Redox control of non-shivering thermogenesis

Background: Thermogenic adipocytes reorganize their metabolism during cold exposure. Metabolic reprogramming requires readily available bioenergetics substrates, such as glucose and fatty acids, to increase mitochondrial respiration and produce heat via the uncoupling protein 1 (UCP1). This condition generates a finely-tuned production of mitochondrial reactive oxygen species (ROS) that support non-shivering thermogenesis.Scope of review: Herein, the findings underlining the mechanisms that regulate ROS production and control of the adaptive responses tuning thermogenesis in adipocytes are described. Furthermore, this review describes the metabolic responses to substrate availability and the consequence of mitochondrial failure to switch fuel oxidation in response to changes in nutrient availability. A framework to control mitochondrial ROS threshold to maximize non-shivering thermogenesis in adipocytes is provided.Major conclusions: Thermogenesis synchronizes fuel oxidation with an acute and transient increase of mitochondrial ROS that promotes the activation of redox-sensitive thermogenic signaling cascade and UCP1. However, an overload of substrate flux to mitochondria causes a massive and damaging mitochondrial ROS production that affects mitochondrial flexibility. Finding novel thermogenic redox targets and manipulating ROS concentration in adipocytes appears to be a promising avenue of research for improving thermogenesis and counteracting metabolic diseases. (C) 2019 The Author. Published by Elsevier GmbH

An Overview of the Ferroptosis Hallmarks in Friedreich's Ataxia

Friedreich's ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths

Effect of plant foods and beverages on plasma non-enzymatic antioxidant capacity in human subjects: a meta-analysis

Non-enzymatic antioxidant capacity (NEAC) represents a sensitive biomarker measuring the in vivo antioxidant potential of vegetable foods. To evaluate the effectiveness of plant-derived foods and beverages on the plasma non-enzymatic antioxidant system, we analysed all literature published upto May 2010. Data were extracted by two authors independently, and the effect size was summarised using standardised mean differences by a random-effects model. For the analysis, eighty-eight studies were included, reporting a total number of 122 interventions and involving 2890 subjects. There was overall evidence of the effectiveness of fruit, vegetables, dietary patterns based on plant foods, red wine and tea in increasing plasma NEAC. No changes were found for chocolate and fruit juices. We observed an overall effect size three times higher in subjects with risk factors when compared with healthy subjects. Total radical-trapping antioxidant parameter, oxygen radical absorbance capacity and ferric-reducing antioxidant power methods showed a similar increase in plasma NEAC following dietary supplementation, whereas Trolox equivalent antioxidant capacity did not respond to dietary supplementation. Data from the present meta-analysis show that plant-derived foods represent an effective strategy to enhance an endogenous antioxidant network in humans. This is particularly evident in the presence of oxidative stress-related risk factors

Glutathione Decrement Drives Thermogenic Program in Adipose Cells

Adipose tissue metabolically adapts to external stimuli. We demonstrate that the induction of the thermogenic program in white adipocytes, through cold exposure in mice or in vitro adrenergic stimulation, is accompanied by a decrease in the intracellular content of glutathione (GSH). Moreover, the treatment with a GSH depleting agent, buthionine sulfoximine (BSO), recapitulates the effect of cold exposure resulting in the induction of thermogenic program. In particular, BSO treatment leads to enhanced uncoupling respiration as demonstrated by increased expression of thermogenic genes (e.g. Ucp1, Ppargc1a), augmented oxygen consumption and decreased mitochondrial transmembrane potential. Buffering GSH decrement by pre-treatment with GSH ester prevents the up-regulation of typical markers of uncoupling respiration. We demonstrate that FoxO1 activation is responsible for the conversion of white adipocytes into a brown phenotype as the "browning" effects of BSO are completely abrogated in cells down-regulating FoxO1. In mice, the BSO-mediated up-regulation of uncoupling genes results in weight loss that is at least in part ascribed to adipose tissue mass reduction. The induction of thermogenic program has been largely proposed to counteract obesity-related diseases. Based on these findings, we propose GSH as a novel therapeutic target to increase energy expenditure in adipocytes.Adipose tissue metabolically adapts to external stimuli. We demonstrate that the induction of the thermogenic program in white adipocytes, through cold exposure in mice or in vitro adrenergic stimulation, is accompanied by a decrease in the intracellular content of glutathione (GSH). Moreover, the treatment with a GSH depleting agent, buthionine sulfoximine (BSO), recapitulates the effect of cold exposure resulting in the induction of thermogenic program. In particular, BSO treatment leads to enhanced uncoupling respiration as demonstrated by increased expression of thermogenic genes (e.g. Ucp1, Ppargc1a), augmented oxygen consumption and decreased mitochondrial transmembrane potential. Buffering GSH decrement by pre-treatment with GSH ester prevents the up-regulation of typical markers of uncoupling respiration. We demonstrate that FoxO1 activation is responsible for the conversion of white adipocytes into a brown phenotype as the "browning" effects of BSO are completely abrogated in cells down-regulating FoxO1. In mice, the BSO-mediated up-regulation of uncoupling genes results in weight loss that is at least in part ascribed to adipose tissue mass reduction. The induction of thermogenic program has been largely proposed to counteract obesity-related diseases. Based on these findings, we propose GSH as a novel therapeutic target to increase energy expenditure in adipocytes

