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

Effects of alpha-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss

Objective: To evaluate the potential body weight lowering effects of dietary supplementation with eicosapentaenoic acid (EPA) and α-lipoic acid separately or combined, in healthy overweight/obese women following a hypocaloric diet. Design and Methods: This is a short-term double-blind placebo-controlled lasted 10-weeks study with parallel design. Of the randomized participants, 97 women received the allocated treatment (Control, EPA (1.3 g/d of EPA), α-lipoic acid (0.3 g/d) and EPA+ α-lipoic acid (1.3 g/d + 0.3 g/d)), finishing 77 volunteers. All groups followed an energy-restricted diet of 30% from the total energy expenditure. Body weight, anthropometric measurements, body composition, resting energy expenditure, blood pressure, serum glucose, insulin and lipid profile, as well as leptin and ghrelin levels, were assessed at baseline and after nutritional intervention. Results: Body weight loss was significantly higher (P < 0.05) in those groups supplemented with α-lipoic acid. EPA supplementation significantly attenuated (P < 0.001) the decrease in leptin levels that occurs during weight loss. Body weight loss improved lipid and glucose metabolism parameters, but without significant differences between groups. Conclusion: The intervention suggests that α-lipoic acid supplementation alone or in combination with EPA may help to promote body weight loss in healthy overweight/obese women following energy-restricted diets

PPARGC1A gene promoter methylation as a biomarker of insulin secretion and sensitivity in response to glucose challenges

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose

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

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

PPARGC1A gene promoter methylation as a biomarker of insulin secretion and sensitivity in response to glucose challenges

Methylation in CpG sites of the PPARGC1A gene (encoding PGC1-α) has been associated with adiposity, insulin secretion/sensitivity indexes and type 2 diabetes. We assessed the association between the methylation profile of the PPARGC1A gene promoter gene in leukocytes with insulin secretion/sensitivity indexes in normoglycemic women. A standard oral glucose tolerance test (OGTT) and an abbreviated version of the intravenous glucose tolerance test (IVGTT) were carried out in n = 57 Chilean nondiabetic women with measurements of plasma glucose, insulin, and C-peptide. Bisulfite-treated DNA from leukocytes was evaluated for methylation levels in six CpG sites of the proximal promoter of the PPARGC1A gene by pyrosequencing (positions -816, -783, -652, -617, -521 and -515). A strong correlation between the DNA methylation percentage of different CpG sites of the PPARGC1A promoter in leukocytes was found, suggesting an integrated epigenetic control of this region. We found a positive association between the methylation levels of the CpG site -783 with the insulin sensitivity Matsuda composite index (rho = 0.31; p = 0.02) derived from the OGTT. The CpG hypomethylation in the promoter position -783 of the PPARGC1A gene in leukocytes may represent a biomarker of reduced insulin sensitivity after the ingestion of glucose