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Gómez-Fernández D, Romero-González A, Suárez-Rivero JM, Cilleros-Holgado P, Álvarez-Córdoba M, Piñero-Pérez R, Romero-Domínguez JM, Reche-López D, López-Cabrera A, Ibáñez-Mico S, Castro de Oliveira M, Rodríguez-Sacristán A, González-Granero S, García-Verdugo JM, Sánchez-Alcázar JA. A Multi-Target Pharmacological Correction of a Lipoyltransferase LIPT1 Gene Mutation in Patient-Derived Cellular Models. Antioxidants (Basel) 2024; 13:1023. [PMID: 39199267 PMCID: PMC11351668 DOI: 10.3390/antiox13081023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/12/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic acidosis, and increased urine lactate, ketoglutarate, and 2-oxoacid levels. In this article, we characterized the disease pathophysiology using fibroblasts and induced neurons derived from a patient bearing a compound heterozygous mutation in LIPT1. A Western blot analysis revealed a reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits. Accordingly, activities of PDH and α-KGDH were markedly reduced, associated with cell bioenergetics failure, iron accumulation, and lipid peroxidation. In addition, using a pharmacological screening, we identified a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and α-lipoic acid, which is capable of rescuing LIPT1 pathophysiology, increasing the LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation. Furthermore, our data suggest that the beneficial effect of the treatment is mainly mediated by SIRT3 activation. In conclusion, we have identified a promising therapeutic approach for correcting LIPT1 mutations.
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Affiliation(s)
- David Gómez-Fernández
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Ana Romero-González
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Juan M. Suárez-Rivero
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Paula Cilleros-Holgado
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Mónica Álvarez-Córdoba
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Rocío Piñero-Pérez
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - José Manuel Romero-Domínguez
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Diana Reche-López
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Alejandra López-Cabrera
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
| | - Salvador Ibáñez-Mico
- Hospital Clínico Universitario Virgen de la Arrixaca, Servicio de Neuropediatría, 30120 Murcia, Spain;
| | - Marta Castro de Oliveira
- Neuropediatria, Neurolinkia, C. Jardín de la Isla, 8, Local 4 y 5, 41014 Sevilla, Spain;
- FEA Pediatría, Centro Universitario Hospitalar de Faro, R. Leão Penedo, 8000-386 Faro, Portugal
- Neuropediatria, Servicio de Pediatría, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain;
| | - Andrés Rodríguez-Sacristán
- Neuropediatria, Servicio de Pediatría, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain;
- Departamento de Farmacología, Radiología y Pediatría de la Facultad de Medicina de la Universidad de Sevilla, 41009 Sevilla, Spain
| | - Susana González-Granero
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain; (S.G.-G.); (J.M.G.-V.)
| | - José Manuel García-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, 46980 Valencia, Spain; (S.G.-G.); (J.M.G.-V.)
| | - José A. Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD-CSIC-Universidad Pablo de Olavide), 41013 Sevilla, Spain; (D.G.-F.); (A.R.-G.); (J.M.S.-R.); (P.C.-H.); (M.Á.-C.); (R.P.-P.); (J.M.R.-D.); (D.R.-L.); (A.L.-C.)
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2
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Xie YP, Lin S, Xie BY, Zhao HF. Recent progress in metabolic reprogramming in gestational diabetes mellitus: a review. Front Endocrinol (Lausanne) 2024; 14:1284160. [PMID: 38234430 PMCID: PMC10791831 DOI: 10.3389/fendo.2023.1284160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 12/11/2023] [Indexed: 01/19/2024] Open
Abstract
Gestational diabetes mellitus is a prevalent metabolic disease that can impact the normal course of pregnancy and delivery, leading to adverse outcomes for both mother and child. Its pathogenesis is complex and involves various factors, such as insulin resistance and β-cell dysfunction. Metabolic reprogramming, which involves mitochondrial oxidative phosphorylation and glycolysis, is crucial for maintaining human metabolic balance and is involved in the pathogenesis and progression of gestational diabetes mellitus. However, research on the link and metabolic pathways between metabolic reprogramming and gestational diabetes mellitus is limited. Therefore, we reviewed the relationship between metabolic reprogramming and gestational diabetes mellitus to provide new therapeutic strategies for maternal health during pregnancy and reduce the risk of developing gestational diabetes mellitus.
