21 results on '"Riccardo, Turchi"'
Search Results
2. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich’s ataxia mouse model
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Riccardo Turchi, Francesca Sciarretta, Veronica Ceci, Marta Tiberi, Matteo Audano, Silvia Pedretti, Concetta Panebianco, Valentina Nesci, Valerio Pazienza, Alberto Ferri, Simone Carotti, Valerio Chiurchiù, Nico Mitro, Daniele Lettieri-Barbato, and Katia Aquilano
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Pharmacology ,Natural sciences ,Biological sciences ,Neuroscience ,Science - Abstract
Summary: Friedreich’s ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
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- 2023
- Full Text
- View/download PDF
3. Validation of a biomarker tool capable of measuring the absorbed dose soon after exposure to ionizing radiation
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Anna Giovanetti, Raffaella Marconi, Noha Awad, Hala Abuzied, Neveen Agamy, Mohamed Barakat, Cecilia Bartoleschi, Gianluca Bossi, Marco Canfora, Amr A. Elsaid, Laura Ioannilli, Horeya M. Ismail, Yasmine Amr Issa, Flavia Novelli, Maria Chiara Pardini, Claudio Pioli, Paola Pinnarò, Giuseppe Sanguineti, Mohamed M. Tahoun, Riccardo Turchi, and Lidia Strigari
- Subjects
Medicine ,Science - Abstract
Abstract A radiological or nuclear attack could involve such a large number of subjects as to overwhelm the emergency facilities in charge. Resources should therefore be focused on those subjects needing immediate medical attention and care. In such a scenario, for the triage management by first responders, it is necessary to count on efficient biological dosimetry tools capable of early detection of the absorbed dose. At present the validated assays for measuring the absorbed dose are dicentric chromosomes and micronuclei counts, which require more than 2–3 days to obtain results. To overcome this limitation the NATO SPS Programme funded an Italian–Egyptian collaborative project aimed at validating a fast, accurate and feasible tool for assessing the absorbed dose early after radiation exposure. Biomarkers as complete blood cell counts, DNA breaks and radio-inducible proteins were investigated on blood samples collected before and 3 h after the first fraction of radiotherapy in patients treated in specific target areas with doses/fraction of about: 2, 3.5 or > 5 Gy and compared with the reference micronuclei count. Based on univariate and multivariate multiple linear regression correlation, our results identify five early biomarkers potentially useful for detecting the extent of the absorbed dose 3 h after the exposure.
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- 2021
- Full Text
- View/download PDF
4. Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth
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Riccardo Turchi, Flavia Tortolici, Monica Benvenuto, Carolina Punziano, Anastasia De Luca, Stefano Rufini, Raffaella Faraonio, Roberto Bei, Daniele Lettieri-Barbato, and Katia Aquilano
- Subjects
NRF2 ,p53 ,lipid peroxidation ,mitochondria ,ferrostatin-1 ,ferroptosis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy.
