The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation

We report here studies that integrate data of respiration rate from mouse skeletal muscle in response to leptin and pharmacological interference with intermediary metabolism, together with assays for phosphatidylinositol 3-kinase (PI3K) and AMP- activated protein kinase (AMPK). Our results suggest that the direct effect of leptin in stimulating thermogenesis in skeletal muscle is mediated by substrate cycling between de novo lipogenesis and lipid oxidation, and that this cycle requires both PI3K and AMPK signaling. This substrate cycling linking glucose and lipid metabolism to thermogenesis provides a novel thermogenic mechanism by which leptin protects skeletal muscle from excessive fat storage and lipotoxicity

ATMOSFERA MODIFICADA E TEMPERATURA DE ARMAZENAMENTO PARA PÓS-COLHEITA DE AMEIXA DA MATA

O objetivo deste trabalho foi avaliar o efeito da atmosfera modificada e temperatura de armazenamento na conservação pós-colheita de ameixa da mata. Foram conduzidos dois experimentos, ambos em delineamento inteiramente casualizado ambos com 4 repetições de 20 frutos. O primeiro em fatorial 2x3 (embalagem x temperatura), onde os frutos foram acondicionados em bandejas de poliestireno revestidas ou não por filme de PVC, em condições de temperatura ambiente, 5±1 °C ou 15±1 °C. No segundo, em fatorial 2x3x2 (pedúnculo x embalagem x temperatura). Para o fator pedúnculo foi considerada a presença ou ausência nos frutos, sendo estes acondicionados em bandejas de poliestireno com e sem filme de PVC ou com biofilme (fécula de mandioca) e armazenados em duas temperaturas (ambiente e 5±1 °C). Foram avaliados a perda de massa de matéria fresca, murchamento, podridão, teor de sólidos solúveis, açúcares totais e redutores, teores de antocianinas e flavonoides. O uso de atmosfera modificada associada a temperatura de 5 ºC, permitiu armazenar frutos de ameixeira da mata por período de até 34 dias. Sugere-se manter o pedúnculo aderido ao fruto, pois estes mantiveram a qualidade e a aparência por mais tempo, além de conservarem as características bioquímicas dos mesmos

The DCCT/EDIC study: epigenetic clues after three decades

International audienc

Essential roles of four-carbon backbone chemicals in the control of metabolism

International audienceThe increasing incidence of obesity worldwide and its related cardiometabolic complications is an urgent public health problem. While weight gain results from a negative balance between the energy expenditure and calorie intake, recent research has demonstrated that several small organic molecules containing a four-carbon backbone can modulate this balance by favoring energy expenditure, and alleviating endoplasmic reticulum stress and oxidative stress. Such small molecules include the bacterially produced short chain fatty acid butyric acid, its chemically produced derivative 4-phenylbutyric acid, the main ketone body D-beta-hydroxybutyrate - synthesized by the liver - and the recently discovered myokine beta-aminoisobutyric acid. Conversely, another butyrate-related molecule, alpha-hydroxybutyrate, has been found to be an early predictor of insulin resistance and glucose intolerance. In this minireview, we summarize recent advances in the understanding of the mechanism of action of these molecules, and discuss their use as therapeutics to improve metabolic homeostasis or their detection as early biomarkers of incipient insulin resistance

The Methylation Status of the Epigenome: Its Emerging Role in the Regulation of Tumor Angiogenesis and Tumor Growth, and Potential for Drug Targeting

Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time display minimal toxic side effects to healthy tissues. Bevacizumab (Avastin)—a humanized monoclonal anti VEGF-A antibody—is now used as anti-angiogenic drug in several forms of cancers, yet with variable results. Recent years brought significant progresses in our understanding of the role of chromatin remodeling and epigenetic mechanisms in the regulation of angiogenesis and tumorigenesis. Many inhibitors of DNA methylation as well as of histone methylation, have been successfully tested in preclinical studies and some are currently undergoing evaluation in phase I, II or III clinical trials, either as cytostatic molecules—reducing the proliferation of cancerous cells—or as tumor angiogenesis inhibitors. In this review, we will focus on the methylation status of the vascular epigenome, based on the genomic DNA methylation patterns with DNA methylation being mainly transcriptionally repressive, and lysine/arginine histone post-translational modifications which either promote or repress the chromatin transcriptional state. Finally, we discuss the potential use of “epidrugs” in efficient control of tumor growth and tumor angiogenesis

Dysregulation of sirtuins and key metabolic genes in skeletal muscle of pigs with intrauterine growth restriction is associated to alterations of circulating IGF-1

