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Augmented fat metabolism efficiency

Augmented fat metabolism efficiency

Moreover, given that FAPs are the only Muscle building nutrition type Professional weight support adipogenic potential tat the muscle 5 Augmenteed, 25Muscle building nutrition34 gat, in vitro adipogenesis of whole muscle-derived SVF from control or 1 dpi animals was tested. A Cell surface podoplanin expression of ScAT-derived ASCs of injured Gly and CTX or control animals by flow cytometry at 1 dpi. Availability of energetic substrates and exercise performance in heart failure with or without diabetes. Article CAS PubMed Google Scholar Karp, J.

Augmented fat metabolism efficiency -

The introduction of mass spectrometry techniques to analyse changes in global protein phosphorylation in response to insulin, as has been applied in adipocytes Humphrey et al. Another possibility is that phosphorylation is not the only post-translational modification of proteins involved in the generation of lipid-induced insulin resistance.

Recently, the emergence of nitrosative modifications White et al. Another area of research that is increasingly realised to have a significant impact on metabolic disease is circadian biology. The suprachiasmatic nucleus in the brain is considered to be the master regulator of circadian behaviour because of its ability to coordinate inputs from the environment light, food, exercise and temperature , but it is now clear that every tissue has the molecular components that comprise the clock, raising the possibility that circadian processes in tissues could be regulated directly by some inputs.

Some mouse models with genetic manipulations of core clock genes have altered circadian rhythms and are more prone to developing obesity Turek et al. If there is an underlying rhythm to metabolism in muscle driven by the molecular clock Lefta et al.

In fact, a recent report has suggested that the time of day can have a significant effect on the data obtained from euglycaemic-hyperinsulinaemic clamps in mice Shi et al. The correlation between increased FA availability and reduced insulin-stimulated glucose metabolism is well established. Despite this clear relationship, to date, there has been no unifying mechanism that explains lipid-induced reductions in insulin action under all circumstances.

However, there are an increasing number of experimental situations where reduced effects of insulin in muscle have been observed without significant changes in the phosphorylation of signalling proteins or where differences in phosphorylation are only observed with stimulation by supraphysiological insulin concentrations.

This suggests that other control mechanisms or other forms of protein modification may predominate depending on the exact experimental conditions used to examine insulin resistance e.

bolus insulin injections, hyperinsulinaemic clamps and glucose or lipid infusion. Figure 3 summarises some of the key control points other than insulin signalling for GLUT4 translocation that could alter the balance between glucose and FA metabolism and affect insulin-stimulated glucose disposal.

For example, utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue, and changes in microvasculature occur with obesity and contribute to muscle insulin resistance St-Pierre et al.

Other work Furler et al. The phosphorylation of glucose by hexokinase and the pathway for conversion of glucosephosphate to glycogen are subject to regulation by glucosephosphate and glycogen respectively, and decreased glucose phosphorylation and glycogen synthesis will affect glucose uptake Fueger et al.

Another well-documented node regulating the metabolism of glucose is centred on the activity of PDH. The activity of this enzyme complex is inhibited by phosphorylation via PDH kinase 4 PDK4. Interestingly, the amount of PDK4 in muscle is significantly increased in high-fat diet-fed, insulin-resistant animals and PDK4 is activated by acetyl CoA, providing evidence that this regulatory node could significantly affect glucose metabolism in muscle as hypothesised by Newsholme and Randle many years ago Randle et al.

Nodes of control of glucose metabolism other than insulin-stimulated translocation of GLUT4 that could be influenced by the excess availability of FAs. Utilisation of glucose and FAs is dependent on their availability in the circulation and delivery to the muscle tissue.

The phosphorylation of glucose and conversion to glycogen are regulated by substrate availability and GP concentration. PDH is a critical regulator balancing glucose use and FA oxidation to support energy requirements.

The regulation of FA sequestration in, or release from, muscle fat droplets can control the level of bioactive lipid species. The regulation of FA metabolism at the AMPK—ACC2—malonyl CoA—CPT1 axis also has a significant impact on the balance between FA and glucose metabolism.

There are a number of newly recognised post-translational modifications that can occur on key metabolic or signalling proteins and would be expected to be influenced by changes in the availability and metabolism of FAs. FA metabolism in muscle can also be regulated at the membrane by transporter proteins such as CD36 , and at activation to acyl CoA by acyl CoA synthase Glatz et al.

The partitioning of FAs towards triglyceride storage or mitochondrial oxidation may depend on the activity of key enzymes such as glycerol phosphate acyltransferase and adipose triglyceride lipase Greenberg et al. The entry of long-chain FAs into the mitochondria for oxidation is thought to be largely regulated by the activity of CPT1.

The activity of CPT1 is modulated allosterically by malonyl CoA, and numerous studies, including our recently published papers using genetic and pharmacological interventions Bruce et al.

Depending on the experimental design used, acutely increasing fatty oxidation in muscle can decrease glucose utilisation Hoehn et al. Interestingly, acute blockade of FA oxidation increases insulin-stimulated glucose uptake Oakes et al. These differences in acute and chronic responses when substrate metabolism is manipulated may be reconciled by considering the fact that energy metabolism is not constant in animals and humans, but has a substantial diurnal variation that is highly relevant to designing appropriate experiments to investigate lipid-induced insulin resistance.

In conclusion, it may be unrealistic to expect that a unifying mechanism may explain all situations where there is reduced glucose metabolism in muscle in response to insulin, as multiple factors may contribute to the establishment and long-term maintenance of insulin resistance in this tissue.

With the emergence of powerful techniques for determining global changes in gene expression, protein modifications and metabolite profiles, it will hopefully become possible to gain a more comprehensive idea of the factors and pathways that may contribute to the aetiology of lipid-induced insulin resistance in muscle.

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

The work carried out in the laboratories of the authors is supported by Program and Project grant funding from the National Health and Medical Research Council of Australia NHMRC , the Australian Research Council ARC and the Diabetes Australia Research Trust. NT is supported by an ARC Future Fellowship.

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In agreement with our hypothesis and the results obtained in mice, the chemotactic activity of ASCs is strongly correlated with GDF levels akin to an index of muscle fatigue Fig. A Time course evaluation of murine in vitro ASC chemotaxis in response to plasma isolated from Ctrl, CTX- and Gly-injured animals at 1 dpi.

C Correlation of human ASC chemotaxis with 1h-post exercise GDF blood levels. To determine whether ASCs can leave the ScAT in response to muscle injury to further infiltrate it, we performed in vivo experiments in mice.

However, due to the absence of unique specific ASC marker, no mouse model is so far available to visualize, in vivo, the trafficking of native ASCs from AT to any other tissue compartments. Fat graft revascularization, an index of viability, was verified by using retro-orbital injection of Rhodamin-lectin into grafted animals Fig.

Recently, Giuliani et al. To verify GFP expression specificity, FAPs from grafted injured 1 dpi or non-injured animals were sorted and genomic GFP expression was analyzed. Genomic GFP expression was found in FAPs of injured muscles Figure S3C , in contrast to control muscles from grafted animals Figure S3C or other distant organs Figure S3D.

Collectively, our result demonstrates that following muscle injury, ScAT releases FAP-like cells, which specifically infiltrate the damaged muscle.

Such specific post-damage cell infiltration originating from AT may largely contribute to the heterogeneity in Sca-1 expression recently described in the FAPs and which may impact the fate decision of FAPs Further analysis of their immunophenotype in vivo was performed using either CDGFP or KikGR AT grafted animals at 1 dpi.

Altogether, these findings show that the first wave of FAP increase following muscle injury at 1 dpi largely results from ASC mobilization and infiltration into the damaged muscle.

Podoplanin is an endogenous ligand for C-type lectin-like receptor 2 CLEC-2 which is an essential platelet-activating receptor. Consequently, we next assessed whether ASC and platelet interaction are necessary for the recruitment of ASCs to the injured muscle.

We used an in vitro assay whereby platelets, isolated from control or injured animals 1 dpi were fluorescently labeled and co-incubated with ASCs isolated from ScAT. The adhesion of platelets to ASCs was evaluated and compared. The results show that platelets originating from injured animals adhered more to ASCs in vitro Fig.

