Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances lipid oxidation in skeletal muscle and adipose tissue

2011 ◽  
Vol 164 ◽  
pp. S7 ◽  
Author(s):  
Alessandra Ferrari ◽  
Andrea Galmozzi ◽  
Nico Mitro ◽  
Elise Gers ◽  
Federica Gilardi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Lipid Oxidation ◽  
Histone Deacetylases ◽  
Class I

scholarly journals Inhibition of Class I Histone Deacetylases Unveils a Mitochondrial Signature and Enhances Oxidative Metabolism in Skeletal Muscle and Adipose Tissue

Diabetes ◽  
2012 ◽  
Vol 62 (3) ◽  
pp. 732-742 ◽  
Author(s):  
A. Galmozzi ◽  
N. Mitro ◽  
A. Ferrari ◽  
E. Gers ◽  
F. Gilardi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Oxidative Metabolism ◽  
Histone Deacetylases ◽  
Class I

scholarly journals Epigenetic Signatures of Human Myocardium and Brown Adipose Tissue Revealed with Simultaneous Positron Emission Tomography and Magnetic Resonance of Class I Histone Deacetylases

2020 ◽  
Author(s):  
David Izquierdo-Garcia ◽  
Jacob M. Hooker ◽  
Frederick A. Schroeder ◽  
Choukri Mekkaoui ◽  
Tonya M. Gilbert ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Positron Emission Tomography ◽  
Adipose Tissue ◽  
Histone Deacetylases ◽  
Human Heart ◽  
Emission Tomography ◽  
Class I ◽  
Positron Emission ◽  
Class I Hdacs

AbstractRationaleHistone deacetylases (HDACs) play a central role in cardiac hypertrophy and fibrosis in preclinical models. However, their impact in the human heart remains unknown.ObjectiveWe aimed to image HDAC expression in the human heart in vivo with PET-MR (positron emission tomography and magnetic resonance) using [11C]Martinostat, a novel radiotracer targeted to class I HDACs. We further aimed to compare HDAC expression in the heart with its expression in skeletal muscle and brown/white adipose tissue (BAT/WAT).Methods and ResultsThe specificity and selectivity of [11C]Martinostat binding in the heart was assessed in non-human primates (n=2) by in vivo blocking studies and with an ex vivo cellular thermal shift assay (CETSA) of HDAC paralog stabilization by Martinostat. PET-MR imaging of [11C]Martinostat was performed in healthy volunteers (n=6) for 60 minutes to obtain time-activity curves of probe uptake and kinetics. qPCR of class I HDACs was performed in specimens of BAT obtained from patients (n=7) undergoing abdominal surgery and in specimens of human subcutaneous WAT (n=7). CETSA and the blocking studies demonstrated that Martinostat was specific for class I HDACs in the heart. HDAC density, measured by standardized uptake values of [11C]Martinostat, was 8 times higher in the myocardium than skeletal muscle (4.4 ± 0.6 vs. 0.54 ± 0.29, p<0.05) and also significantly higher in BAT than WAT (0.96 ± 0.29 vs. 0.17 ± 0.08, p<0.05). qPCR confirmed higher class I HDAC expression in BAT, particularly HDAC2 and HDAC3 (2.6 and 2.7-fold higher than WAT respectively, p<0.01).ConclusionsClass I HDAC expression in the human heart can be imaged in vivo and is dramatically higher than any other peripheral tissue, including skeletal muscle. The high levels of HDAC in the myocardium and BAT suggest that epigenetic regulation plays an important role in tissues with high energetic demands and metabolic plasticity.

