipogenesis, and levels of key lipogenic enzymes. The involvement of AMP-activated protein kinase (AMPK) activation was also evaluated. Results: α-LA down-regulated triglyceride content by inhibiting fatty acid esterification and de novo lipogenesis. These effects were mediated by reduction in fatty acid synthase (FAS), stearoyl-coenzyme A desaturase 1, and diacylglycerol O-acyltransferase 1 protein levels. Interestingly, α-LA increased AMPK and acetyl CoA carboxylase phosphorylation, while the presence of the AMPK inhibitor Compound C reversed the inhibition observed on FAS protein levels. Conclusions: α-LA down-regulates key lipogenic enzymes, inhibiting lipogenesis and reducing triglyceride accumulation through the activation of AMPK signaling pathway in human subcutaneous adipocytes from overweight/obese subjects. © 2014 The Obesity Society. Source


Fernandez-Galilea M.,University of Navarra | Perez-Matute P.,University of Navarra | Perez-Matute P.,HIV and Associated Metabolic Alterations Unit | Prieto-Hontoria P.L.,University of Navarra | And 2 more authors.
Journal of Lipid Research | Year: 2012

Lipoic acid (LA) is a naturally occurring compound with beneficial effects on obesity. The aim of this study was to evaluate its effects on lipolysis in 3T3-L1 adipocytes and the mechanisms involved. Our results revealed that LA induced a dose- and time-dependent lipolytic action, which was reversed by pretreatment with the c-Jun N-terminal kinase inhibitor SP600125, the PKA inhibitor H89, and the AMP-activated protein kinase activator AICAR. In contrast, the PI3K/Akt inhibitor LY294002 and the PDE3B antagonist cilostamide enhanced LA-induced lipolysis. LA treatment for 1 h did not modify total protein content of hormone-sensitive lipase (HSL) but significantly increased the phosphorylation of HSL at Ser563 and at Ser660, which was reversed by H89. LA treatment also induced a marked increase in PKA-mediated perilipin phosphorylation. LA did not significantly modify the protein levels of adipose triglyceride lipase or its activator comparative gene identification 58 (CGI-58) and inhibitor G(0)/G(1) switch gene 2 (G0S2). Furthermore, LA caused a significant inhibition of adiposespecific phospholipase A2 (AdPLA) protein and mRNA levels in parallel with a decrease in the amount of prostaglandin E 2 released and an increase in cAMP content. Together, these data suggest that the lipolytic actions of LA are mainly mediated by phosphorylation of HSL through cAMP-mediated activation of protein kinase A probably through the inhibition of AdPLA and prostaglandin E2. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Source

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