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Affiliation(s)
- Ya-ping Xie
- Nursing Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Bao-yuan Xie
- Nursing Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Hui-fen Zhao
- Nursing Department, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
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Nie X, Dong X, Hu Y, Xu F, Hu C, Shu C. Coenzyme Q10 Stimulate Reproductive Vatality. Drug Des Devel Ther 2023; 17:2623-2637. [PMID: 37667786 PMCID: PMC10475284 DOI: 10.2147/dddt.s386974] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/15/2023] [Indexed: 09/06/2023] Open
Abstract
Female infertility and pregnancy maintenance are associate with various factors, including quantity and quality of oocytes, genital inflammation, endometriosis, and other diseases. Women are even diagnosed as unexplained infertility or unexplained recurrent spontaneous abortion when failed to achieve pregnancy with current treatment, which are urgent clinical issues need to be addressed. Coenzyme Q10 (CoQ10) is a lipid-soluble electron carrier in the mitochondrial electron transport chain. It is not only essential for the mitochondria to produce energy, but also function as an antioxidant to maintain redox homeostasis in the body. Recently, the capacity of CoQ10 to reduce oxidative stress (OS), enhance mitochondrial activity, regulate gene expression and inhibit inflammatory responses, has been discovered as a novel adjuvant in male reproductive performance enhancing in both animal and human studies. Furthermore, CoQ10 is also proved to regulate immune balance, antioxidant, promote glucose and lipid metabolism. These properties will bring highlight for ovarian dysfunction reversing, ovulation ameliorating, oocyte maturation/fertilization promoting, and embryonic development optimizing. In this review, we systematically discuss the pleiotropic effects of CoQ10 in female reproductive disorders to investigate the mechanism and therapeutic potential to provide a reference in subsequent studies.
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Affiliation(s)
- Xinyu Nie
- Obstetrics and Gynecology Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- Reproductive Medicine Center, Prenatal Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Xinru Dong
- Obstetrics and Gynecology Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- Reproductive Medicine Center, Prenatal Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Yuge Hu
- Obstetrics and Gynecology Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- Reproductive Medicine Center, Prenatal Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Fangjun Xu
- Obstetrics and Gynecology Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Cong Hu
- Reproductive Medicine Center, Prenatal Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Chang Shu
- Obstetrics and Gynecology Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
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Singh V. F 1F o adenosine triphosphate (ATP) synthase is a potential drug target in non-communicable diseases. Mol Biol Rep 2023; 50:3849-3862. [PMID: 36715790 DOI: 10.1007/s11033-023-08299-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Accepted: 01/19/2023] [Indexed: 01/31/2023]
Abstract
F1Fo adenosine triphosphate (ATP) synthase, also known as the complex V, is the central ATP-producing unit in the cells arranged in the mitochondrial and plasma membranes. F1Fo ATP synthase also regulates the central metabolic processes in the human body driven by proton motive force (Δp). Numerous studies have immensely contributed toward highlighting its regulation in improving energy homeostasis and maintaining mitochondrial integrity, which otherwise gets compromised in illnesses. Yet, its role in the implication of non-communicable diseases remains unknown. F1Fo ATP synthase dysregulation at gene level leads to reduced activity and delocalization in the cristae and plasma membranes, which is directly associated with non-communicable diseases: cardiovascular diseases, diabetes, neurodegenerative disorders, cancer, and renal diseases. Individual subunits of the F1Fo ATP synthase target ligand-based competitive or non-competitive inhibition. After performing a systematic literature review to understand its specific functions and its novel drug targets, the present article focuses on the central role of F1Fo ATP synthase in primary non-communicable diseases. Next, it discusses its involvement through various pathways and the effects of multiple inhibitors, activators, and modulators specific to non-communicable diseases with a futuristic outlook.
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Affiliation(s)
- Varsha Singh
- Centre for Life Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, 140401, India.
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Pang S, Zhang Z, Zhou Y, Zhang J, Yan B. Genetic Variants of SIRT1 Gene Promoter in Type 2 Diabetes. Int J Endocrinol 2023; 2023:6919275. [PMID: 36747995 PMCID: PMC9899147 DOI: 10.1155/2023/6919275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/05/2023] [Accepted: 01/19/2023] [Indexed: 01/29/2023] Open
Abstract
Type 2 diabetes (T2D) is a highly heterogeneous and polygenic disease. To date, genetic causes and underlying mechanisms for T2D remain unclear. SIRT1, one member of highly conserved NAD-dependent class III deacetylases, has been implicated in many human diseases. Accumulating evidence indicates that SIRT1 is involved in insulin resistance and impaired pancreatic β-cell function, the two hallmarks of T2D. Thus, we speculated that altered SIRT1 levels, resulting from the genetic variants within its regulatory region of SIRT1 gene, may contribute to the T2D development. In this study, the SIRT1 gene promoter was genetically analyzed in T2D patients (n = 218) and healthy controls (n = 358). A total of 20 genetic variants, including 7 single-nucleotide polymorphisms (SNPs), were identified. Five heterozygous genetic variants (g.4114-15InsA, g.4801G > A, g.4816G > C, g.4934G > T, and g.4963_64Ins17bp) and one SNP (g.4198A > C (rs35706870)) were identified in T2D patients, but in none of the controls. The frequencies of two SNPs (g.4540A > G (rs3740051) (OR: 1.75, 95% CI: 1.24-2.47, P < 0.001 in dominant genetic model) and g.4821G > T (rs35995735)) (OR: 3.58, 95% CI: 1.94-6.60, P < 0.001 in dominant genetic model) were significantly higher in T2D patients. Further association and haplotype analyses confirmed that these two SNPs were strongly linked, contributing to the T2D (OR: 1.442, 95% CI: 1.080-1.927, P < 0.05). Moreover, most of the genetic variants identified in T2D were disease-specific. Taken together, the genetic variants within SIRT1 gene promoter might contribute to the T2D development by altering SIRT1 levels. Underlying molecular mechanism needs to be further explored.