Uncoupling protein 3 and fatty acid metabolism

2001 ◽  
Vol 29 (6) ◽  
pp. 785-791 ◽  
Author(s):  
A. G. Dulloo ◽  
S. Samec ◽  
J. Seydoux
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Fatty Acid ◽  
Lipid Oxidation ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Gene Knockout ◽  
Uncoupling Protein ◽  
Brown Adipose ◽  
Genes Encoding

A role for uncoupling protein (UCP) 3 in fatty acid metabolism is reviewed within the context of our proposal, first put forward in 1998, that this homologue of UCP1 may be involved in the regulation of lipids as fuel substrate rather than in the mediation of thermogenesis. Since then, the demonstrations of muscle-type differences in UCP3 gene regulation in response to dietary manipulations (starvation, high-fat feeding) or to pharmacological interferences with the flux of lipid substrates between adipose-tissue stores and skeletal-muscle mitochondrial oxidation are all in accord with this proposed role for UCP3 in regulating lipids as fuel substrate. However, given the current limitations of gene-knockout technology for evaluating/interpreting the functional importance of genes encoding mitochondrial membrane proteins, the transition from ‘associative’ to ‘cause-and-effect’ evidence for a physiological role of UCP3 in regulating fatty acid metabolism will have to await the development of assays that are sensitive to changes in UCP3 activity. Furthermore, in evaluating the physiological regulators of UCP3, the available evidence points to the existence of adipose-derived factor(s) which, independently of circulating levels of free fatty acids, initiates events leading to the transcription of genes encoding UCP3 and key enzymes of lipid oxidation in the fast glycolytic or fast oxidative-glycolytic muscles, i.e. in the bulk of the skeletal-muscle mass. It is proposed that in tissues where UCP3 co-exists with UCP2 (skeletal muscle, brown adipose tissue, heart) they may act in concert in the overall regulation of lipid oxidation, concomitant to the prevention of lipid-induced oxidative damage.

scholarly journals Histone Deacetylase 3 Regulates Adipocyte Phenotype at Early Stages of Differentiation

2021 ◽  
Vol 22 (17) ◽  
pp. 9300
Author(s):  
Dalma Cricrí ◽  
Lara Coppi ◽  
Silvia Pedretti ◽  
Nico Mitro ◽  
Donatella Caruso ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Histone Deacetylases ◽  
Coupling Efficiency ◽  
Class I ◽  
Metabolic Phenotype ◽  
Mitochondrial Activity ◽  
Tissue Mass ◽  
White Adipocyte ◽  
Class I Hdacs

Obesity is a condition characterized by uncontrolled expansion of adipose tissue mass resulting in pathological weight gain. Histone deacetylases (HDACs) have emerged as crucial players in epigenetic regulation of adipocyte metabolism. Previously, we demonstrated that selective inhibition of class I HDACs improves white adipocyte functionality and promotes the browning phenotype of murine mesenchymal stem cells (MSCs) C3H/10T1/2 differentiated to adipocytes. These effects were also observed in db/db and diet induced obesity mouse models and in mice with adipose-selective inactivation of HDAC3, a member of class I HDACs. The molecular basis of class I HDACs action in adipose tissue is not deeply characterized and it is not known whether the effects of their inhibition are exerted on adipocyte precursors or mature adipocytes. Therefore, the aim of the present work was to explore the molecular mechanism of class I HDAC action in adipocytes by evaluating the effects of HDAC3-specific silencing at different stages of differentiation. HDAC3 was silenced in C3H/10T1/2 MSCs at different stages of differentiation to adipocytes. shRNA targeting HDAC3 was used to generate the knock-down model. Proper HDAC3 silencing was assessed by measuring both mRNA and protein levels of mouse HDAC3 via qPCR and western blot, respectively. Mitochondrial DNA content and gene expression were quantified via qPCR. HDAC3 silencing at the beginning of differentiation enhanced adipocyte functionality by amplifying the expression of genes regulating differentiation, oxidative metabolism, browning and mitochondrial activity, starting from 72 h after induction of differentiation and silencing. Insulin signaling was enhanced as demonstrated by increased AKT phosphorylation following HDAC3 silencing. Mitochondrial content/density did not change, while the increased expression of the transcriptional co-activator Ppargc1b suggests the observed phenotype was related to enhanced mitochondrial activity, which was confirmed by increased maximal respiration and proton leak linked to reduced coupling efficiency. Moreover, the expression of pro-inflammatory markers increased with HDAC3 early silencing. To the contrary, no differences in terms of gene expression were found when HDAC3 silencing occurred in terminally differentiated adipocyte. Our data demonstrated that early epigenetic events mediated by class I HDAC inhibition/silencing are crucial to commit adipocyte precursors towards the above-mentioned metabolic phenotype. Moreover, our data suggest that these effects are exerted on adipocyte precursors.