Effect of ingestion of dark chocolates with similar lipid composition and different cocoa content on antioxidant and lipid status in healthy humans

The association between in vitro antioxidant capacity of dark chocolates with different cocoa percentage and the in vivo response on antioxidant status was investigated. In a randomized crossover design, 15 healthy volunteer consumed 100 g of high antioxidants dark chocolate (HADC) or dark chocolate (DC). In vitro, HADC displayed a higher Total Antioxidant Capacity (TAC) than DC. In vivo, plasma TAC significantly peaked 2 h after ingestion of both chocolates. TAC levels went back to zero 5 h after DC ingestion whilst levels remained significantly higher for HADC. HADC induced a significantly higher urinary TAC in the 5-12 h interval time than DC. No change was detected in urinary excretion of F2-isoprostanes. Plasma thiols and triacylglycerol (TG) levels significantly increased for both chocolate with a peak at 2 h remaining significantly higher for DC after 5 h respect to HADC. Results provide evidence of a direct association between antioxidant content of chocolate and the extent of in vivo response on plasma antioxidant capacity. (C) 2011 Elsevier Ltd. All rights reserved

Intermittent fasting applied in combination with rotenone treatment exacerbates dopamine neurons degeneration in mice

Intermittent fasting (IF) was suggested to be a powerful nutritional strategy to prevent the onset of age-related neurodegenerative diseases associated with compromised brain bioenergetics. Whether the application of IF in combination with a mitochondrial insult could buffer the neurodegenerative process has never been explored yet. Herein, we defined the effects of IF in C57BL/6J mice treated once per 24 h with rotenone (Rot) for 28 days. Rot is a neurotoxin that inhibits the mitochondrial complex I and causes dopamine neurons degeneration, thus reproducing the neurodegenerative process observed in Parkinson\u2019s disease (PD). IF (24 h alternate-day fasting) was applied alone or in concomitance with Rot treatment (Rot/IF). IF and Rot/IF groups showed the same degree of weight loss when compared to control and Rot groups. An accelerating rotarod test revealed that only Rot/IF mice have a decreased ability to sustain the test at the higher speeds. Rot/IF group showed a more marked decrease of dopaminergic neurons and increase in alpha-synuclein (a-syn) accumulation with respect to Rot group in the substantia nigra (SN). Through lipidomics and metabolomics analyses, we found that in the SN of Rot/IF mice a significant elevation of excitatory amino acids, inflammatory lysophospholipids and sphingolipids occurred. Collectively, our data suggest that, when applied in combination with neurotoxin exposure, IF does not exert neuroprotective effects but rather exacerbate neuronal death by increasing the levels of excitatory amino acids and inflammatory lipids in association with altered brain membrane composition

Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth

Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model

Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNAseq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management

Exogenous miRNAs from Moringa oleifera Lam. recover a dysregulated lipid metabolism

A balanced diet is critical for human health, and edible plants play an important role in providing essential micronutrients as well as specific microRNAs (miRNAs) that can regulate human gene expression. Here we present the effects of Moringa oleifera (MO) miRNAs (mol-miRs) on lipid metabolism. Through in silico studies we identified the potential genes involved in lipid metabolism targeted by mol-miRs. To this end, we tested the efficacy of an aqueous extract of MO seeds (MOES), as suggested in traditional African ethnomedicine, or its purified miRNAs. The biological properties of MO preparations were investigated using a human derived hepatoma cell line (HepG2) as a model. MOES treatment decreased intracellular lipid accumulation and induced apoptosis in HepG2. In the same cell line, transfection with mol-miRs showed similar effects to MOES. Moreover, the effect of the mol-miR pool was investigated in a pre-obese mouse model, in which treatment with mol-miRs was able to prevent dysregulation of lipid metabolism