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Affiliation(s)
- Shuchao Pang
- Shandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China
| | - Zhengjun Zhang
- Division of Endocrinology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China
| | - Yu Zhou
- Shandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China
| | - Jie Zhang
- Cardiovascular Center, Beijing Tongren Hospital, Capital Medical University, Dongcheng, Beijing 100730, China
| | - Bo Yan
- Shandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China
- Institute of Precision Medicine, Jining Medical University, Jining, Shandong 272067, China
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6
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Douvris A, Viñas J, Burns KD. miRNA-486-5p: signaling targets and role in non-malignant disease. Cell Mol Life Sci 2022; 79:376. [PMID: 35731367 PMCID: PMC9217846 DOI: 10.1007/s00018-022-04406-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/27/2022] [Accepted: 05/29/2022] [Indexed: 11/30/2022]
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs, highly conserved between species, that are powerful regulators of gene expression. Aberrant expression of miRNAs alters biological processes and pathways linked to human disease. miR-486-5p is a muscle-enriched miRNA localized to the cytoplasm and nucleus, and is highly abundant in human plasma and enriched in small extracellular vesicles. Studies of malignant and non-malignant diseases, including kidney diseases, have found correlations with circulating miR-486-5p levels, supporting its role as a potential biomarker. Pre-clinical studies of non-malignant diseases have identified miR-486-5p targets that regulate major signaling pathways involved in cellular proliferation, migration, angiogenesis, and apoptosis. Validated miR-486-5p targets include phosphatase and tensin homolog (PTEN) and FoXO1, whose suppression activates phosphatidyl inositol-3-kinase (PI3K)/Akt signaling. Targeting of Smad1/2/4 and IGF-1 by miR-486-5p inhibits transforming growth factor (TGF)-β and insulin-like growth factor-1 (IGF-1) signaling, respectively. Other miR-486-5p targets include matrix metalloproteinase-19 (MMP-19), Sp5, histone acetyltransferase 1 (HAT1), and nuclear factor of activated T cells-5 (NFAT5). In this review, we examine the biogenesis, regulation, validated gene targets and biological effects of miR-486-5p in non-malignant diseases.
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Affiliation(s)
- Adrianna Douvris
- Division of Nephrology, Department of Medicine and Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, 1967 Riverside Dr., Rm. 535, Ottawa, ON, K1H 7W9, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jose Viñas
- Division of Nephrology, Department of Medicine and Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, 1967 Riverside Dr., Rm. 535, Ottawa, ON, K1H 7W9, Canada
| | - Kevin D Burns
- Division of Nephrology, Department of Medicine and Kidney Research Centre, The Ottawa Hospital Research Institute, University of Ottawa, 1967 Riverside Dr., Rm. 535, Ottawa, ON, K1H 7W9, Canada. .,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
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Abdelnabi ALSM, Esmayel IM, Hussein S, Ali RM, AbdelAal AA. Sirtuin-1 in Egyptian patients with coronary artery disease. BENI-SUEF UNIVERSITY JOURNAL OF BASIC AND APPLIED SCIENCES 2021. [DOI: 10.1186/s43088-021-00164-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Coronary artery disease (CAD) represents the leading cause of death worldwide. Animal and human studies have demonstrated that silent information regulator 1 (SIRT1) is involved in a wide range of physiological and pathological processes. This study aimed to measure the plasma level of SIRT1 in patients with CAD and explore its correlation with cardiovascular risk factors.
Results
Plasma SIRT1 was significantly lower in patients with chronic coronary syndrome (CCS) than in those in the control group and was significantly lower in patients with both acute myocardial infarction and unstable angina than in those in the control group and with CCS. Moreover, plasma SIRT1 was positively correlated with platelet count and negatively correlated with cholesterol and triglyceride levels.
Conclusions
The plasma level of SIRT1 is lower in patients with CAD compared to control and it could be a possible marker for this disease. Multi-center studies with follow-up measurements are recommended for further investigation.