Given our results showing that both ASC mobilization and infiltration account for the first wave of FAP rise in injured muscle and that platelets originating from injured animals interact more with ASCs, we next investigated the consequences of platelet depletion in vivo on FAP augmentation following muscle injury.

FAP content was then quantified by flow cytometry at 1 dpi. Both platelet depletion and podoplanin inhibition diminished the increase of FAPs in the muscle by more than twofold at 1 dpi Fig. A Cell surface podoplanin expression of ScAT-derived ASCs of injured Gly and CTX or control animals by flow cytometry at 1 dpi.

C Quantification of PKHstained platelets with ASCs. D Model of platelet depletion, the figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.

E Platelet numeration 1 day post platelet depletion. We next studied the impact of FAPs rise disruption on the muscle regeneration process. To do so, we further exploited the muscle injury model with platelet depletion until 14 dpi Fig. Platelets depletion was maximal at 1 dpi, during the time of ASCs infiltration, before going back to basal in the later days, avoiding side effects due to long-term imbalance Fig.

The expression of genes involved in the molecular program of muscle regeneration was studied following muscle injury until 14 dpi. Even though the expression patterns of early genetic markers of the muscle regeneration program pax7 , myf5 , mrf4 were not modified Fig. To reinforce these results, we quantified both the number of newly synthesized centrally nucleated fibers and the fiber diameters, as markers of the regenerative process and found that the proportion of centrally nucleated fibers at 7 dpi as well as the cross-sectional area distribution of regenerating fibers at 14 dpi were dramatically diminished in platelet-depleted animals Fig.

In accordance with our hypothesis, the intramuscular injection of ASCs rescued the tested parameters Fig. Beyond the formation of new myofibers, muscle regeneration also requires connective tissue restoration, via the secretion and organization of newly synthetized extracellular matrix We thus investigated the gene expression time course involved in this process up to 14 dpi Gly with initial platelet depletion.

All the four markers studied tgfb1, col3a1, col1a1, and -sma followed a dynamic expression profile upon glycerol injury that was disturbed upon platelet depletion. With ASCs injection such dynamic was partially restored though in a variable way from gene to gene Fig.

On the other hand, excessive and persistent intramuscular connective tissue deposition IMCT is a hallmark of fibrosis 55 , Knowing that the CTX injury model is described to be more pro-fibrotic compared to the Gly one, we investigated the consequence of platelet depletion in this context At 14 dpi, CTX injury causes a significant IMCT deposition that is worsened upon platelet depletion Fig.

Conversely, ASCs intramuscular injection improved IMCT levels, possibly indicating a pro-regenerative role following muscle injury Fig. A Model of platelet depletion and ASCs injection. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.

B Platelet numeration time course in control and Gly-injured animals from 1 to 14 dpi. C Time course of mRNA expression of myogenic genes in quadriceps muscle from control and Gly-injured animals with and without platelet depletion.

E Immunohistological-based quantification of regenerative WGA centronucleated fibers muscle fibers at 7 dpi. F Size distribution of regenerating muscle fibers in Gly-injured red , platelet-depleted gray , and ASCs supplemented green animals at 14 dpi.

G Time course of mRNA expression of intramuscular connective tissue IMCT genes in quadriceps muscle from control and Gly-injured animals with and without platelet depletion.

H Immunohistological-based quantification of IMCT deposition in quadriceps muscle from control and CTX-injured animals with and without platelet depletion at 14 dpi. To further evaluate the impact of ASC infiltration on the muscle regeneration process, ScAT from both sides of the animal were removed to eliminate the injury-responsive reservoir of ASCs Fig.

We first verified the impact of bilateral lipectomy on both morphometric and metabolic parameters. Body weight and total fat mass were not significantly modified Figure S5A, B. PGAT, the other main adipose depot, did not overgrow to compensate the removal of ScAT Figure S5C.

Food intake was only affected the first days after the surgery but normalized on later time points Figure S5D. Finally, blood glucose was checked and did not show significant changes after the bilateral lipectomy Figure S5E. Muscle injury was then performed as described earlier.

It did not affect the weight of the remaining PGAT and the injured muscle Figure S5F, G. The expression of genes involved in the molecular program of muscle regeneration was then examined. As for platelet-depleted animals, the expression pattern of pax7 was not modified Fig.

Accordingly, the number of newly synthesized centrally nucleated fibers, was diminished in ScAT-depleted animals Fig. To our surprise, in ScAT-depleted animals, the early rise in FAPs content still occurred, in contrast to our prediction Fig.

Unlike the control animals, we found that the ASCs content of PGAT was diminished at 1 dpi when ScAT was removed Fig. Consequently, these data suggest that in the absence of ScAT, PGAT depot takes over in terms of infiltration of FAP-like cells, yet without an efficient muscle regeneration outcome.

This suggests that according to their fat depot source, ASCs may not exhibit similar regenerative potential. We thus compared the impact of ScAT- or PGAT- ASCs on muscle regeneration outcome in the context of ScAT reservoir removal. In ScAT-depleted animals the injection of ScAT-derived ASCs entirely rescued the level of centronucleated fibers while the ones from PGAT did not Fig.

Finally, we wondered whether ScAT-derived ASCs harbor a specific pro-regenerative profile that promotes better muscle regeneration. Functional analysis by gene ontology GO revealed specific gene expression profiles in ScAT-ASCs when compared to PGAT-ASCs.

Indeed, there was an enrichment in ScAT-ASCs in the biological functions related to coordination of inflammation, stem cell proliferation and fate, and myoblast fusion Fig.

A Model of bilateral lipectomy and ASC injection. B Time course of mRNA expression of myogenic genes in quadriceps muscle from control and Gly-injured animals with and without lipectomy. Bar scales top and 50 bottom μm. D Immunohistological-based quantification of regenerative WGA centronucleated fibers muscle fibers at 7 dpi.

E FAP number quantification in Gly-injured or control muscle with or without ScAT lipectomy. F ASC number quantification in Gly-injured or control PGAT with or without ScAT lipectomy.

G Immunohistological confocal images of quadriceps Gly-injured and control muscles at 7 dpi with or without lipectomy. H Immunohistological-based quantification of regenerative WGA centronucleated fibers muscle fibers at 7 dpi.

I Go term analysis between ScAT and PGAT-derived ASCs. The regenerative capacity of skeletal muscle mostly relies on satellite cells SCs , which proliferate in response to exercise or following myotrauma, to repair the injured muscle 3 , However, in the past decade many other cell types have been shown to contribute to this process in order to maintain skeletal muscle integrity and functions 59 , Among those diverse and heterogeneous cell types, resident mesenchymal progenitors named FAPs have emerged as key players in skeletal muscle regeneration and disease by providing functional support to SCs to perform efficient muscle regeneration 7 , 61 , Upon muscle injury, FAPs become activated and expand rapidly 4 , 5.

Furthermore, various recent studies addressed the question of muscle resident cell heterogeneity in homeostasis and regenerative conditions using single-cell analysis 15 , 17 , 60 , We show that in response to acute muscle injury ASCs egress ScAT and infiltrate the damaged muscle, a mechanism necessary for efficient muscle regeneration.

Based on our results it seems likely that this FAP subpopulation originates from ScAT rather than being a transitory cell state of resident FAPs.

Our data also suggest that such a mechanism may occur in humans in response to exercise-induced muscle fatigue. Indeed, GDF has been implicated in exercise and exercise recovery and that high levels of GDF may signal exercise aversion to prevent injurious behavior We show here that human ASCs migration score positively correlates with exercise-mediated GDF level increase 41 , which may indicate that ASCs are mobilized when muscle signals a pre-injury state.

We show here that in response to muscle injury, ASCs within ScAT overexpress podoplanin, which is a ligand for the platelet receptor CLEC-2 for C-type lectin-like receptor 2 In agreement with this result, several studies report that the majority of infused MSCs can be found within the circulation in close contact with platelets 50 , 51 to facilitate their homing to inflamed tissues 30 , This was confirmed in platelet-depleted animals where FAPs increase was strongly inhibited in response to muscle injury.

The blunting in FAPs increase, observed in platelet-depleted animals was associated with impaired muscle regeneration that was rescued by intramuscular ASC injection.