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- 2022
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5. Low Sulfur Amino Acid, High Polyunsaturated Fatty Acid Diet Inhibits Breast Cancer Growth
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Riccardo Turchi, Flavia Tortolici, Monica Benvenuto, Carolina Punziano, Anastasia De Luca, Stefano Rufini, Raffaella Faraonio, Roberto Bei, Daniele Lettieri-Barbato, Katia Aquilano, Turchi, Riccardo, Tortolici, Flavia, Benvenuto, Monica, Punziano, Carolina, De Luca, Anastasia, Rufini, Stefano, Faraonio, Raffaella, Bei, Roberto, Lettieri-Barbato, Daniele, and Aquilano, Katia
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p53 ,Settore BIO/12 ,Organic Chemistry ,lipid peroxidation ,General Medicine ,Settore MED/04 ,Settore BIO/09 ,Catalysis ,ferroptosis ,Computer Science Applications ,ferroptosi ,NRF2 ,Inorganic Chemistry ,mitochondria ,ferrostatin-1 ,Physical and Theoretical Chemistry ,Settore BIO/10 ,Molecular Biology ,Spectroscopy ,NRF2, p53 - Abstract
Cancer cells may acquire resistance to stress signals and reprogram metabolism to meet the energetic demands to support their high proliferation rate and avoid death. Hence, targeting nutrient dependencies of cancer cells has been suggested as a promising anti-cancer strategy. We explored the possibility of killing breast cancer (BC) cells by modifying nutrient availability. We used in vitro models of BC (MCF7 and MDA-MB-231) that were maintained with a low amount of sulfur amino acids (SAAs) and a high amount of oxidizable polyunsatured fatty acids (PUFAs). Treatment with anti-apoptotic, anti-ferroptotic and antioxidant drugs were used to determine the modality of cell death. We reproduced these conditions in vivo by feeding BC-bearing mice with a diet poor in proteins and SAAs and rich in PUFAs (LSAA/HPUFA). Western blot analysis, qPCR and histological analyses were used to assess the anti-cancer effects and the molecular pathways involved. We found that BC cells underwent oxidative damage to DNA and proteins and both apoptosis and ferroptosis were induced. Along with caspases-mediated PARP1 cleavage, we found a lowering of the GSH-GPX4 system and an increase of lipid peroxides. A LSAA/HPUFA diet reduced tumor mass and its vascularization and immune cell infiltration, and induced apoptosis and ferroptotic hallmarks. Furthermore, mitochondrial mass was found to be increased, and the buffering of mitochondrial reactive oxygen species limited GPX4 reduction and DNA damage. Our results suggest that administration of custom diets, targeting the dependency of cancer cells on certain nutrients, can represent a promising complementary option for anti-cancer therapy.
- Published
- 2023
6. The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia
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Piergiorgio La Rosa, Sara Petrillo, Riccardo Turchi, Francesco Berardinelli, Tommaso Schirinzi, Gessica Vasco, Daniele Lettieri-Barbato, Maria Teresa Fiorenza, Enrico S. Bertini, Katia Aquilano, and Fiorella Piemonte
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Friedreich ataxia ,Nrf2 ,Ferroptosis ,Redox imbalance ,Sulforaphane ,EPI-743 ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.
- Published
- 2021
- Full Text
- View/download PDF
7. Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenesis in subcutaneous adipose tissue
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Katia Aquilano, Francesca Sciarretta, Riccardo Turchi, Bo-Han Li, Marco Rosina, Veronica Ceci, Giulio Guidobaldi, Simona Arena, Chiara D'Ambrosio, Matteo Audano, Illari Salvatori, Barbara Colella, Raffaella Faraonio, Concita Panebianco, Valerio Pazienza, Donatella Caruso, Nico Mitro, Sabrina Di Bartolomeo, Andrea Scaloni, Jing-Ya Li, and Daniele Lettieri-Barbato
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Systems physiology ,Mitochondria ,Metabolism ,Serca ,Ucp1 ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Low-protein/high-carbohydrate (LPHC) diet has been suggested to promote metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1-and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.
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- 2020
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8. Nrf2 Induction Re-establishes a Proper Neuronal Differentiation Program in Friedreich’s Ataxia Neural Stem Cells
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Piergiorgio La Rosa, Marta Russo, Jessica D’Amico, Sara Petrillo, Katia Aquilano, Daniele Lettieri-Barbato, Riccardo Turchi, Enrico S. Bertini, and Fiorella Piemonte
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Nrf2 ,Friedreich’s Ataxia ,neural stem cells ,frataxin ,neurogenesis ,antioxidant ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Frataxin deficiency is the pathogenic cause of Friedreich’s Ataxia, an autosomal recessive disease characterized by the increase of oxidative stress and production of free radicals in the cell. Although the onset of the pathology occurs in the second decade of life, cognitive differences and defects in brain structure and functional activation are observed in patients, suggesting developmental defects to take place during fetal neurogenesis. Here, we describe impairments in proliferation, stemness potential and differentiation in neural stem cells (NSCs) isolated from the embryonic cortex of the Frataxin Knockin/Knockout mouse, a disease animal model whose slow-evolving phenotype makes it suitable to study pre-symptomatic defects that may manifest before the clinical onset. We demonstrate that enhancing the expression and activity of the antioxidant response master regulator Nrf2 ameliorates the phenotypic defects observed in NSCs, re-establishing a proper differentiation program.