International audience[b]Background and aims[/b]: [br/]Prenatal and early postnatal lives are important determinants of future health, and intrauterine growth restriction (IUGR) - associated low birth weight predisposes to the development of metabolic and cardiovascular disease in adult life, but the mechanisms are largely unknown.We hypothesize here that IUGR might confer gene expression alterations, predisposing to metabolic disease.[br/][b]Materials and methods[/b]:[br/]Using a porcine model of spontaneous IUGR, we determined in utero (71, 112 days post-conception) and earlypostnatal (2 days post-birth) IGF-1, insulin and leptin levels, and in parallel we investigated skeletalmuscle (Longissimus dorsi) gene expression of sirtuins and key metabolic genes (IRS1, GLUT4, HK2 and GAPDH).[br/][b]Results[/b]: In IUGR, we observed impaired IGF-1, insulin and leptin serum levels. Gene expression of sirtuin 1, 5, 6, 7, GLUT4 and HK2 exhibited significant correlations with gestational age or fetus/newborn body weight. SIRT1 and HK2 expression displayed an age- and weight dependent downregulation in controls, which was lost in IUGR pigs. Conversely, SIRT2 and GLUT4 were upregulated in IUGR pigs. Within the set of genes studied, we found a significant correlation between IGF-1 levels and gene expression, indicating that IGF-1 is limiting in IUGR.IUGR-dependent gene alterations were partly linked to epigenetic changes on histone H3 acetylation and methylation. [br/][b]Conclusion[/b]: [br/]Our observations indicate that several sirtuins andmetabolic genes display specific gene expression trajectories during fetal and early postnatal life, which are altered in IUGR, and are related to hormonal dysregulations observed in IUGR. Given the importance of these genes in metabolic control, their perinatal alterations might contribute to the predisposition to metabolic disease and diabetes in adulthood

The histone deacetylase inhibitor sodium butyrate improves insulin signalling in palmitate-induced insulin resistance in L6 rat muscle cells through epigenetically-mediated up-regulation of Irs1

Dietary administration of the histone deacetylase (HDAC) inhibitor butyric acid a short chain fatty acid present in milk products and also bacterially produced in the intestine has been shown to increase energy expenditure and favour insulin sensitivity in mice through induction of PGCl alpha (peroxisome proliferator-activated receptor gamma co-activator l alpha) and AMPK (AMP-activated protein kinase) in skeletal muscle, and a consequential increase of mitochondrial fatty acid oxidation. Here, we investigate whether such physiological improvements are associated to epigenetic effects dependent on increased histone acetylation and whether butyrate exerts a direct action on skeletal muscle insulin signalling. We show that sodium butyrate (NaBut) ameliorates the insulin-resistant phenotype, induced in L6 myotubes by prolonged exposure to palmitate, by i) increasing the insulin-induced phosphorylation of both PKB (protein kinase B) and MAPK (mitogen activated protein kinase), the two branches of insulin signalling and ii) increasing histone H3 acetylation - even in the presence of palmitate - on chromatin in proximity of the Irs1 (insulin receptor substrate 1) transcriptional start site. Consequently, NaBut induced Irs1 mRNA and protein overexpression, which in turn relayed higher insulin-stimulated IRS1 tyrosine phosphorylation and PI 3-kinase (phosphoinositide 3-kinase) association, suggesting that the increased IRS1 expression may mediate the insulin-sensitizing effects of NaBut. Furthermore, downstream of PKB, NaBut induced GSK3 beta gene upregulation. Our observations indicate that NaBut through its action as HDAC inhibitor can promote insulin responsiveness in L6 myotubes under conditions of lipid-induced insulin resistance

Ketone Bodies as Metabolites and Signalling Molecules at the Crossroad between Inflammation and Epigenetic Control of Cardiometabolic Disorders

For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of carbohydrates and promoting the synthesis of ketone bodies imitating the metabolic effects of fasting, has been shown to provide a possible nutritional solution to alleviating diseases triggered by an inflammatory environment. The main ketone body, β-hydroxybutyrate (BHB), acts as an alternative fuel, and also as a substrate for a novel histone post-translational modification, β-hydroxybutyrylation. β-hydroxybutyrylation influences the state of chromatin architecture and promotes the transcription of multiple genes. BHB has also been shown to modulate inflammation in chronic diseases. In this review, we discuss, in the pathological context of cardiovascular risks, the current understanding of how ketone bodies, or a ketogenic diet, are able to modulate, trigger, or inhibit inflammation and how the epigenome and chromatin remodeling may be a key contributor

Dietary Polyphenols and Their Effects on Cell Biochemistry and Pathophysiology

Polyphenols, occurring in fruit and vegetables, wine, tea, extra virgin olive oil, chocolate, and other cocoa products, have been demonstrated to exert beneficial effects in a large array of disease states, including cancer, cardiovascular disease, and neurodegenerative disorders. Many of the biological effects of polyphenols have been attributed to their antioxidant properties, either through their reducing capacities per se or through their possible influences on intracellular redox status. As such, polyphenols may protect cell constituents against oxidative damage and have been reported to limit the risk of various degenerative diseases associated with oxidative stress, including cardiovascular diseases, type 2 diabetes, and cancer. However, accumulating evidence suggests that the classical hydrogen-donating antioxidant activity is unlikely to be the sole explanation for their cellular effects in vivo. Indeed, it has recently become clear that, in complex biological systems, polyphenols are able to exhibit several additional properties which are yet poorly understood. It is evident that polyphenols are potent bioactive molecules and a clear understanding of their precise mechanisms of action as either antioxidants or modulators of cell signaling is crucial to the evaluation of their potential as chemopreventive or anticancer agents and inhibitors of neurodegeneration

Intrauterine growth restriction is associated to altered expression patterns of sirtuins and key metabolic genes in pig skeletal muscle

National audienc