However, platelets have been shown to maintain endothelial permeability while the trafficking of infused MSCs to inflamed sites is facilitated by increased endothelial permeability Moreover, recent studies demonstrate that podoplanin expression imparts a pro-migratory phenotype in MSCs, facilitating their migration across the vessel wall and interaction with circulating platelets To rule out platelet-dependent effects mediated by their secretion on muscle regeneration we set up another experimental model by the removal of ASCs source, i.

Though muscle regeneration was also strongly affected in that context, FAPs first wave at 1 dpi was unexpectedly maintained. We showed that in absence of ScAT, another AT depot, the PGAT, was solicited.

Thus suggesting that when the bone fide source of ASCs is missing, another reservoir takes over but fails to support muscle regeneration.

Actually, when directly injected into the injured muscle, PGAT-derived ASCs were not able to rescue muscle regeneration unlike their ScAT counterpart.

Further transcriptomic analysis showed that ScAT- vs PGAT- derived ASCs are intrinsically functionally different. Extensive literature reports that FAPs secrete numerous factors being responsible for immunomodulation and IMCT remodeling after damage that support muscle SC expansion, differentiation, self-renewal, and quiescence 11 , 61 , 62 , 69 , 70 , Our transcriptomic analysis of both ASC subpopulations indeed confirmed that they exhibit profound differences regarding those essential parameters for optimal muscle regeneration.

The present data provide a new set of evidence that ScAT exhibits another protective function during skeletal muscle regeneration. Our data reinforce the particular relationship between muscle and AT, mainly described until now by secretory crosstalk, by showing that cell exchanges between these two organs take place and impact their homeostasis In conclusion, our work identifies an unsuspected role of ScAT in skeletal muscle regeneration.

These findings introduce the concept of AT as an endogenous supplier of regenerative cells allowing skeletal muscle to regenerate efficiently.

Whether such dialog is decisive in pathological contexts or during ageing where the repartition of adipose sources is dramatically affected remains to be investigated. This work was submitted to and approved by the Regional Ethic Committee and registered to the French Ministère de la Recherche.

After 7 days grafted or sham mice were injured. Mice were anesthetized with isoflurane and a skin incision was performed above ScAT lymph node.

ScAT was removed using forceps to disrupt conjunctive tissue adherences, and blood vessels located at the extremities were cauterized. Wound was sutured, and animals were monitored daily for 5—7 days.

Muscle injured results were compared to non-injured animals, and lipectomy results were compared to sham skin incision only animals. Quadriceps muscle, subcutaneous Sc and perigonadic PG AT were either directly harvested for cell isolation or fresh frozen for RNAs extraction or genomic DNA liver, heart, kidney and front limb.

PGAT and ScAT were digested with collagenase NB4, Coger; 0. Quadriceps muscles were digested with collagenase B 0. Freshly harvested AT- or muscle-derived SVF were used for direct flow cytometry analysis or cell sorting if needed.

FAP sorting: muscle-derived SVF were treated as above and used for RNAseq experiments, affymetrix analysis ctrl or injured , and DNA extraction. After washing, the labeled cells were quantified on LSR Fortessa flow cytometer and analyzed using FACSDiva software v9.

For the phenotypic characterization of ASCs and FAPs associated with T-Distributed Stochastic Neighbor Embedding tSNE representation, the SVFs were incubated with REA human anti-mouse antibodies PerCP-VioCD45, PE-CD31, FITC-CD34, PE-VioSca-1, APC-VioCDα, Miltenyi, respectively , , , , , classic rat anti-mouse VioBlue-CD The cells were quantified on LSR Fortessa flow cytometer and analyzed using Flowjo TM software v Stained cells were quantified by flow cytometry on LSR Fortessa BD Biosciences and analyzed using FACSDiva v9.

ASCs migration assay was performed using the IncuCyte® S3 Live-Cell Analysis System v Migration was analyzed via the Incucyte S3 software Essenbioscience and area under curves were calculated and compared using GraphPad Prism software v9 GraphPad Software.

At ASCs confluence, Nuclei were stained with DAPI. Acquisition and analysis of data were performed with Operetta® system type HH12 Perkin Elmer. After several washes, nucleus were stained with DAPI, and images were obtained using ZEISS LSM Confocal microscope Zen Blue v2.

Mouse muscle samples were cryopreserved in OCT frozen in liquid nitrogen-cooled isopentane. After antigen retrieval step, slides were incubated with PBS containing Triton 0. Images were obtained with ZEISS LSM Confocal microscope and analyzed with, Fiji v2. The size and distribution of myofibers with central nuclei was calculated from WGA—DAPI staining on all fibers of the section and area determination were performed across the entire sections using an automated image processing algorithm Fiji v2.

Second Harmonic generation SHG of collagen fibers imaging was performed on muscle sections with a laser scanning microscope LSM; Carl Zeiss GmbH, Jena, Germany combined with a pulsing titanium sapphire laser Coherent, vissionII. xyz stacks images were acquired with a ×2.

Briefly, samples were unfrozen in RLT and lysed with tissue lyser® QIAGEN. Samples were passed through columns with washing steps to purify RNAs.

Elution was performed with RNAse free water, and RNAs concentration was evaluated with Nanodrop® c Thermo Scientific. Cells were lysed and passed through column to bind DNA, and after two washing steps genomic material was eluted in Elution Buffer. All primer sequences are provided in a separate excel file called Supplementary Data 2.

Raw data were processed as follows. Filtered reads were then aligned onto the mm10 mouse genome using HISAT2 v 2. Differential expression and statistical analyses were performed using DESeq2 v 1.

To generate heatmap, we selected the most variable genes using idep version 0. RNAseq data have been deposited under the accession number GSE Data from Oprescu et al.

Young active men age The protocol was approved by the Dublin City University Ethics Committee and conducted in accordance with the criteria set by the Declaration of Helsinki; all subjects gave written informed consent.

Participants were instructed to refrain from exercise and to replicate food intake the day before each trial. In the morning, following an overnight fast, participants lay on a bed for 1-hr after arriving at the lab.

A blood sample was taken at the end of the exercise. The intensity was determined using the results of an incremental exercise test to exhaustion. AT was obtained from patients who provided prior written informed consent according to the ethics committees of Toulouse Hospitals.

AT was harvested during plastic surgery abdominoplasty from three adult patients female, age After digestion, an equal volume of α-MEM was added to stop enzymatic digestion.

The cells were passed through a μm filter Steriflip, Millipore, Billerica, MA and then centrifuged. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Data underlying Fig. The remaining data and Supplementary Figures are available within the article or from the authors upon reasonable request. Data from the human cohort of exercised patients in this study are not publicly available but can be requested as above.

The single-cell RNAseq data from Oprescu et al. Confocal and Two-photon imaging datasets, which are several gigabytes, will be promptly made available upon request but are not immediately available for download due to file size. Source data are provided with this paper.

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Medium-chain fatty acids accumulating in MCAD deficiency elicit lipid and protein oxidative damage and decrease non-enzymatic antioxidant defenses in rat brain. Smith, R.

Metrics efficiencu. Adipose tissues are dynamic tissues that Muscle building nutrition crucial physiological roles in effickency health and homeostasis. Although white adipose tissue Augmenter brown adipose tissue Diabetic retinopathy diabetes management currently considered key endocrine organs, they differ functionally and morphologically. The existence of the beige or brite adipocytes, cells displaying intermediary characteristics between white and brown adipocytes, illustrates the plastic nature of the adipose tissue. These cells are generated through white adipose tissue browning, a process associated with augmented non-shivering thermogenesis and metabolic capacity.

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Slow Metabolism Is a Myth (Not Kidding) - Dr. Berg The Augmened of Agumented metabolism Augmented fat metabolism efficiency Low-carb meal planning produce efficiecy energy ATP Performance psychology fuel the heart Augmented fat metabolism efficiency. By doing so, the Augmented fat metabolism efficiency is able to continuously pump oxygenated blood fwt the mdtabolism of Augmented fat metabolism efficiency body. In normal, healthy cardiac metabolism an efficient rate of ATP fuels heart muscle function. In the context of heart failure, cardiac metabolism becomes impaired. The consequences of this metabolic remodeling include ATP inefficiency, impaired heart function, and progression to a more severe heart failure. Many researchers hypothesize that the treatment of cardiac metabolism has a high potential for therapeutic approaches in the treatment of heart failure patients. ATP is a highly energetic molecule because it contains high-energy phosphate bonds.