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Masi S, Ambrosini S, Mohammed SA, Sciarretta S, Lüscher TF, Paneni F, Costantino S. Epigenetic Remodeling in Obesity-Related Vascular Disease. Antioxid Redox Signal 2021; 34:1165-1199. [PMID: 32808539 DOI: 10.1089/ars.2020.8040] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: The prevalence of obesity and cardiometabolic phenotypes is alarmingly increasing across the globe and is associated with atherosclerotic vascular complications and high mortality. In spite of multifactorial interventions, vascular residual risk remains high in this patient population, suggesting the need for breakthrough therapies. The mechanisms underpinning obesity-related vascular disease remain elusive and represent an intense area of investigation. Recent Advances: Epigenetic modifications-defined as environmentally induced chemical changes of DNA and histones that do not affect DNA sequence-are emerging as a potent modulator of gene transcription in the vasculature and might significantly contribute to the development of obesity-induced endothelial dysfunction. DNA methylation and histone post-translational modifications cooperate to build complex epigenetic signals, altering transcriptional networks that are implicated in redox homeostasis, mitochondrial function, vascular inflammation, and perivascular fat homeostasis in patients with cardiometabolic disturbances. Critical Issues: Deciphering the epigenetic landscape in the vasculature is extremely challenging due to the complexity of epigenetic signals and their function in regulating transcription. An overview of the most important epigenetic pathways is required to identify potential molecular targets to treat or prevent obesity-related endothelial dysfunction and atherosclerotic disease. This would enable the employment of precision medicine approaches in this setting. Future Directions: Current and future research efforts in this field entail a better definition of the vascular epigenome in obese patients as well as the unveiling of novel, cell-specific chromatin-modifying drugs that are able to erase specific epigenetic signals that are responsible for maladaptive transcriptional alterations and vascular dysfunction in obese patients. Antioxid. Redox Signal. 34, 1165-1199.
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Affiliation(s)
- Stefano Masi
- Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy
| | - Samuele Ambrosini
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland
| | - Shafeeq A Mohammed
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland
| | - Sebastiano Sciarretta
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.,Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Thomas F Lüscher
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.,Heart Division, Royal Brompton and Harefield Hospital Trust, National Heart & Lung Institute, Imperial College, London, United Kingdom
| | - Francesco Paneni
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland.,Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland.,Department of Research and Education, University Hospital Zurich, Zurich, Switzerland
| | - Sarah Costantino
- Center for Molecular Cardiology, University of Zürich, Zurich, Switzerland
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Dakroub A, A. Nasser S, Younis N, Bhagani H, Al-Dhaheri Y, Pintus G, Eid AA, El-Yazbi AF, Eid AH. Visfatin: A Possible Role in Cardiovasculo-Metabolic Disorders. Cells 2020; 9:2444. [PMID: 33182523 PMCID: PMC7696687 DOI: 10.3390/cells9112444] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/27/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023] Open
Abstract
Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine with several intriguing properties. It was first identified as pre-B-cell colony-enhancing factor but turned out to possess enzymatic functions in nicotinamide adenine dinucleotide biosynthesis, with ubiquitous expression in skeletal muscles, liver, cardiomyocytes, and brain cells. Visfatin exists in an intracellular (iNAMPT) and extracellular (eNAMPT) form. Intracellularly, visfatin/iNAMPT plays a regulatory role in NAD+ biosynthesis and thereby affects many NAD-dependent proteins such as sirtuins, PARPs, MARTs and CD38/157. Extracellularly, visfatin is associated with many hormone-like signaling pathways and activates some intracellular signaling cascades. Importantly, eNAMPT has been associated with several metabolic disorders including obesity and type 1 and 2 diabetes. In this review, a brief overview about visfatin is presented with special emphasis on its relevance to metabolic diseases. Visfatin/NAMPT appears to be a unique molecule with clinical significance with a prospective promising diagnostic, prognostic, and therapeutic applications in many cardiovasculo-metabolic disorders.
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Affiliation(s)
- Ali Dakroub
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon; (A.D.); (N.Y.); (H.B.); (A.F.E.-Y.)
| | - Suzanne A. Nasser
- Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut P.O. Box 11-5020, Lebanon;
| | - Nour Younis
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon; (A.D.); (N.Y.); (H.B.); (A.F.E.-Y.)
| | - Humna Bhagani
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon; (A.D.); (N.Y.); (H.B.); (A.F.E.-Y.)
| | - Yusra Al-Dhaheri
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain P.O. Box 15551, UAE;
| | - Gianfranco Pintus
- Department of Medical Laboratory Sciences, University of Sharjah, Sharjah P.O. Box 27272, UAE;
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy
| | - Assaad A. Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon;
| | - Ahmed F. El-Yazbi
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon; (A.D.); (N.Y.); (H.B.); (A.F.E.-Y.)
- Department of Pharmacology and Toxicology, Alexandria University, Alexandria 21521, El-Mesallah, Egypt
| | - Ali H. Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut P.O. Box 11-0236, Lebanon; (A.D.); (N.Y.); (H.B.); (A.F.E.-Y.)