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- 2019
- Full Text
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9. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a mouse model of Friedreich’s ataxia
- Author
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Riccardo Turchi, Francesca Sciarretta, Marta Tiberi, Matteo Audano, Silvia Pedretti, Concetta Panebianco, Valentina Nesci, Valerio Pazienza, Alberto Ferri, Simone Carotti, Valerio Chiurchiù, Nico Mitro, Daniele Lettieri-Barbato, and Katia Aquilano
- Abstract
Friedreich’s ataxia (FA) is a genetic neurodegenerative disease caused by mutation inFXNgene encoding for the mitochondrial protein frataxin (FXN). Patients with FA display an increased risk of developing diabetes that may aggravate disease prognosis. Recent studies have indicated that in addition to increased visceral adiposity, FA patients undergo a low-grade inflammatory state. The expansion of white adipose tissue (WAT) plays a fundamental role in the development of type 2 diabetes as it becomes insulin-resistant and a source of inflammatory molecules (adipokines). In this work, we have characterized visceral WAT (vWAT) at metabolic and immunological level in a murine FA model (KIKO) to test whether dysfunction of vWAT could be involved in FA metabolic complications. Through RNAseq analyses we found an alteration of inflammatory, angiogenesis and fibrosis genes in vWAT of KIKO mice. We also found other diabetes-related hallmarks such as increased lipid droplet size, immune cell infiltration and increased expression of pro-inflammatory cytokines. In addition, by targeted metabolomics we disclosed a raise in lactate production, an event usually associated with obesity and diabetes and that triggers activation of vWAT resident macrophages. To reproduce anin vitromodel of FA, we downregulated FXN protein in cultured white adipocytes and recapitulated the diabetes-like features observed in vWAT. Real time monitoring of adipocyte metabolism evidenced metabolic rewiring towards glycolysis according to increased lactate production. Analysis of fecal samples revealed a reduction of some butyrate-producing bacteria in KIKO mice. As this microbiota derived short-chain fatty was demonstrated to exert anti-diabetic function, we fed KIKO mice with a butyrate-enriched diet for 16 weeks. This dietary approach limited vWAT alterations and mitigated other diabetes-like signatures both inin vitroandin vivomodels.In conclusion, this study identified vWAT as an important player in the onset of metabolic complications typical of FA and suggests butyrate as safe and promising adjuvant tool to treat metabolic complications in FA.
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- 2023
10. An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia
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Riccardo Turchi, Raffaella Faraonio, Daniele Lettieri-Barbato, and Katia Aquilano
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Iron metabolism ,FRDA ,ROS ,neurodegeneration ,lipid metabolism ,GPX4 ,Microbiology ,QR1-502 - Abstract
Background: Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Scope of review: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.