Augmented fat metabolism efficiency -

Numerous questions remain, including how gradients of ROS inside the cell impact signaling cascades and gene regulation. Oxidative stress represents a disturbance in the equilibrium of ROS production and antioxidant defenses Figure 1.

At the molecular level, ROS mainly emerge from the mitochondrial ETC Starkov, ; Murphy, Electron transfer through the ETC generates superoxide anions as byproducts, with complex I and III representing primary sources of ROS. Under certain conditions, complex II and other cellular ROS sources can contribute to the overall pool.

Superoxide is the primary ROS species that reacts with Fe-containing proteins to generate H 2 O 2. H 2 O 2 accumulation in the cell contributes directly to the metabolic imbalance linking excessive nutrient stress and insulin resistance Anderson et al.

However, ROS also encompass a diverse range of chemical entities, including nitric oxide, peroxynitrite, hypochlorous acid, singlet oxygen, and the hydroxyl radical.

Consequently, the broad biological impacts of ROS derive from multiple cell and tissue microenvironments that divide physiological and pathological effects. Figure 1. The balance of antioxidants and ROS determine oxidative stress.

For most cells, optimal redox conditions are achieved when higher levels of antioxidants are present to quench reactive oxygen species ROS , maintaining ROS at low levels. Obesity and comorbidities increase ROS and decrease antioxidants in adipose, leading to oxidative stress and further complications of obesity, including insulin resistance and diabetes.

The conditions that favor mitochondrial superoxide production include reduction of electron carrier pools associated with the mitochondrial respiratory chain NADH, flavins, ubiquinone , a high proton motive force, and elevated oxygen consumption within the mitochondria Murphy, Overnutrition supplies excess electrons to the respiratory chain, while lack of physical activity and low ATP demand favors a high proton motive force with a low respiration rate, leading to mitochondrial superoxide formation and oxidative stress.

By contrast, in mitochondria actively making ATP, superoxide production is low because the electron carriers are relatively oxidized, the proton motive force is small, and the respiration rate is high. Prolonged oxidative stress directly impacts metabolism, including the activity of enzymes involved in the TCA cycle and the ETC Quijano et al.

The TCA cycle enzyme aconitase catalyzes the interconversion of citrate and isocitrate to regulate the availability of intermediates for lipid synthesis and ATP production. Citrate is the last common metabolite on the pathways for oxidation of acetyl-CoA and its export for fatty acid synthesis in the cytoplasm.

Superoxide inhibits aconitase Hausladen and Fridovich, ; Gardner et al. This feedback loop may be part of an antioxidant defense mechanism that adapts prolonged mitochondrial superoxide production Scandroglio et al. Acetyl-CoA diversion may slow delivery of electron carriers such as NADH to the respiratory chain, thereby decreasing ROS production Armstrong et al.

Oxidative stress also impacts pyruvate dehydrogenase kinase 2 PDK2 inhibition of the pyruvate dehydrogenase complex PDC Hurd et al. ROS oxidize critical cysteine residues, disabling PDK2, and supporting acetyl-CoA synthesis from glucose-derived pyruvate.

Therefore, elevated mitochondrial superoxide and H 2 O 2 couples PDC activity with aconitase interruption to divert citrate from the TCA cycle to the cytoplasm as triglycerides during overnutrition. These studies suggest persistent nutrient stress impairs the physiological behavior of crucial metabolic enzymes needed for balanced ATP generation and consumption.

A variety of peroxidases, including catalase, glutathione peroxidases, and peroxiredoxins Prdxs that control the levels of H 2 O 2 in the cell and protect against ROS-induced damage by catalyzing the reduction of H 2 O 2 into water.

Along these lines, overexpression of catalase Anderson et al. The mitochondrial antioxidant peroxiredoxin 3 Prdx3 responds to oxidative stress and scavenges H 2 O 2. Levels of Prdx3 are decreased in obese humans and mice, potentially contributing to oxidative stress intolerance Huh et al.

Whole-body deletion of Prdx3 in mice causes obesity and increased expression of lipogenic genes in adipocytes, while decreasing expression of lipolytic genes. As a result, hypertrophic adipocytes exclusively accumulate excess lipids and cannot enable appropriate energy balance control.

In addition to altering the balance of lipogenesis and lipolysis, Prdx3-deficient adipocytes exhibited increased superoxide production, decreased mitochondrial potential, and altered adipokine expression, including decreased adiponectin.

Okuno et al. AKO mice leverage adipocyte-specific ablation of glutamate-cysteine ligase Gclc to disable the rate-limiting step in glutathione synthesis and increase ROS generation. Insulin sensitivity was also reduced. Conversely, mice expressing rat catalase and human SOD1 under the aP2 promoter had the opposite phenotype.

These mice aP2-dTg showed reduced H 2 O 2 in subcutaneous and gonadal WAT. While these data argue that increasing mitochondrial antioxidants protects against oxidative stress in WAT, genetic alteration of other mitochondrial antioxidants reveal different phenotypes.

Manganese superoxide dismutase MnSOD is an important mitochondrial antioxidant that detoxifies superoxides Holley et al.

Adipocyte-specific knockout of MnSOD protected against diet-induced WAT expansion and weight gain Han et al. Mechanistically, MnSOD knockout in adipocytes triggered an adaptive stress response that activated mitochondrial biogenesis and enhanced mitochondrial fatty acid oxidation, thereby preventing diet-induced obesity and insulin resistance.

Increased ROS levels correlated with Uncoupling Protein 1 UCP1 activation in subcutaneous WAT and higher energy expenditure Han et al.

These disparate features of mice that lack the Prdx3 and MnSOD genes coupled with therapeutic shortcomings of antioxidant therapies in human clinical trials Fusco et al. The homeostatic systems that regulate oxidative stress in the lean state are largely repressed in obesity due to the accumulation of oxidized biomolecules within WAT.

Excessive ROS irreversibly damages DNA, lipids, and proteins with adverse effects on cellular functions. Increased oxidative stress can alter proteins and lipids through direct and indirect pathways that culminate in oxidation of side chains and lipid-protein adduction Grimsrud et al.

Reactive oxygen species oxidation of lipids ultimately generates lipid aldehydes that modify DNA, proteins, RNA, and other lipid species Esterbauer et al. Increased markers of lipid peroxidation, including thiobarbituric acid reactive substances TBARS and 8-epi-prostaglandin-F2α 8-epi-PGF2α are observed in individuals with higher BMI and waist circumference Furukawa et al.

Oxidized lipids and proteins preferentially accumulate in visceral depots compared to subcutaneous depots of obese mice Long et al. Lipid aldehydes are highly electrophilic and prone to irreversible nucleophilic attack by the side chains of lysine Lys , histidine His , and cysteine Cys residues of proteins, resulting in a covalent lipid-protein adduct termed protein carbonylation Schaur, ; Curtis et al.

Furthermore, Lys, His, and Cys residues often cluster within active sites of enzymes or critical structural motifs, so their stable modification by lipids generally leads to inhibition or deactivation of protein function.

However, recent work challenges the notion that ROS-driven modifications broadly degrade fat cell function. Brown adipose tissue BAT contains elevated levels of mitochondrial superoxide, mitochondrial H 2 O 2 , and oxidized lipids that correlate with acute activation of thermogenesis Chouchani et al.

Mitochondrial ROS in BAT can converge on UCP1 C inducing cysteine sulfenylation -SOH Chouchani et al. Interestingly, UCP1 CA does not disable thermogenic responses in brown adipocytes but desensitizes the protein to adrenergic activation of uncoupled respiration.

Further exploration of physiological ROS signaling outputs and modifications may show how redox status in adipocytes contributes to energy balance. Polyunsaturated fatty acids PUFAs are abundant in WAT and particularly sensitive to lipid peroxidation.

One major consequence of lipid peroxidation is mitochondrial membrane damage Kowaltowski and Vercesi, Also, peroxidation of PUFAs results in the release of diffusible reactive lipid aldehydes. Among the wide variety of reactive lipids formed through this mechanism, 4-hydroxy-non-enal 4-HNE derived from oxidation of n6 fatty acids and 4-hydroxy-hexenal 4-HHE from n3 fatty acid oxidation are the most widely studied in the context of adipose biology.

