Marta Fernández-Galilea

Role of obesity-associated dysfunctional adipose tissue in cancer: A molecular nutrition approach

Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer.

Lipoic acid prevents body weight gain induced by a high fat diet in rats: Effects on intestinal sugar transport

Several studies have suggested that oxidative stress might cause and aggravate the inflammatory state associated with obesity and could be the link between excessive weight gain and its related disorders such as insulin resistance and cardiovascular diseases. Thus, antioxidant treatment has been proposed as a therapy to prevent and manage obesity and associated complications. Therefore, the aim of the present study was to investigate the effects of supplementation of a standard or high fat diet with the antioxidant lipoic acid (LA) during 56 days, on body weight gain, adiposity, feed efficiency and intestinal sugar absorption, in male Wistar rats. LA supplementation induced a lower body weight gain and adipose tissue size in both control or high fat fed rats accompanied by a reduction in food intake. The group fed on a high fat diet and treated with LA (OLIP group) showed a lower body weight gain than its corresponding Pair-Fed (PF) group (P<0.05), which received the same amount of food than LA-treated animals but with no LA. In fact, LA induced a reduction on feed efficiency and also significantly decreased intestinal α-methylglucoside (α-MG) absorption both in lean and obese rats. These results suggest that the beneficial effects of dietary supplementation with LA on body weight gain are mediated, at least in part, by the reduction observed in food intake and feed efficiency. Furthemore, the inhibitory action of LA on intestinal sugar transport could explain in part the lower feed efficiency observed in LA-treated animals and therefore, highlighting the beneficial effects of LA on obesity.ResumenVarios estudios han sugerido que el estrés oxidativo podría actuar como desencadenante y agravante del estado inflamatorio asociado a la obesidad y podría ser un potencial nexo de unión entre la excesiva ganancia de peso y las co-morbilidades asociadas. Así, se ha propuesto el tratamineto con antioxidantes naturales como posible terapia contra el desarrollo de obesidad así como sus complicaciones asociadas. Por ello, el objeto del presente trabajo fue investigar en ratas Wistar macho los efectos de la suplementación de una dieta estándar o alta en grasa con un antioxidante, el ácido lipoico (AL) (0,25g/ 100g de comida) durante 56 días sobre la ganancia de peso corporal, la adiposidad, la eficiencia metabólica y la absorción intestinal de azúcares. La suplementación de la dieta con AL indujo una menor ganacia de peso corporal y redujo el tamaño del tejido adiposo blanco total, tanto en ratas alimentadas con dieta control como alta en grasa. Además, disminuyó la ingesta. La ganancia de peso en el grupo alimentado con dieta alta en grasa y AL fue menor que la de su correspondiente grupoPair-Fed (P<0,05), el cual recibía la misma cantidad de comida que los animales tratados con AL pero sin este ácido. De hecho, la suplementación con ácido lipoico redujo la eficiencia metabólica y disminuyó significativamente la absorción intestinal de α-metilglucósido (α-MG) tanto en ratas control como obesas. Estos resultados sugieren que los efectos beneficiosos de la suplementación de la dieta con AL sobre la ganancia de peso corporal están mediados, al menos en parte, por la reducción observada en la ingesta de comida y en la eficiencia metabólica. Además, la acción inhibitoria del AL sobre el transporte intestinal de azúcares podría explicar, en parte, la menor eficiencia metabólica observada en los animales tratados con AL justificando, por consiguiente, los efectos beneficiosos del AL sobre la obesidad.

Effects of lipoic acid on lipolysis in 3T3-L1 adipocytes

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 adipose-specific phospholipase A2 (AdPLA) protein and mRNA levels in parallel with a decrease in the amount of prostaglandin E2 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.

Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes

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.

Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats

BackgroundLipoic 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 studyThe 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.ResultsDietary 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.

Effects of lipoic acid on apelin in 3T3-L1 adipocytes and in high-fat fed rats

Lipoic acid (LA) is an antioxidant with therapeutic properties on several diseases like diabetes and obesity. Apelin is a novel adipokine with potential beneficial actions on glucose metabolism and insulin resistance. The aim of this study was to examine in 3T3-L1 adipocytes the effects of LA on apelin gene expression and secretion, as well as elucidate the signaling pathways involved. We also tested the regulation of adipose apelin gene expression by LA supplementation in a model of high-fat diet-induced obesity. LA increased apelin secretion but not apelin gene expression in 3T3-L1 adipocytes. The AMPK inhibitor Compound C induced an increase in LA-stimulated apelin production, and, on the contrary, the AMPK activator AICAR completely reversed the LA stimulatory effects on apelin secretion, also inducing a significant reduction in apelin mRNA levels in this in vitro model. Apelin mRNA levels were increased in those animals fed with the high-fat diet, while the caloric restriction decreased apelin mRNA to control levels. However, apelin gene expression was not significantly modified in rats treated with LA compared with the obese group. The current data suggest the ability of LA to modulate apelin secretion by adipocytes. However the insulin-sensitizing effect of LA in vivo is not related to changes in apelin gene expression in our model of diet-induced obesity.