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- 2020
- Full Text
- View/download PDF
11. Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue
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Marco Rosina, Veronica Ceci, Riccardo Turchi, Chuan Li, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L. Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A.F. de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R. Brestoff, Katia Aquilano, Daniele Lettieri-Barbato, European Foundation for the Study of Diabetes, Boehringer Ingelheim Fonds, Fondation Leducq, Ministerio de Ciencia e Innovación (España), and Fundación La Caixa
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brown adipocytes ,thermogenesis ,Physiology ,mitochondrial quality control ,Macrophages ,immunometabolism ,Thermogenesis ,Cell Biology ,Settore BIO/09 ,Mitochondria ,adipose tissue ,macrophages ,mitochondria ,Adipocytes, Brown ,Adipose Tissue, Brown ,homeostasis ,Settore BIO/10 ,extracellular vesicles ,Molecular Biology ,Uncoupling Protein 1 - Abstract
Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT. This work was partially supported by the European Foundation for the Study of Diabetes (EFSD/Lilly, 2017 and EFSD/Boehringer Ingelheim European Research Programme on ‘‘Multi-System Challenges in Diabetes’’) and the Italian Ministry of Health (GR-2018-12367588) to D.L.-B.; Associazione Italiana per la Ricerca sul Cancro (AIRC) under IG 2019 - ID. 23562 project to K.A.; MIUR ‘‘Progetto Eccellenza’’ to Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita` degli Studi di Milano, and NUTRAGE (CNR FOE 2019, DSB.AD004.271) to A.S; Italian Foundation of Multiple Sclerosis (grant 2017/R/8), the Italian Ministry of Health (grant GR-2016-02362380) and the MAI Award grant to V. Chiurchiu; National Institutes of Health (NIH) common fund (DP5 OD028125) and the Burroughs Wellcome Fund (1019648) to J.R.B.; NIH K01DK125608 to F.S.; R01DK102898 and R01DK122808 to Y.- H.T.; and NIH RO1 DK121805 and AHA 19TPA34910079 to B.Z. A.H. was supported by RTI2018-095497-B-I00 from MICINN, HR17_00527 from La Caixa Foundation, and TNE-18CVD04 from the Leducq Foundation. M.S-D was supported by a fellowship PRE2019-08746 from the Ministerio de Ciencia e Innovacio´ n. M.R. was partially supported by a fellowship from AIRC (IG 2019 - ID. 23562) and by the Italian Ministry of Health (SG-2019-12368589). V.C. is part of the PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata. Sí
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- 2022
12. Hyperbaric exposure and oxidative stress in occupational activities (HEOxS): the study protocol
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Katia, Aquilano, Tiziana Paola Baccolo, Bersani, Alberto Maria, Matteo, Bordi, FLAVIA BUONAURIO, Rita Businaro, Cerocchi, Chiara, Corrado, Costanzo, Nazzareno De Angelis, Ornella De Pità, Maria Concetta D’Ovidio, Luigi Fattorini, Giuseppe, Filomeni, Cristian, Ieno, Lettieri Barbato, Daniele, Maggi, Elisa, Enrico, Marchetti, Maria Rosaria Marchetti, Paola, Melis, Alfredo Miccheli, OTTAVIA GIAMPAOLI, Enrico, Paci, Daniela, Pigini, Alessandro Pinto, Floriana, Sacco, Fabio, Sciubba, Mariangela, Spagnoli, Aurora, Summa, Alberta, Tomassini, Elisa Tosti, M., Giovanna, Tranfo, Riccardo, Turchi, and Giuliana Valente, .
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hyperbaric exposure ,Hyperbaric exposure ,Oxidative Stress ,Diet Habits ,Fitness ,Cytokines ,Metabolomics ,oxidative stress ,cytokines ,metabolomics ,diet habits ,fitness - Abstract
Background: Hyperbaric exposure (HE) is proven to be a stressor to several mechanisms in living cells. Even if after homeostasis restoration, harmful effects are expected, in particular a presence of free radicals. These latter are the stimulus to negative phenomenon as inflammation or cancer. In Italy, with 7500 km of sea shores, a large quantity of workers is exposed to HE during occupational activities. A deep knowledge of HE and bodily effects is not well defined; hence a multidisciplinary assessment of risk is needed. To detect one or more indicators of HE a research group is organised, under the INAIL sponsorship. The research project focused on the oxidative stress (OxS) and this paper details on the possible protocol to estimate, with a large amount of techniques on several human liquids, the relationship between OxS and HE. Specific attention will be paid to identify confounding factors and their influence. Methods: Blood and urine will be sampled. Several lab techniques will be performed on samples, both targeted, to measure the level of well-known biomarkers, and untargeted. Regard the formers: products of oxidation of DNA and RNA in urine; inflammation and temperature cytokines and protein carbonyles in blood. Untargeted evaluation will be performed for a metabolomics analysis in urine. Confounding factors: temperature, body fat, fitness, allergies and dietary habits. These factors will be assessed, directly or indirectly, prior and after HE. The final scope of the project is to determine one or more indicators that relates to HE in hits twofold nature: depth and duration. Conclusion: The relationship between OxS and HE is not deeply investigated and literature proposes diverging results. The project aims to define the time dependence of biomarkers related to OxS, to rise knowledge in risk assessment in workers exposed to HE.