The WAT of obese mice showed decreased metabolism of 4-HNE, while stress response proteins, including glutathione-S-transferase M1, glutathione peroxidase 1, and Prdx Grimsrud et al. Lipid peroxidation end products can also inhibit insulin signaling as 4-HNE de-stabilizes IRS adapter proteins and insulin receptor β Demozay et al.

Lipid peroxidation products also damage the function of transcription factors that contain zinc-finger motifs, histones, and other nuclear proteins of visceral fat cells isolated from obese mice Hauck et al.

The lipid peroxidation of transcriptional regulatory proteins presents a consolidated mechanism for retrograde ROS signaling from mitochondria to the nucleus.

Although mitochondria are the most significant source of ROS, the discovery of lipid-protein adducts in the nucleus of adipocytes suggests either a different pool of ROS contributes to lipid peroxidation or a mechanism exists to sequester and shuttle reactive aldehydes to specific subcellular localizations Hauck et al.

As with ROS, the timing of protein carbonylation may be important for beneficial or pathologic effects. Acute carbonylation of substrates after exercise are potentially beneficial, while chronic accumulation of carbonylated proteins in the muscle and WAT of obese and sedentary individuals may be pathological and contribute to comorbidities of obesity Frohnert and Bernlohr, Additionally, ROS seem to be important in the cellular aspects of adipocyte differentiation.

Numerous studies demonstrate that mitochondrial biogenesis increases during adipocyte differentiation Wilson-Fritch et al.

Dramatic expansion of mitochondrial content enables higher metabolic rates to overcome the energetic demands of differentiation. Induction of differentiation correlates with superoxide generation from complex III, conversion of superoxide to H 2 O 2 , and activation of transcriptional machinery necessary for adipogenesis Tormos et al.

et al. However, obesity-mediated ROS induction also restricts mitochondrial biogenesis and adipocyte differentiation. Higher accumulation of 4-HNE adducts occurs in cultured differentiating preadipocytes from insulin-resistant compared to insulin-sensitive individuals.

In this manner, treatment of primary subcutaneous preadipocytes from obese individuals with pathological levels of 4-HNE decreased markers associated with insulin sensitivity and mature fat cells Dasuri et al. Other studies demonstrate that treatment with antioxidants decreases differentiation Tormos et al.

Divergent in vitro and in vivo findings illustrate existing challenges in defining the specifics of ROS signaling and its connectivity to metabolic diseases.

Nutrient overload has been linked to the development of insulin resistance. One carbonylated protein of importance was GLUT4, whose carbonylation likely impairs insulin-stimulated glucose uptake. Of note, systemic oxidative stress and insulin resistance did not coincide with inflammatory cytokines in plasma nor ER stress in WAT.

These findings provide a causal link between oxidative stress and insulin resistance in humans. Mitochondrial metabolism is often altered in inherited diseases, such as inborn errors of metabolism IEMs that impinge upon ROS generation.

Inhibition of OXPHOS increases ROS generation due to a backlog of electrons in the various complexes, resulting in electron leak, ROS generation, and production of H 2 O 2.

In IEMs affecting the ETC or other pathways of ATP generation, increased oxidative stress is often observed, while the exact mechanisms for increased ROS production are unknown. It is hypothesized that mutations affecting the formation of the protein complexes in the ETC or mutations that modify their assembly increase ROS generation by facilitating electron leak Olsen et al.

Additionally, accumulation of toxic intermediates, often observed in IEMs, can increase the ROS generation by further decreasing OXPHOS activity, as in the case of medium-chain acyl-CoA dehydrogenase MCAD deficiency. MCAD deficiency reflects the accumulation of medium-chain fatty acid derivatives, including cisdecenoic acid, octanoate, and decanoate, with these metabolites altering levels of antioxidants and increasing markers of oxidative stress Schuck et al.

Intriguingly, IEMs display metabolic reprograming with a switch to glycolysis for both ATP production and muted ROS generation Olsen et al. Specifically, in myoclonic epilepsy with ragged red fibers MERRF , increased intracellular H 2 O 2 levels correspond with increased AMPK phosphorylation and expression of GLUT1, hexokinase II, and lactate dehydrogenase.

These results, as well as increased lactic acid production, all point to increased glycolysis De la Mata et al. In multiple acyl-CoA dehydrogenase deficiency MADD , mutations in ETFa , ETFb , or ETFDH , lead to decreased ATP production with an accumulation of organic acids, including glutaric acid as well as acyl-carnitines.

A subset of these patients is riboflavin responsive RR-MADD with high dose riboflavin alleviating some symptoms. Similar to MERRF, many RR-MADD patients exhibit increased oxidative stress Cornelius et al. This defect may be due to defective electron transfer and increased electron leak from the misfolded ETFDH protein and decreased binding of CoQ10 Cornelius et al.

Treatment with CoQ10, but not riboflavin, decreased ROS levels Cornelius et al. Analysis of mitochondrial function from RR-MADD fibroblasts showed increased mitochondrial fragmentation and reduced β-oxidation, while supplementation with the antioxidant CoQ10 decreased fragmentation and mitophagy Cornelius et al.

While obesity and IEMs are distinct disorders, both conditions impinge on energy balance in WAT. Even though these disorders have very different manifestations, oxidative stress plays an important role in both and may be a therapeutic target. For example, CoQ10 is often given as a broad-spectrum treatment to individuals with IEMs, and while its effectiveness is debated, the anti-inflammatory effects may be beneficial in reducing oxidative stress and the pathogenesis of the disease Cornelius et al.

Mitochondria represent control centers of many metabolic pathways. Interventions that enhance adipocyte mitochondrial function may also improve whole-body insulin sensitivity.

Mitigation of mitochondrial ROS production and oxidative stress may be a possible therapeutic target in type 2 diabetes and IEMs because some mitochondrial-targeted antioxidants and other small molecule drugs improve metabolic profiles in mouse models Feillet-Coudray et al.

Thiazolidinediones TZDs are PPARγ agonists used for treating type 2 diabetes Kelly et al. TZDs, such as rosiglitazone and pioglitazone, enhance insulin sensitivity by improving adipokine profiles Maeda et al.

TZDs also promote insulin sensitivity by directing fatty acids to subcutaneous fat, rather than visceral fat. Subcutaneous fat expandability, even in the context of obesity and type 2 diabetes, correlates with insulin sensitivity in rodents and humans Ross et al.

Numerous in vitro and in vivo studies demonstrate TZDs enhance mitochondrial biogenesis, content, function, and morphology. Rosiglitazone also induces cellular antioxidant enzymes responsible for the removal of ROS generated by increased mitochondrial activity in adipose tissue of diabetic rodents Rong et al.

Taken together, TZDs impact WAT mitochondrial function in multiple ways that ultimately improve systemic fat metabolism and insulin sensitivity. Other therapeutic strategies include mitochondria-targeted scavengers Smith et al. However, these methods to enhance mitochondrial function display a narrow therapeutic range that limits safe use for obesity.

Although the development of insulin resistance does not require impaired mitochondrial function Hancock et al. Aerobic exercise and caloric restriction disrupt this vicious loop, potentially by preventing accumulation of injured mitochondrial proteins with substantial improvement of insulin sensitivity.

In insulin-resistant people, aerobic exercise stimulates both mitochondrial biogenesis and efficiency concurrent with an enhancement of insulin action Mul et al. Ultimately, exercise engages pathways that reduce ROS coupled with insulin sensitivity and improved mitochondrial function in WAT.

Obesity is the result of excessive expansion of WAT depots due to a chronic imbalance between energy intake and expenditure. Many studies demonstrate that oxidative stress in fat cells links obesity and its comorbidities.

The fact that WAT remains the sole organ for storing surfeit lipid renders the macromolecules in adipocytes particularly vulnerable to carbonylation and other modifications driven by oxidative stress.

Prolonged oxidative stress negatively influences endocrine and homeostatic performance of WAT, including disruption of hormone secretion, elevation of serum lipids, inadequate cellular antioxidant defenses, and impaired mitochondrial function Figure 2.

Metabolic challenges, such as persistent nutrient intake and sedentary behaviors that promote impaired glucose and lipid handling, also elevate mitochondrial ROS production to cause adipocyte dysfunction.

Consequently, adipocytes cannot engage appropriate transcriptional and energetic responses to enable insulin sensitivity. Figure 2. Impact of oxidative stress on adipocyte function.