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
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Coloured Rice Phenolic Extracts Increase Expression of Genes Associated with Insulin Secretion in Rat Pancreatic Insulinoma β-cells. Int J Mol Sci 2020; 21:ijms21093314. [PMID: 32392844 PMCID: PMC7246603 DOI: 10.3390/ijms21093314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/23/2020] [Accepted: 05/06/2020] [Indexed: 12/11/2022] Open
Abstract
Glucose-induced oxidative stress is associated with the overproduction of reactive oxygen species (ROS), which may dysregulate the expression of genes controlling insulin secretion leading to β-cell dysfunction, a hallmark of type 2 diabetes mellitus (T2DM). This study investigated the impact of coloured rice phenolic extracts (CRPEs) on the expression of key genes associated with β-cell function in pancreatic β-cells (INS-1E). These genes included glucose transporter 2 (Glut2), silent mating type information regulation 2 homolog 1 (Sirt1), mitochondrial transcription factor A (Tfam), pancreatic/duodenal homeobox protein 1 (Pdx-1) and insulin 1 (Ins1). INS-1E cells were cultured in high glucose (25 mM) to induce glucotoxic stress conditions (HGSC) and in normal glucose conditions (NGC-11.1 mM) to represent normal β-cell function. Cells were treated with CRPEs derived from two coloured rice cultivars, Purple and Yunlu29-red varieties at concentrations ranged from 50 to 250 µg/mL. CRPEs upregulated the expression of Glut2, Sirt1 and Pdx-1 significantly at 250 µg/mL under HGSC. CRPEs from both cultivars also upregulated Glut2, Sirt1, Tfam, Pdx-1 and Ins1 markedly at 250 µg/mL under NGC with Yunlu29 having the greatest effect. These data suggest that CRPEs may reduce β-cell dysfunction in T2DM by upregulating the expression of genes involved in insulin secretion pathways.
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11
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Tripathi M, Yen PM, Singh BK. Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases. Int J Mol Sci 2020; 21:E1645. [PMID: 32121253 PMCID: PMC7084735 DOI: 10.3390/ijms21051645] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/24/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders.
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Affiliation(s)
| | | | - Brijesh Kumar Singh
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore; (M.T.); (P.M.Y.)
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12
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Chandrasekaran K, Salimian M, Konduru SR, Choi J, Kumar P, Long A, Klimova N, Ho CY, Kristian T, Russell JW. Overexpression of Sirtuin 1 protein in neurons prevents and reverses experimental diabetic neuropathy. Brain 2019; 142:3737-3752. [PMID: 31754701 PMCID: PMC6885680 DOI: 10.1093/brain/awz324] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 08/26/2019] [Accepted: 08/30/2019] [Indexed: 02/07/2023] Open
Abstract
In diabetic neuropathy, there is activation of axonal and sensory neuronal degeneration pathways leading to distal axonopathy. The nicotinamide-adenine dinucleotide (NAD+)-dependent deacetylase enzyme, Sirtuin 1 (SIRT1), can prevent activation of these pathways and promote axonal regeneration. In this study, we tested whether increased expression of SIRT1 protein in sensory neurons prevents and reverses experimental diabetic neuropathy induced by a high fat diet (HFD). We generated a transgenic mouse that is inducible and overexpresses SIRT1 protein in neurons (nSIRT1OE Tg). Higher levels of SIRT1 protein were localized to cortical and hippocampal neuronal nuclei in the brain and in nuclei and cytoplasm of small to medium sized neurons in dorsal root ganglia. Wild-type and nSIRT1OE Tg mice were fed with either control diet (6.2% fat) or a HFD (36% fat) for 2 months. HFD-fed wild-type mice developed neuropathy as determined by abnormal motor and sensory nerve conduction velocity, mechanical allodynia, and loss of intraepidermal nerve fibres. In contrast, nSIRT1OE prevented a HFD-induced neuropathy despite the animals remaining hyperglycaemic. To test if nSIRT1OE would reverse HFD-induced neuropathy, nSIRT1OE was activated after mice developed peripheral neuropathy on a HFD. Two months after nSIRT1OE, we observed reversal of neuropathy and an increase in intraepidermal nerve fibre. Cultured adult dorsal root ganglion neurons from nSIRT1OE mice, maintained at high (30 mM) total glucose, showed higher basal and maximal respiratory capacity when compared to adult dorsal root ganglion neurons from wild-type mice. In dorsal root ganglion protein extracts from nSIRT1OE mice, the NAD+-consuming enzyme PARP1 was deactivated and the major deacetylated protein was identified to be an E3 protein ligase, NEDD4-1, a protein required for axonal growth, regeneration and proteostasis in neurodegenerative diseases. Our results indicate that nSIRT1OE prevents and reverses neuropathy. Increased mitochondrial respiratory capacity and NEDD4 activation was associated with increased axonal growth driven by neuronal overexpression of SIRT1. Therapies that regulate NAD+ and thereby target sirtuins may be beneficial in human diabetic sensory polyneuropathy.
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Affiliation(s)
- Krish Chandrasekaran
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Mohammad Salimian
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Sruthi R Konduru
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Joungil Choi
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Veterans Affairs Medical Center, Baltimore, MD 21201, USA
| | - Pranith Kumar
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Aaron Long
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Nina Klimova
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Cheng-Ying Ho
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Tibor Kristian
- Veterans Affairs Medical Center, Baltimore, MD 21201, USA
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - James W Russell
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Veterans Affairs Medical Center, Baltimore, MD 21201, USA
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Correspondence to: James W. Russell, MBChB, MS Professor, Department of Neurology, Anatomy and Neurobiology University of Maryland School of Medicine 3S-129, 110 South Paca Street, Baltimore, MD 21201-1642, USA E-mail:
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13
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Anti-obesity effect of cocoa proteins (Theobroma cacao L.) variety “Criollo” and the expression of genes related to the dysfunction of white adipose tissue in high-fat diet-induced obese rats. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.103519] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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14
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Abstract
The sirtuin family of nicotinamide adenine dinucleotide-dependent deacylases (SIRT1-7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.