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- 2021
13. The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia
- Author
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Piergiorgio La Rosa, Fiorella Piemonte, Riccardo Turchi, Daniele Lettieri-Barbato, Maria Teresa Fiorenza, Francesco Berardinelli, Katia Aquilano, Enrico Bertini, Sara Petrillo, Tommaso Schirinzi, and Gessica Vasco
- Subjects
0301 basic medicine ,Programmed cell death ,Ataxia ,Redox imbalance ,EPI-743 ,NF-E2-Related Factor 2 ,Clinical Biochemistry ,Mitochondrion ,Biochemistry ,Friedreich ataxia ,Nrf2 ,ferroptosis ,redox imbalance ,sulforaphane ,lipid peroxides ,mitochondria ,Settore BIO/09 ,Lipid peroxidation ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Lipid peroxides ,medicine ,Ferroptosis ,Animals ,Humans ,Settore BIO/10 ,lcsh:QH301-705.5 ,Mice, Knockout ,lcsh:R5-920 ,biology ,Organic Chemistry ,Neurodegeneration ,Lipid metabolism ,Neurodegenerative Diseases ,Glutathione ,medicine.disease ,Cell biology ,Mitochondria ,030104 developmental biology ,chemistry ,lcsh:Biology (General) ,Frataxin ,biology.protein ,medicine.symptom ,lcsh:Medicine (General) ,Sulforaphane ,030217 neurology & neurosurgery ,Research Paper - Abstract
Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.
- Published
- 2020
14. An Overview of the Ferroptosis Hallmarks in Friedreich’s Ataxia
- Author
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Katia Aquilano, Daniele Lettieri-Barbato, Raffaella Faraonio, Riccardo Turchi, Turchi, R., Faraonio, R., Lettieri-Barbato, D., and Aquilano, K.
- Subjects
0301 basic medicine ,Programmed cell death ,Ataxia ,Iron ,lcsh:QR1-502 ,Disease ,Review ,GPX4 ,Biochemistry ,lcsh:Microbiology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Iron-Binding Proteins ,lipid metabolism ,medicine ,Ferroptosis ,Humans ,Settore BIO/10 ,Molecular Biology ,chemistry.chemical_classification ,Reactive oxygen species ,FRDA ,frataxin ,biology ,business.industry ,Neurodegeneration ,neurodegeneration ,ROS ,Neurodegenerative Diseases ,Cardiomyopathy, Hypertrophic ,medicine.disease ,Iron metabolism ,Mitochondria ,Oxidative Stress ,030104 developmental biology ,chemistry ,Friedreich Ataxia ,Frataxin ,biology.protein ,Cancer research ,Lipid Peroxidation ,medicine.symptom ,business ,Reactive Oxygen Species ,030217 neurology & neurosurgery - Abstract
Background: Friedreich’s ataxia (FRDA) is a neurodegenerative disease characterized by early mortality due to hypertrophic cardiomyopathy. FRDA is caused by reduced levels of frataxin (FXN), a mitochondrial protein involved in the synthesis of iron-sulphur clusters, leading to iron accumulation at the mitochondrial level, uncontrolled production of reactive oxygen species and lipid peroxidation. These features are also common to ferroptosis, an iron-mediated type of cell death triggered by accumulation of lipoperoxides with distinct morphological and molecular characteristics with respect to other known cell deaths. Scope of review: Even though ferroptosis has been associated with various neurodegenerative diseases including FRDA, the mechanisms leading to disease onset/progression have not been demonstrated yet. We describe the molecular alterations occurring in FRDA that overlap with those characterizing ferroptosis. Major conclusions: The study of ferroptotic pathways is necessary for the understanding of FRDA pathogenesis, and anti-ferroptotic drugs could be envisaged as therapeutic strategies to cure FRDA.