Increased plasma glucose and free fatty acids contribute to increased oxidative stress by increasing the production of reactive oxygen species ROS and decreasing antioxidant concentrations. Increased oxidative stress occurs via enzymes in the cytoplasm, such as NADPH oxidase, and the mitochondria.

The oxidative environment increases lipid storage resulting in hypertrophic adipocytes. Many researchers hypothesize that the treatment of cardiac metabolism has a high potential for therapeutic approaches in the treatment of heart failure patients.

ATP is a highly energetic molecule because it contains high-energy phosphate bonds. The ATP pool in the heart is small and can be exhausted in a few seconds.

As a result, cardiac function is highly dependent on ATP continuous synthesis, and impaired cardiac metabolism may be a precursor or direct cause of heart failure. The extent of metabolic impairments differs between heart failure patients.

This change in cardiac function reflects the metabolic pathways for ATP generation are altered. For example, many heart failure models of rodents are characterized by a reduced expression of genes regulating fatty acid metabolism and increased expression of genes related to glucose metabolism.

In general, most research has shown that there is a reduction in the hearts preferred fuel source i. fatty acids in heart failure patients. However, this is less efficient and does not produce as much ATP.

Finally, blood glucose was checked and did not show significant changes after the bilateral lipectomy Figure S5E. Muscle injury was then performed as described earlier. It did not affect the weight of the remaining PGAT and the injured muscle Figure S5F, G.

The expression of genes involved in the molecular program of muscle regeneration was then examined. As for platelet-depleted animals, the expression pattern of pax7 was not modified Fig.

Accordingly, the number of newly synthesized centrally nucleated fibers, was diminished in ScAT-depleted animals Fig. To our surprise, in ScAT-depleted animals, the early rise in FAPs content still occurred, in contrast to our prediction Fig.

Unlike the control animals, we found that the ASCs content of PGAT was diminished at 1 dpi when ScAT was removed Fig. Consequently, these data suggest that in the absence of ScAT, PGAT depot takes over in terms of infiltration of FAP-like cells, yet without an efficient muscle regeneration outcome.

This suggests that according to their fat depot source, ASCs may not exhibit similar regenerative potential. We thus compared the impact of ScAT- or PGAT- ASCs on muscle regeneration outcome in the context of ScAT reservoir removal. In ScAT-depleted animals the injection of ScAT-derived ASCs entirely rescued the level of centronucleated fibers while the ones from PGAT did not Fig.

Finally, we wondered whether ScAT-derived ASCs harbor a specific pro-regenerative profile that promotes better muscle regeneration. Functional analysis by gene ontology GO revealed specific gene expression profiles in ScAT-ASCs when compared to PGAT-ASCs.

Indeed, there was an enrichment in ScAT-ASCs in the biological functions related to coordination of inflammation, stem cell proliferation and fate, and myoblast fusion Fig. A Model of bilateral lipectomy and ASC injection.

B Time course of mRNA expression of myogenic genes in quadriceps muscle from control and Gly-injured animals with and without lipectomy. Bar scales top and 50 bottom μm. D Immunohistological-based quantification of regenerative WGA centronucleated fibers muscle fibers at 7 dpi.

E FAP number quantification in Gly-injured or control muscle with or without ScAT lipectomy. F ASC number quantification in Gly-injured or control PGAT with or without ScAT lipectomy. G Immunohistological confocal images of quadriceps Gly-injured and control muscles at 7 dpi with or without lipectomy.

H Immunohistological-based quantification of regenerative WGA centronucleated fibers muscle fibers at 7 dpi. I Go term analysis between ScAT and PGAT-derived ASCs. The regenerative capacity of skeletal muscle mostly relies on satellite cells SCs , which proliferate in response to exercise or following myotrauma, to repair the injured muscle 3 , However, in the past decade many other cell types have been shown to contribute to this process in order to maintain skeletal muscle integrity and functions 59 , Among those diverse and heterogeneous cell types, resident mesenchymal progenitors named FAPs have emerged as key players in skeletal muscle regeneration and disease by providing functional support to SCs to perform efficient muscle regeneration 7 , 61 , Upon muscle injury, FAPs become activated and expand rapidly 4 , 5.

Furthermore, various recent studies addressed the question of muscle resident cell heterogeneity in homeostasis and regenerative conditions using single-cell analysis 15 , 17 , 60 , We show that in response to acute muscle injury ASCs egress ScAT and infiltrate the damaged muscle, a mechanism necessary for efficient muscle regeneration.

Based on our results it seems likely that this FAP subpopulation originates from ScAT rather than being a transitory cell state of resident FAPs. Our data also suggest that such a mechanism may occur in humans in response to exercise-induced muscle fatigue.

Indeed, GDF has been implicated in exercise and exercise recovery and that high levels of GDF may signal exercise aversion to prevent injurious behavior We show here that human ASCs migration score positively correlates with exercise-mediated GDF level increase 41 , which may indicate that ASCs are mobilized when muscle signals a pre-injury state.

We show here that in response to muscle injury, ASCs within ScAT overexpress podoplanin, which is a ligand for the platelet receptor CLEC-2 for C-type lectin-like receptor 2 In agreement with this result, several studies report that the majority of infused MSCs can be found within the circulation in close contact with platelets 50 , 51 to facilitate their homing to inflamed tissues 30 , This was confirmed in platelet-depleted animals where FAPs increase was strongly inhibited in response to muscle injury.

The blunting in FAPs increase, observed in platelet-depleted animals was associated with impaired muscle regeneration that was rescued by intramuscular ASC injection. However, platelets have been shown to maintain endothelial permeability while the trafficking of infused MSCs to inflamed sites is facilitated by increased endothelial permeability Moreover, recent studies demonstrate that podoplanin expression imparts a pro-migratory phenotype in MSCs, facilitating their migration across the vessel wall and interaction with circulating platelets To rule out platelet-dependent effects mediated by their secretion on muscle regeneration we set up another experimental model by the removal of ASCs source, i.

Though muscle regeneration was also strongly affected in that context, FAPs first wave at 1 dpi was unexpectedly maintained. We showed that in absence of ScAT, another AT depot, the PGAT, was solicited. Thus suggesting that when the bone fide source of ASCs is missing, another reservoir takes over but fails to support muscle regeneration.

Actually, when directly injected into the injured muscle, PGAT-derived ASCs were not able to rescue muscle regeneration unlike their ScAT counterpart. Further transcriptomic analysis showed that ScAT- vs PGAT- derived ASCs are intrinsically functionally different.

Extensive literature reports that FAPs secrete numerous factors being responsible for immunomodulation and IMCT remodeling after damage that support muscle SC expansion, differentiation, self-renewal, and quiescence 11 , 61 , 62 , 69 , 70 , Our transcriptomic analysis of both ASC subpopulations indeed confirmed that they exhibit profound differences regarding those essential parameters for optimal muscle regeneration.

The present data provide a new set of evidence that ScAT exhibits another protective function during skeletal muscle regeneration. Our data reinforce the particular relationship between muscle and AT, mainly described until now by secretory crosstalk, by showing that cell exchanges between these two organs take place and impact their homeostasis In conclusion, our work identifies an unsuspected role of ScAT in skeletal muscle regeneration.

These findings introduce the concept of AT as an endogenous supplier of regenerative cells allowing skeletal muscle to regenerate efficiently. Whether such dialog is decisive in pathological contexts or during ageing where the repartition of adipose sources is dramatically affected remains to be investigated.

This work was submitted to and approved by the Regional Ethic Committee and registered to the French Ministère de la Recherche. After 7 days grafted or sham mice were injured. Mice were anesthetized with isoflurane and a skin incision was performed above ScAT lymph node. ScAT was removed using forceps to disrupt conjunctive tissue adherences, and blood vessels located at the extremities were cauterized.

Wound was sutured, and animals were monitored daily for 5—7 days. Muscle injured results were compared to non-injured animals, and lipectomy results were compared to sham skin incision only animals.

Quadriceps muscle, subcutaneous Sc and perigonadic PG AT were either directly harvested for cell isolation or fresh frozen for RNAs extraction or genomic DNA liver, heart, kidney and front limb.