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Affiliation(s)
- Alice E Kane
- From the Department of Genetics, Harvard Medical School, Boston, MA (A.E.K., D.A.S.)
| | - David A Sinclair
- From the Department of Genetics, Harvard Medical School, Boston, MA (A.E.K., D.A.S.).,Department of Pharmacology, The University of New South Wales, Sydney, Australia (D.A.S.)
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15
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Abdollahi S, Salehi-Abargouei A, Toupchian O, Sheikhha MH, Fallahzadeh H, Rahmanian M, Tabatabaie M, Mozaffari-Khosravi H. The Effect of Resveratrol Supplementation on Cardio-Metabolic Risk Factors in Patients with Type 2 Diabetes: A Randomized, Double-Blind Controlled Trial. Phytother Res 2019; 33:3153-3162. [PMID: 31475415 DOI: 10.1002/ptr.6487] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/28/2019] [Accepted: 08/06/2019] [Indexed: 12/15/2022]
Abstract
The aim of the present randomized controlled trial was to evaluate the effect of a micronized resveratrol supplement on glycemic status, lipid profile, and body composition in patients with type 2 diabetes mellitus (T2DM). A total of 71 overweight patients with T2DM (body mass index ranged 25-30) were randomly assigned to receive 1000 mg/day trans-resveratrol or placebo (methyl cellulose) for 8 weeks. Anthropometric indices and biochemical indices including lipid and glycemic profile were measured before and after the intervention. In adjusted model (age, sex, and baseline body mass index), resveratrol decreased fasting blood sugar (-7.97±13.6 mg/dL, p=0.05) and increased high density lipoprotein (3.62±8.75 mg/dL, p=0.01) levels compared with placebo. Moreover, the mean difference in insulin levels reached significance (-0.97±1.91, μIU/mL, p= 0.02). However, no significant differences were observed for anthropometric measures. It was found that 8-week resveratrol supplementation produced useful effects on some cardio-metabolic parameters in patients with T2DM. More studies are needed to confirm these findings.
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Affiliation(s)
- Shima Abdollahi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Nutrition and Public Health, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amin Salehi-Abargouei
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Omid Toupchian
- Department of Nutrition and Public Health, School of Public Health, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mohammad Hasan Sheikhha
- Department of Genetics, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Yazd Clinical and Research Center for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Fallahzadeh
- Department of Biostatistics and Epidemiology, Research Center of Prevention and Epidemiology of Non-Communicable Disease, School of Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Masoud Rahmanian
- Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahtab Tabatabaie
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hassan Mozaffari-Khosravi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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16
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Xia H, Dufour CR, Giguère V. ERRα as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease. Front Endocrinol (Lausanne) 2019; 10:206. [PMID: 31024446 PMCID: PMC6459935 DOI: 10.3389/fendo.2019.00206] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 03/13/2019] [Indexed: 01/01/2023] Open
Abstract
As transcriptional factors, nuclear receptors (NRs) function as major regulators of gene expression. In particular, dysregulation of NR activity has been shown to significantly alter metabolic homeostasis in various contexts leading to metabolic disorders and cancers. The orphan estrogen-related receptor (ERR) subfamily of NRs, comprised of ERRα, ERRβ, and ERRγ, for which a natural ligand has yet to be identified, are known as central regulators of energy metabolism. If AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can be viewed as sensors of the metabolic needs of a cell and responding acutely via post-translational control of proteins, then the ERRs can be regarded as downstream effectors of metabolism via transcriptional regulation of genes for a long-term and sustained adaptive response. In this review, we will focus on recent findings centered on the transcriptional roles played by ERRα in hepatocytes. Modulation of ERRα activity in both in vitro and in vivo models via genetic or pharmacological manipulation coupled with chromatin-immunoprecipitation (ChIP)-on-chip and ChIP-sequencing (ChIP-seq) studies have been fundamental in delineating the direct roles of ERRα in the control of hepatic gene expression. These studies have identified crucial roles for ERRα in lipid and carbohydrate metabolism as well as in mitochondrial function under both physiological and pathological conditions. The regulation of ERRα expression and activity via ligand-independent modes of action including coregulator binding, post-translational modifications (PTMs) and control of protein stability will be discussed in the context that may serve as valuable tools to modulate ERRα function as new therapeutic avenues for the treatment of hepatic metabolic dysfunction and related diseases.