- Published
- 2020
15. Author Reply to Peer Reviews of Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue
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Daniele Lettieri-Barbato, Jing-Ya Li, Andrea Scaloni, Sabrina Di Bartolomeo, Nico Mitro, Donatella Caruso, Valerio Pazienza, Concita Panebianco, Raffaella Faraonio, Barbara Colella, Illari Salvatori, Matteo Audano, Chiara D’Ambrosio, Simona Arena, Giulio Guidobaldi, Veronica Ceci, Marco Rosina, Bo-Han Li, Riccardo Turchi, Francesca Sciarretta, and Katia Aquilano
- Published
- 2020
16. Validation of a biomarker tool capable of measuring the absorbed dose soon after exposure to ionizing radiation
- Author
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Yasmine Amr Issa, Cecilia Bartoleschi, Gianluca Bossi, Laura Ioannilli, Claudio Pioli, Horeya M. Ismail, Mohamed Barakat, Amr A. Elsaid, Riccardo Turchi, Paola Pinnarò, Marco Canfora, Giuseppe Sanguineti, Mohamed Mostafa Tahoun, Anna Giovanetti, Raffaella Marconi, Maria Chiara Pardini, Noha Awad, Neveen F. Agamy, Lidia Strigari, Hala Abuzied, Flavia Novelli, Giovanetti, A., Marconi, R., Awad, N., Abuzied, H., Agamy, N., Barakat, M., Bartoleschi, C., Bossi, G., Canfora, M., Elsaid, A. A., Ioannilli, L., Ismail, H. M., Issa, Y. A., Novelli, F., Pardini, M. C., Pioli, C., Pinnaro, P., Sanguineti, G., Tahoun, M. M., Turchi, R., and Strigari, L.
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Adult ,Male ,medicine.medical_specialty ,Science ,medicine.medical_treatment ,Article ,030218 nuclear medicine & medical imaging ,Ionizing radiation ,03 medical and health sciences ,Prognostic markers ,0302 clinical medicine ,Radiation, Ionizing ,Dosimetry ,Medicine ,Humans ,DNA Breaks, Double-Stranded ,Radiometry ,Aged ,Aged, 80 and over ,Multidisciplinary ,Radiotherapy ,business.industry ,Dose-Response Relationship, Radiation ,Middle Aged ,Radiation Exposure ,Triage ,Blood Cell Count ,Radiation therapy ,ROC Curve ,030220 oncology & carcinogenesis ,Absorbed dose ,Radiological weapon ,Area Under Curve ,Micronucleus test ,Biomarker (medicine) ,Female ,Radiology ,business ,Biomarkers - Abstract
A radiological or nuclear attack could involve such a large number of subjects as to overwhelm the emergency facilities in charge. Resources should therefore be focused on those subjects needing immediate medical attention and care. In such a scenario, for the triage management by first responders, it is necessary to count on efficient biological dosimetry tools capable of early detection of the absorbed dose. At present the validated assays for measuring the absorbed dose are dicentric chromosomes and micronuclei counts, which require more than 2–3 days to obtain results. To overcome this limitation the NATO SPS Programme funded an Italian–Egyptian collaborative project aimed at validating a fast, accurate and feasible tool for assessing the absorbed dose early after radiation exposure. Biomarkers as complete blood cell counts, DNA breaks and radio-inducible proteins were investigated on blood samples collected before and 3 h after the first fraction of radiotherapy in patients treated in specific target areas with doses/fraction of about: 2, 3.5 or > 5 Gy and compared with the reference micronuclei count. Based on univariate and multivariate multiple linear regression correlation, our results identify five early biomarkers potentially useful for detecting the extent of the absorbed dose 3 h after the exposure.