scholarly journals Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis

2021 ◽  
Vol 22 (9) ◽  
pp. 4538
Author(s):  
Helena Kratochvílová ◽  
Miloš Mráz ◽  
Barbora J. Kasperová ◽  
Daniel Hlaváček ◽  
Jakub Mahrík ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Cardiac Surgery ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Mrna Expression ◽  
Coronary Atherosclerosis ◽  
Stress Genes ◽  
Valvular Surgery

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.

scholarly journals Optimizations for identifying reference genes in bone and cartilage bioengineering

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fei Xiong ◽  
Xiangyun Cheng ◽  
Chao Zhang ◽  
Roland Manfred Klar ◽  
Tao He
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Real Time ◽  
Reference Gene ◽  
Muscle Tissue ◽  
Reference Genes ◽  
Target Genes ◽  
The Stability ◽  
And Cartilage

Abstract Background Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) remains one of the best-established techniques to assess gene expression patterns. However, appropriate reference gene(s) selection remains a critical and challenging subject in which inappropriate reference gene selction can distort results leading to false interpretations. To date, mixed opinions still exist in how to choose the most optimal reference gene sets in accodrance to the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guideline. Therefore, the purpose of this study was to investigate which schemes were the most feasible for the identification of reference genes in a bone and cartilage bioengineering experimental setting. In this study, rat bone mesenchymal stem cells (rBMSCs), skeletal muscle tissue and adipose tissue were utilized, undergoing either chondrogenic or osteogenic induction, to investigate the optimal reference gene set identification scheme that would subsequently ensure stable and accurate interpretation of gene expression in bone and cartilage bioengineering. Results The stability and pairwise variance of eight candidate reference genes were analyzed using geNorm. The V0.15- vs. Vmin-based normalization scheme in rBMSCs had no significant effect on the eventual normalization of target genes. In terms of the muscle tissue, the results of the correlation of NF values between the V0.15 and Vmin schemes and the variance of target genes expression levels generated by these two schemes showed that different schemes do indeed have a significant effect on the eventual normalization of target genes. Three selection schemes were adopted in terms of the adipose tissue, including the three optimal reference genes (Opt3), V0.20 and Vmin schemes, and the analysis of NF values with eventual normalization of target genes showed that the different selection schemes also have a significant effect on the eventual normalization of target genes. Conclusions Based on these results, the proposed cut-off value of Vn/n + 1 under 0.15, according to the geNorm algorithm, should be considered with caution. For cell only experiments, at least rBMSCs, a Vn/n + 1 under 0.15 is sufficient in RT-qPCR studies. However, when using certain tissue types such as skeletal muscle and adipose tissue the minimum Vn/n + 1 should be used instead as this provides a far superior mode of generating accurate gene expression results. We thus recommended that when the stability and variation of a candidate reference genes in a specific study is unclear the minimum Vn/n + 1 should always be used as this ensures the best and most accurate gene expression value is achieved during RT-qPCR assays.

scholarly journals Cardio- and Neurometabolic Adipobiology: Consequences and Implications for Therapy

2021 ◽  
Vol 22 (8) ◽  
pp. 4137
Author(s):  
Jan Frohlich ◽  
George N. Chaldakov ◽  
Manlio Vinciguerra
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Nerve Growth Factor ◽  
Human Life ◽  
Signaling Proteins ◽  
New Developments ◽  
Cardiometabolic Diseases ◽  
The Past ◽  
Neurotrophin 3

Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer’s disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose- and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the “vascular hypothesis of AD” was published and in the present review we propose the “vasculometabolic hypothesis of AD.” We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.

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