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Affiliation(s)
- Hui Xia
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
- Department of Biochemistry, McGill University, Montréal, QC, Canada
| | | | - Vincent Giguère
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
- Department of Biochemistry, McGill University, Montréal, QC, Canada
- Medicine and Oncology, McGill University, Montréal, QC, Canada
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17
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Mahmoud M, Abu-Shahba N, Azmy O, El-Badri N. Impact of Diabetes Mellitus on Human Mesenchymal Stromal Cell Biology and Functionality: Implications for Autologous Transplantation. Stem Cell Rev Rep 2019; 15:194-217. [DOI: 10.1007/s12015-018-9869-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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18
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Aging-Induced Biological Changes and Cardiovascular Diseases. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7156435. [PMID: 29984246 PMCID: PMC6015721 DOI: 10.1155/2018/7156435] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/23/2018] [Accepted: 05/03/2018] [Indexed: 12/12/2022]
Abstract
Aging is characterized by functional decline in homeostatic regulation and vital cellular events. This process can be linked with the development of cardiovascular diseases (CVDs). In this review, we discussed aging-induced biological alterations that are associated with CVDs through the following aspects: (i) structural, biochemical, and functional modifications; (ii) autonomic nervous system (ANS) dysregulation; (iii) epigenetic alterations; and (iv) atherosclerosis and stroke development. Aging-mediated structural and biochemical modifications coupled with gradual loss of ANS regulation, vascular stiffening, and deposition of collagen and calcium often disrupt cardiovascular system homeostasis. The structural and biochemical adjustments have been consistently implicated in the progressive increase in mechanical burden and functional breakdown of the heart and vessels. In addition, cardiomyocyte loss in this process often reduces adaptive capacity and cardiovascular function. The accumulation of epigenetic changes also plays important roles in the development of CVDs. In summary, the understanding of the aging-mediated changes remains promising towards effective diagnosis, discovery of new drug targets, and development of new therapies for the treatment of CVDs.
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19
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Stefanowicz M, Nikołajuk A, Matulewicz N, Karczewska-Kupczewska M. Adipose tissue, but not skeletal muscle, sirtuin 1 expression is decreased in obesity and related to insulin sensitivity. Endocrine 2018; 60:263-271. [PMID: 29417372 PMCID: PMC5893655 DOI: 10.1007/s12020-018-1544-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 01/19/2018] [Indexed: 12/30/2022]
Abstract
PURPOSE Sirtuin 1 may regulate glucose and lipid metabolism. We aimed to assess adipose tissue and skeletal muscle sirtuin 1 expression in relation to insulin sensitivity, the expression of proinflammatory and metabolic genes, and to study the regulation of sirtuin 1 expression by hyperinsulinemia and circulating free fatty acids elevation. METHODS We examined 60 normal-weight, 42 overweight and 15 obese young subjects. The hyperinsulinemic-euglycemic clamp technique was applied throughout to measure insulin sensitivity. In 20 subjects, two 6 h clamps were performed, one of them with concurrent Intralipid/heparin infusion. Biopsies of subcutaneous adipose tissue and skeletal muscle were collected for the measurement of gene and protein expression. RESULTS Obese subjects had lower adipose sirtuin 1 in comparison with normal-weight and overweight participants. Muscle sirtuin 1 did not differ between the groups. Adipose tissue sirtuin 1 was related to insulin sensitivity, adipose tissue SLC2A4. The relationship between adipose tissue sirtuin 1 and insulin sensitivity was still present after controlling for BMI, however, it disappeared after controlling for adipose tissue SLC2A4. Muscle sirtuin 1 was not related to insulin sensitivity. Hyperisulinemia decreased adipose tissue and increased muscle sirtuin 1 expression. Intralipid/heparin infusion negated these effects. CONCLUSIONS Adipose tissue, but not muscle, sirtuin 1 is associated with insulin sensitivity in humans, possibly because of its correlation with adipose tissue SLC2A4 expression. Insulin differentially regulates adipose tissue and skeletal muscle sirtuin 1 expression in the short-term and circulating free fatty acids elevation negates these effects, which may be associated with lipid-induced insulin resistance.
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Affiliation(s)
- Magdalena Stefanowicz
- Department of Metabolic Diseases, Medical University of Bialystok, Bialystok, Poland
| | - Agnieszka Nikołajuk
- Department of Prophylaxis of Metabolic Diseases, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
| | - Natalia Matulewicz
- Department of Metabolic Diseases, Medical University of Bialystok, Bialystok, Poland
| | - Monika Karczewska-Kupczewska
- Department of Metabolic Diseases, Medical University of Bialystok, Bialystok, Poland.