- Published
- 2020
17. Correction: Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
- Author
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Flavia Tortolici, Raffaella Faraonio, Viviana Casagrande, Daniele Lettieri-Barbato, Lorenzo De Angelis, Fiorella Piemonte, Maria Francesconi, Simone Carotti, Stefano Rufini, Federico Iacovelli, Maria Zingariello, Riccardo Turchi, Mattia Falconi, Piergiorgio La Rosa, Katia Aquilano, Massimo Federici, Maurizio Mattei, Giulio Guidobaldi, Roberta Bernardini, and Sergio Morini
- Subjects
Leptin ,Male ,Cancer Research ,medicine.medical_specialty ,Lipid accumulation ,Lipolysis ,Immunology ,Hyperlipidemias ,Biochemistry ,Mice ,Cellular and Molecular Neuroscience ,Adipose Tissue, Brown ,Microscopy, Electron, Transmission ,Iron-Binding Proteins ,Internal medicine ,Brown adipose tissue ,Adipocytes ,medicine ,Animals ,Ferroptosis ,RNA-Seq ,Citation data ,Mice, Knockout ,biology ,Correction ,Thermogenesis ,Cell Biology ,Lipid Metabolism ,Phospholipid Hydroperoxide Glutathione Peroxidase ,Cyclic AMP-Dependent Protein Kinases ,Mitochondria ,Cold Temperature ,Mice, Inbred C57BL ,Biological sciences ,Oxidative Stress ,medicine.anatomical_structure ,Endocrinology ,Diabetes Mellitus, Type 2 ,Friedreich Ataxia ,Frataxin ,biology.protein ,Insulin Resistance - Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
- Published
- 2020
18. Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue
- Author
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Matteo Audano, Chiara D'Ambrosio, Daniele Lettieri-Barbato, Marco Rosina, Katia Aquilano, Bo-Han Li, Jing-Ya Li, Simona Arena, Nico Mitro, Illari Salvatori, Riccardo Turchi, C. Panebianco, Barbara Colella, Donatella Caruso, Raffaella Faraonio, Giulio Guidobaldi, Francesca Sciarretta, Sabrina Di Bartolomeo, Valerio Pazienza, Andrea Scaloni, and Veronica Ceci
- Subjects
2. Zero hunger ,chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,SERCA ,biology ,Catabolism ,ATPase ,AMPK ,White adipose tissue ,Oxidative phosphorylation ,Cell biology ,Amino acid ,03 medical and health sciences ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,030304 developmental biology - Abstract
Low-protein/high-carbohydrate (LPHC) diet promotes metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1- and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.
- Published
- 2020
19. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
- Author
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Massimo Federici, Roberta Bernardini, Federico Iacovelli, Stefano Rufini, Riccardo Turchi, Maria Zingariello, Raffaella Faraonio, Mattia Falconi, Lorenzo De Angelis, Katia Aquilano, Fiorella Piemonte, Giulio Guidobaldi, Piergiorgio La Rosa, Daniele Lettieri-Barbato, Simone Carotti, Maria Francesconi, Maurizio Mattei, Sergio Morini, Flavia Tortolici, Viviana Casagrande, Turchi, R, Tortolici, F, Guidobaldi, G, Iacovelli, F, Falconi, M, Rufini, S, Faraonio, R, Casagrande, V, Federici, M, De Angelis, L, Carotti, S, Francesconi, M, Zingariello, M, Morini, S, Bernardini, R, Mattei, M, La Rosa, P, Piemonte, F, Lettieri-Barbato, D, and Aquilano, K.