Eicosapentaenoic acid inhibits tumour necrosis factor-α-induced lipolysis in murine cultured adipocytes

Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid with beneficial effects in obesity and insulin resistance. High levels of proinflammatory cytokine tumour necrosis factor-α (TNF-α) in obesity promote lipolysis in adipocytes, leading to the development of insulin resistance. Thus, the aims of the present study were to analyze the potential antilipolytic properties of EPA on cytokine-induced lipolysis and to investigate the possible mechanisms involved. The EPA effects on basal and TNF-α-induced lipolysis were determined in both primary rat and 3T3-L1 adipocytes. Treatment of primary rat adipocytes with EPA (100 and 200 μM) significantly decreased basal glycerol release (P<.01) and prevented cytokine-induced lipolysis in a dose-dependent manner (P<.001). Moreover, EPA decreased TNF-α-induced activation of nuclear factor-κB and extracellular-related kinase 1/2 phosphorylation. In addition, the antilipolytic action of EPA was stimulated by the AMP-kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside and blocked by the AMPK-inhibitor compound C. Moreover, we found that EPA stimulated hormone-sensitive lipase (HSL) phosphorylation on serine-565, which further supports the involvement of AMPK in EPAs antilipolytic actions. Eicosapentaenoic acid treatment (24 h), alone and in the presence of TNF-α, also decreased adipose triglyceride lipase (ATGL) protein content in cultured adipocytes. However, oral supplementation with EPA for 35 days was able to partially reverse the down-regulation of HSL and ATGL messenger RNA observed in retroperitoneal adipose tissue of high-fat-diet-fed rats. These findings suggest that EPA inhibits proinflammatory cytokine-induced lipolysis in adipocytes. This effect might contribute to explain the insulin-sensitizing properties of EPA.

α-lipoic acid reduces fatty acid esterification and lipogenesis in adipocytes from overweight/obese subjects.

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.

Eicosapentaenoic acid promotes mitochondrial biogenesis and beige-like features in subcutaneous adipocytes from overweight subjects.

Eicosapentaenoic acid (EPA), a n-3 long-chain polyunsaturated fatty acid, has been reported to have beneficial effects in obesity-associated metabolic disorders. The objective of the present study was to determine the effects of EPA on the regulation of genes involved in lipid metabolism, and the ability of EPA to induce mitochondrial biogenesis and beiging in subcutaneous adipocytes from overweight subjects. Fully differentiated human subcutaneous adipocytes from overweight females (BMI: 28.1-29.8kg/m2) were treated with EPA (100-200 μM) for 24 h. Changes in mRNA expression levels of genes involved in lipogenesis, fatty acid oxidation and mitochondrial biogenesis were determined by qRT-PCR. Mitochondrial content was evaluated using MitoTracker® Green stain. The effects on peroxisome proliferator-activated receptor gamma, co-activator 1 alpha (PGC-1α) and AMP-activated protein kinase (AMPK) were also characterized. EPA down-regulated lipogenic genes expression while up-regulated genes involved in fatty acid oxidation. Moreover, EPA-treated adipocytes showed increased mitochondrial content, accompanied by an up-regulation of nuclear respiratory factor-1, mitochondrial transcription factor A and cytochrome c oxidase IV mRNA expression. EPA also promoted the activation of master regulators of mitochondrial biogenesis such as sirtuin 1, PGC1-α and AMPK. In parallel, EPA induced the expression of genes that typify beige adipocytes such as fat determination factor PR domain containing 16, uncoupling protein 1 and cell death-inducing DFFA-like effector A, T-Box protein 1 and CD137. Our results suggest that EPA induces a remodeling of adipocyte metabolism preventing fat storage and promoting fatty acid oxidation, mitochondrial biogenesis and beige-like markers in human subcutaneous adipocytes from overweight subjects.

Cardiotrophin-1 stimulates lipolysis through the regulation of main adipose tissue lipases.

Cardiotrophin-1 (CT-1) is a cytokine with antiobesity properties and with a role in lipid metabolism regulation and adipose tissue function. The aim of this study was to analyze the molecular mechanisms involved in the lipolytic actions of CT-1 in adipocytes. Recombinant CT-1 (rCT-1) effects on the main proteins and signaling pathways involved in the regulation of lipolysis were evaluated in 3T3-L1 adipocytes and in mice. rCT-1 treatment stimulated basal glycerol release in a concentration- and time-dependent manner in 3T3-L1 adipocytes. rCT-1 (20 ng/ml for 24 h) raised cAMP levels, and in parallel increased protein kinase (PK)A-mediated phosphorylation of perilipin and hormone sensitive lipase (HSL) at Ser660. siRNA knock-down of HSL or PKA, as well as pretreatment with the PKA inhibitor H89, blunted the CT-1-induced lipolysis, suggesting that the lipolytic action of CT-1 in adipocytes is mainly mediated by activation of HSL through the PKA pathway. In ob/ob mice, acute rCT-1 treatment also promoted PKA-mediated phosphorylation of perilipin and HSL at Ser660 and Ser563, and increased adipose triglyceride lipase (desnutrin) content in adipose tissue. These results showed that the ability of CT-1 to regulate the activity of the main lipases underlies the lipolytic action of this cytokine in vitro and in vivo, and could contribute to CT-1 antiobesity effects.