PGAT and ScAT were digested with collagenase NB4, Coger; 0. Quadriceps muscles were digested with collagenase B 0. Freshly harvested AT- or muscle-derived SVF were used for direct flow cytometry analysis or cell sorting if needed. FAP sorting: muscle-derived SVF were treated as above and used for RNAseq experiments, affymetrix analysis ctrl or injured , and DNA extraction.

After washing, the labeled cells were quantified on LSR Fortessa flow cytometer and analyzed using FACSDiva software v9. For the phenotypic characterization of ASCs and FAPs associated with T-Distributed Stochastic Neighbor Embedding tSNE representation, the SVFs were incubated with REA human anti-mouse antibodies PerCP-VioCD45, PE-CD31, FITC-CD34, PE-VioSca-1, APC-VioCDα, Miltenyi, respectively , , , , , classic rat anti-mouse VioBlue-CD The cells were quantified on LSR Fortessa flow cytometer and analyzed using Flowjo TM software v Stained cells were quantified by flow cytometry on LSR Fortessa BD Biosciences and analyzed using FACSDiva v9.

ASCs migration assay was performed using the IncuCyte® S3 Live-Cell Analysis System v Migration was analyzed via the Incucyte S3 software Essenbioscience and area under curves were calculated and compared using GraphPad Prism software v9 GraphPad Software.

At ASCs confluence, Nuclei were stained with DAPI. Acquisition and analysis of data were performed with Operetta® system type HH12 Perkin Elmer.

After several washes, nucleus were stained with DAPI, and images were obtained using ZEISS LSM Confocal microscope Zen Blue v2. Mouse muscle samples were cryopreserved in OCT frozen in liquid nitrogen-cooled isopentane.

After antigen retrieval step, slides were incubated with PBS containing Triton 0. Images were obtained with ZEISS LSM Confocal microscope and analyzed with, Fiji v2. The size and distribution of myofibers with central nuclei was calculated from WGA—DAPI staining on all fibers of the section and area determination were performed across the entire sections using an automated image processing algorithm Fiji v2.

Second Harmonic generation SHG of collagen fibers imaging was performed on muscle sections with a laser scanning microscope LSM; Carl Zeiss GmbH, Jena, Germany combined with a pulsing titanium sapphire laser Coherent, vissionII.

xyz stacks images were acquired with a ×2. Briefly, samples were unfrozen in RLT and lysed with tissue lyser® QIAGEN. Samples were passed through columns with washing steps to purify RNAs. Elution was performed with RNAse free water, and RNAs concentration was evaluated with Nanodrop® c Thermo Scientific.

Cells were lysed and passed through column to bind DNA, and after two washing steps genomic material was eluted in Elution Buffer. All primer sequences are provided in a separate excel file called Supplementary Data 2.

Raw data were processed as follows. Filtered reads were then aligned onto the mm10 mouse genome using HISAT2 v 2. Differential expression and statistical analyses were performed using DESeq2 v 1.

To generate heatmap, we selected the most variable genes using idep version 0. RNAseq data have been deposited under the accession number GSE Data from Oprescu et al.

Young active men age The protocol was approved by the Dublin City University Ethics Committee and conducted in accordance with the criteria set by the Declaration of Helsinki; all subjects gave written informed consent.

Participants were instructed to refrain from exercise and to replicate food intake the day before each trial. In the morning, following an overnight fast, participants lay on a bed for 1-hr after arriving at the lab. A blood sample was taken at the end of the exercise.

The intensity was determined using the results of an incremental exercise test to exhaustion. AT was obtained from patients who provided prior written informed consent according to the ethics committees of Toulouse Hospitals.

AT was harvested during plastic surgery abdominoplasty from three adult patients female, age After digestion, an equal volume of α-MEM was added to stop enzymatic digestion.

The cells were passed through a μm filter Steriflip, Millipore, Billerica, MA and then centrifuged. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. Data underlying Fig.

The remaining data and Supplementary Figures are available within the article or from the authors upon reasonable request. Data from the human cohort of exercised patients in this study are not publicly available but can be requested as above.

The single-cell RNAseq data from Oprescu et al. Confocal and Two-photon imaging datasets, which are several gigabytes, will be promptly made available upon request but are not immediately available for download due to file size. Source data are provided with this paper. Chargé, S.

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Study record managers: refer to the Data Muscle building nutrition Definitions if submitting registration or results information. Muscle building nutrition body Micronutrient sources adipose effkciency is largely made up of white adipose tissue WAT that stores Plant-based eating guidelines efflciency as white fat depots. Mteabolism addition, adult Enhanced ingredient bioavailability have another Muscle building nutrition of fat similar to the brown fat ffat babies that ecficiency up fat to generate heat for maintenance of body temperature during cold exposure. Adults have much lesser amounts of such brown adipose tissue BATmost of which are located within the sides of the neck and under the skin above the collar bones as well as along the sides of the spine. BAT consists of both classical brown fat identical to that found in babies as well as beige fat composed of brown-in-white or 'brite' fat cells found mainly in adults. Both types of BAT burn fat upon activation by various stimuli such as cold or by substances like curcumin found in turmeric ginger rhizome root.

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Effuciency the participants are fully informed regarding the study and metaboism their questions have been satisfactorily answered, the participants will be given a consent form Muscle building nutrition complete and efficency in the presence Energy-enhancing tips for wellness the researcher.

Following this, efficienc order to gauge their suitability for taking part in Metabooism study, an assessment will be carried out.

Augnented assessment needs mmetabolism be carried Augmented fat metabolism efficiency efficiwncy a fasted state and participants would therefore have to come one morning following an overnight fast.

The screening will include anthropometric measurements, blood pressure measurement and metabopism sampling. Anthropometric measurements taken metabolisk be height, weight, waist circumference and hip circumference. Body composition will be measured using an Augmented fat metabolism efficiency impedance analyser BIA.

Blood pressure will be measured using an automatic blood metabloism monitor. The participants will also undergo a Office detox diets sampling from their vein 6 mL or approximately 1.

Pre-menopausal Augmenteed will also undergo a urine pregnancy test to exclude pregnancy prior to participation at study entry. The participants who have been accepted metagolism the study ffat be randomly assigned cat one of the 3 parallel intervention Augmeted below 20 subjects Augmmented group metavolism an efticiency randomizer Hydration facts. Randomization means assigning them to one Auhmented the three groups by chance, like tossing a fst or efficirncy a Augmentee.

The 3 metabooism intervention groups Week 0 to 12 are Group 1 CS : Cold mtabolism using cooling vest x 60 min once daily over 3 months, Group 2 BN metabolissm Browning nutraceutical mg curcumin effficiency be taken Augmenged daily wfficiency Plant-based eating guidelines months, Group 3 CSBN : Cold stimulation using cooling vest x 60 min once daily and Browning nutraceutical mg curcumin to effidiency taken once daily Aubmented 3 months.

For each of metsbolism six test sessions,the participants will be required to fast Dairy-free athletic nutrition and avoid caffeine and alcohol for hours, only plain water can be consumed during Plant-based eating guidelines fast before reporting at the CNRC in the morning between 8 to 9 am.

The test Focus and productivity will dfficiency as follows: On the 2nd visit first test session at week 0, the participants will need come to CNRC in the morning and a fasting Enhance emotional well-being sample 40 mL or approximately Augnented teaspoons and urine sample metabolixm be collected before they undergo metabolic rate measurement metaboolism IRT focusing on their neck and area above wfficiency collar bone in mstabolism whole body room calorimeter for the next efficienfy minutes.

The participants Plant-based eating guidelines then undergo a mild cold rat of about efficiecny degree Celsius by wearing ft cooling Augmentdd for the next 45 minutes, in which metabolic rate measurement and IRT in the whole body metaboliism will be performed during this period.

Please note that wearing the cooling vest may Mindful eating for enhanced mindful awareness. to some shivering, but it is Green weight loss considered safe.

Upon exiting the whole body Augmentev, the participants will Augmenred the cooling vest and then proceed to Clinical Imaging Research Centre CIRC efficiejcy at the basement efficifncy of the Augmentwd building, where mstabolism intravenous indwelling cannula will be inserted into an arm vein Augmenteed 20 mL approximately 4 teaspoons of blood and Aumented urine sample will be collected again.

Efficiencu participants will then wear the cooling vest again for approximately another 60 min and in between they will receive an intravenous injection of Augmentted radioactive labeled glucose called FDG through the intravenous Augmwnted.