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,diabetes mellitus, type 2 ,Friedreich ataxia ,insulin resistance ,Immunology ,Adipose tissue ,GPX4 ,Biochemistry ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Adipocyte ,Brown adipose tissue ,medicine ,lcsh:QH573-671 ,Settore BIO/10 ,biology ,lcsh:Cytology ,Lipid metabolism ,Cell Biology ,Biological sciences ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,type 2 ,Adipogenesis ,diabetes mellitus ,Frataxin ,biology.protein ,Thermogenesis ,030217 neurology & neurosurgery - Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich’s ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
- Published
- 2020
20. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
- Author
-
Flavia Tortolici, Raffaella Faraonio, Stefano Rufini, Sergio Morini, Daniele Lettieri-Barbato, Giulio Guidobaldi, Federico Iacovelli, Maria Francesconi, Riccardo Turchi, Viviana Casagrande, Roberta Bernardini, Maria Zingariello, Maurizio Mattei, Mattia Falconi, Lorenzo De Angelis, Simone Carotti, Katia Aquilano, and Massimo Federici
- Subjects
medicine.medical_specialty ,biology ,Leptin ,Transcriptome ,Endocrinology ,medicine.anatomical_structure ,Downregulation and upregulation ,Adipogenesis ,Internal medicine ,Brown adipose tissue ,Frataxin ,biology.protein ,medicine ,Lipolysis ,Thermogenesis - Abstract
Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreich’s ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice.Collectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.
- Published
- 2019
- Full Text
- View/download PDF
21. Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenesis in subcutaneous adipose tissue
- Author
-
Raffaella Faraonio, Valerio Pazienza, Concetta Panebianco, Marco Rosina, Illari Salvatori, Daniele Lettieri-Barbato, Andrea Scaloni, Riccardo Turchi, Jing Ya Li, Simona Arena, Francesca Sciarretta, Giulio Guidobaldi, Veronica Ceci, Chiara D'Ambrosio, Katia Aquilano, Matteo Audano, Bo Han Li, Barbara Colella, Sabrina Di Bartolomeo, Donatella Caruso, Nico Mitro, Aquilano, K, Sciarretta, F, Turchi, R, Li, Bh, Rosina, M, Ceci, V, Guidobaldi, G, Arena, S, D'Ambrosio, C, Audano, M, Salvatori, I, Colella, B, Faraonio, R, Panebianco, C, Pazienza, V, Caruso, D, Mitro, N, Di Bartolomeo, S, Scaloni, A, Li, Jy, and Lettieri-Barbato, D.
- Subjects
0301 basic medicine ,SERCA ,subcutaneous fat ,Adipose Tissue, White ,amp-activated protein kinases ,Clinical Biochemistry ,carbohydrates ,White adipose tissue ,Oxidative phosphorylation ,Mitochondrion ,Settore BIO/09 ,Biochemistry ,ucp1 ,03 medical and health sciences ,0302 clinical medicine ,Metabolism ,Mitochondria ,Serca ,Systems physiology ,Ucp1 ,energy metabolism ,humans ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Catabolism ,Chemistry ,Organic Chemistry ,metabolism ,mitochondria ,serca ,systems physiology ,adipose tissue ,white ,animals ,diet ,thermogenesis ,AMPK ,Cell biology ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:Medicine (General) ,Thermogenesis ,030217 neurology & neurosurgery ,Research Paper - Abstract
Low-protein/high-carbohydrate (LPHC) diet has been suggested to promote metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1-and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes., Highlights • LPHC diet promotes brown- and muscular-like features in sWAT. • In vitro amino acid shortage mimics the effects of LPHC diet. • AMPK controls canonical and non-canonical thermogenesis in sWAT. • L-Cys replenishment limits the AMPK-mediated adaptive responses in sWAT.
- Published
- 2020
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