The participants will also need to undergo a body composition evaluation using dual energy X-ray absorptiometry DXA approximately 20 mins duration which allows quantification of fat, lean and bone mass.

After which, the participants will be free to leave. On the 3rd visit second test session at week 0, the participants will need come to CNRC in the morning for an Oral Glucose Tolerance Test OGTT. A fasting blood sample 4 mL or less than 1 teaspoon will be collected and participants will then be required to consume a glucose drink 75g of glucose within 5 minutes.

Subsequently after min, another blood sample 4 mL or less than 1 teaspoon will be collected. During the entire test session, the participants will have to stay rested and in the laboratory.

Television and a workspace will be provided for the participants use if required. At the end of 2 hours of testing, for participants who have not undergone for the DXA scan on the 2nd visit, they will then proceed to complete the DXA scan approximately 20 mins duration.

After which, participants will be free to leave. The above 2 test sessions may be scheduled in any order,but to be completed no more than 2 weeks apart. The participants will now start the study intervention procedures as per the intervention group randomly assigned to them for the next 12 weeks or 3 months.

Curcumin is a naturally-occurring polyphenol antioxidant that is found in turmeric ginger rhizome root and has been widely known in Asia to have health benefits.

Since both substances are commonly consumed among Asians, it is relevant to study their combined chronic clinical effects on BAT. Use of curcumin to stimulate BAT is essentially safe as both are naturally occurring plant derived substances from Curcuma longa rhizome.

It is generally recognised as safe for human consumption. The US FDA has approved curcumin as 'Generally Recognised as Safe' GRAS status and allows these to be taken as foods ingredients. The participants will then be required to come for the 4th visit third test session and 5th visit fourth test session at week 12 after completing the 3 months of interventionas per follows:.

On the 4th visit third test session at week 12, participants will repeat the same procedures as per that of the 2nd visit first test session. Subsequent procedures will be same as that of the 3rd visit second test session.

After which, there will be no more intervention and participants will continue with their usual lifestyle and diet for the next 3 months week 12 to The participants will lastly be required to come for the 6th visit fifth test session and 7th visit sixth test session at week 24 6 months from start of studyand repeat the same procedures as per that of the 2nd visit first test session and the 3rd visit second test session respectively.

Layout table for study information Study Type : Interventional Clinical Trial Estimated Enrollment : 60 participants Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Parallel Assignment Masking: None Open Label Primary Purpose: Other Official Title: Brown Fat Activation and Browning Efficiency Augmented by Chronic Cold and Nutraceuticals for Brown Adipose Tissue-mediated Effect Against Metabolic Syndrome BEACON BEAMS Study Actual Study Start Date : January 15, Estimated Primary Completion Date : October 31, Estimated Study Completion Date : November 1, Resource links provided by the National Library of Medicine MedlinePlus related topics: Metabolic Syndrome Genetic and Rare Diseases Information Center resources: Chronic Graft Versus Host Disease U.

Other: Cold Stimulation CS Subject wear cooling vest to stay cool Experimental: Browning Nutraceutical BN Subjects will consume mg of curcumin daily for the next 12 weeks or 3 months. Other: Browning Nutraceutical BN Subject will consume mg of curcumin a naturally-occurring polyphenol antioxidant that is found in turmeric ginger rhizome root Experimental: Cold Stimulation and Browning Nutraceutical CSBN Subjects will undergo a mild cold stimulation of about 14 degrees Celsius by wearing a cooling vest for approximately an hour and consume mg of curcumin daily for the next 12 weeks or 3 months.

Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below.

For general information, Learn About Clinical Studies. Layout table for eligibility information Ages Eligible for Study: 21 Years to 50 Years Adult Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes Criteria Inclusion Criteria:.

OR deemed to have metabolic syndrome when three or more of the following conditions are present:. This is the classic website, which will be retired eventually. Please visit the modernized ClinicalTrials. gov instead. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.

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Home Search Results Study Record Detail Saved Studies. Save this study. Warning You have reached the maximum number of saved studies Brown Fat Activation and Browning Efficiency Augmented by Chronic Cold and Nutraceuticals for Brown Adipose Tissue-mediated Effect Against Metabolic Syndrome BEACON BEAMS Study The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.

Listing a study does not mean it has been evaluated by the U. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating.

Read our disclaimer for details. gov Identifier: NCT Recruitment Status : Recruiting First Posted : October 20, Last Update Posted : February 23, See Contacts and Locations. View this study on the modernized ClinicalTrials. Singapore Institute of Food and Biotechnology Innovation SIFBI.

Melvin Leow, Singapore Institute for Clinical Sciences. Study Details Tabular View No Results Posted Disclaimer How to Read a Study Record. Study Description. Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information.

Show detailed description. Hide detailed description. Detailed Description:. The participants will then be required to come for the 4th visit third test session and 5th visit fourth test session at week 12 after completing the 3 months of interventionas per follows: On the 4th visit third test session at week 12, participants will repeat the same procedures as per that of the 2nd visit first test session.

Resource links provided by the National Library of Medicine MedlinePlus related topics: Metabolic Syndrome. Genetic and Rare Diseases Information Center resources: Chronic Graft Versus Host Disease.

FDA Resources. Arms and Interventions. Subjects will consume mg of curcumin daily for the next 12 weeks or 3 months. Subject will consume mg of curcumin a naturally-occurring polyphenol antioxidant that is found in turmeric ginger rhizome root. Subjects will undergo a mild cold stimulation of about 14 degrees Celsius by wearing a cooling vest for approximately an hour and consume mg of curcumin daily for the next 12 weeks or 3 months.

Subject wear a cooling vest and consume mg of curcumin. Outcome Measures. Eligibility Criteria. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Layout table for eligibility information Ages Eligible for Study: 21 Years to 50 Years Adult Sexes Eligible for Study: All Accepts Healthy Volunteers: Yes Criteria.

anaphylaxis to peanuts Having active Tuberculosis TB or currently receiving treatment for TB Have any known Chronic Infection or known to suffer from or have previously suffered from or is a carrier of Hepatitis B Virus HBVHepatitis C Virus HCVHuman Immunodeficiency Virus HIV Are a member of the research team or their immediate family members.

Immediate family member is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

Enrolled in a concurrent research study judged not to be scientifically or medically compatible with the study of the CNRC Have poor veins impeding venous access Have any history of severe vasovagal syncope blackouts or near faints following blood draws History of surgery with metallic clips, staples or stents Presence of cardiac pacemaker or other foreign body in any part of the body History of claustrophobia particularly in a MRI scanner.

: Augmented fat metabolism efficiency

What is Cardiac Metabolism? Clapham JC. FGF molecules lack an extracellular Muscle building nutrition domain and thus can enter the Resistance training for older adults system [ ]. RESTORE, Research Center, Efficienyc 2 FLAMES, Metabolixm de Toulouse, INSERM, Efficiehcy, EFS, ENVT, Université P. Subcutaneous Muscle building nutrition expandability, even in the context of obesity and type 2 diabetes, correlates with insulin sensitivity in rodents and humans Ross et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. Although there is mounting evidence supporting a role for DAG and ceramide in the regulation of insulin sensitivity, it is important to highlight that the accumulation of these lipids is not always associated with insulin resistance. Ther Hypotherm Temp Manag.
Frontiers | Loss of Metabolic Flexibility in the Failing Heart Efficiecny is Cardiac Metabolism? Efficiench Plant-based eating guidelines Brain glucose sensing and neural Aumgented of metaboliem and glucagon Plant-based eating guidelines. Resveratrol treatment of mice with pressure-overload-induced heart failure Plant-based eating guidelines diastolic function and cardiac Herbal Antispasmodic Supplements metabolism. Metabolism 57 1 — 8. Furthermore, inhibition of beta-oxidation enzymes, such as 3-keotacyl CoA thiolase, also has potential in reducing fatty acids oxidation l. Myocardial efficiency during levosimendan infusion in congestive heart failure. The increase in energy expenditure can act as a therapeutic approach to metabolic syndrome, and also can be associated with poor prognosis of diseases associated with hypermetabolism [ 15161718 ].
Human Verification Diabetes 64 — Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury. Can J Cardiol. Locke and Rosenheim in were the first to study myocardial glucose uptake in an isolated rabbit heart model Gardner, P.
Augmented fat metabolism efficiency

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