- Department of Prophylaxis of Metabolic Diseases, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
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20
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Modi S, Yaluri N, Kokkola T, Laakso M. Plant-derived compounds strigolactone GR24 and pinosylvin activate SIRT1 and enhance glucose uptake in rat skeletal muscle cells. Sci Rep 2017; 7:17606. [PMID: 29242624 PMCID: PMC5730588 DOI: 10.1038/s41598-017-17840-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 11/22/2017] [Indexed: 12/16/2022] Open
Abstract
Insulin resistance is a characteristic finding in hyperglycaemia and type 2 diabetes. SIRT1 is a NAD+ dependent deacetylase that plays a central role in glucose homeostasis and energy metabolism. SIRT1 activators, including plant polyphenols such as resveratrol, improve insulin sensitivity in skeletal muscle tissue. We hypothesised that the novel plant-derived compounds, strigolactone and pinosylvin, beneficially enhance SIRT1 function, insulin signalling, glucose uptake, and mitochondrial biogenesis in skeletal muscle cells. Rat L6 skeletal muscle myotubes were treated with strigolactone analogue GR24 and pinosylvin. Resveratrol was included in experiments as a reference compound. We measured the effects of these compounds on SIRT1 function, insulin signalling, glucose uptake, mitochondrial biogenesis and gene expression profiles. Strigolactone GR24 upregulated and activated SIRT1 without activating AMPK, enhanced insulin signalling, glucose uptake, GLUT4 translocation and mitochondrial biogenesis. Pinosylvin activated SIRT1 in vitro and stimulated glucose uptake through the activation of AMPK. The regulation of SIRT1 by strigolactone GR24 and the activation of AMPK by pinosylvin may offer novel therapeutic approaches in the treatment of insulin resistance in skeletal muscle.
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Affiliation(s)
- Shalem Modi
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210, Kuopio, Finland
| | - Nagendra Yaluri
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210, Kuopio, Finland
| | - Tarja Kokkola
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210, Kuopio, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210, Kuopio, Finland. .,Department of Medicine, Kuopio University Hospital, 70210, Kuopio, Finland.
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21
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Liu Y, Ge ZP, Sun LZ, Tong P, Lu HM. Genetic variation of rs3811463 is associated with gestational diabetes mellitus susceptibility. Exp Ther Med 2017; 14:5157-5162. [PMID: 29201231 DOI: 10.3892/etm.2017.5188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 08/24/2017] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a growing health concern, and it increases the risk of adverse pregnancy outcomes with substantial long-term adverse health impacts on mothers and their offspring. Several studies have revealed specific associations between genetic variants and the risk of GDM. Single nucleotide polymorphisms (SNPs) are the major type of genetic variation in humans. Let-7 microRNA targets are enriched for genes containing SNPs associated with glucose metabolism, including Lin28. In the present study, the effect of T/C variants of rs3811463 (a SNP located near to the let-7 binding site in Lin28) on GDM risk was investigated. A GDM rat model was successfully constructed using a high fat diet and streptozotocin injection, and the primary skeletal muscle cells were isolated. The cell transfection results demonstrated that rs3811463-T/C significantly affected the glucose uptake and insulin sensitivity. Reverse transcription-quantitative polymerase chain reaction analysis indicated that the C allele at rs3811463 regulated the expression of glucose metabolism-associated genes insulin-like growth factor two binding protein 2 and glucokinase. Western blot analysis data revealed that replacement of the T allele by the C allele at rs3811463 modulated the protein level of Sirtuin 1. Taken together, it was concluded that the let-7/Lin28 axis regulated glucose uptake and insulin sensitivity by modulating the expression of glucose metabolism-associated proteins. These findings provide novel evidence on the association between genetic variations of rs3811463 and GDM susceptibility.
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Affiliation(s)
- Yun Liu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Zhi-Ping Ge
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Women and Children Health Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Li-Zhou Sun
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Women and Children Health Hospital, Nanjing, Jiangsu 210029, P.R. China
| | - Pei Tong
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hong-Mei Lu
- Department of Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Women and Children Health Hospital, Nanjing, Jiangsu 210029, P.R. China
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22
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Tao X, Chen L, Cai L, Ge S, Deng X. Regulatory effects of the AMPKα-SIRT1 molecular pathway on insulin resistance in PCOS mice: An in vitro and in vivo study. Biochem Biophys Res Commun 2017; 494:615-620. [DOI: 10.1016/j.bbrc.2017.09.154] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 09/27/2017] [Indexed: 01/14/2023]
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23
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Elhassan YS, Philp AA, Lavery GG. Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule. J Endocr Soc 2017; 1:816-835. [PMID: 29264533 PMCID: PMC5686634 DOI: 10.1210/js.2017-00092] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/10/2017] [Indexed: 02/06/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an established cofactor for enzymes serving cellular metabolic reactions. More recent research identified NAD+ as a signaling molecule and substrate for sirtuins and poly-adenosine 5'-diphosphate polymerases; enzymes that regulate protein deacetylation and DNA repair, and translate changes in energy status into metabolic adaptations. Deranged NAD+ homeostasis and concurrent alterations in mitochondrial function are intrinsic in metabolic disorders, such as type 2 diabetes, nonalcoholic fatty liver, and age-related diseases. Contemporary NAD+ precursors show promise as nutraceuticals to restore target tissue NAD+ and have demonstrated the ability to improve mitochondrial function and sirtuin-dependent signaling. This review discusses the accumulating evidence for targeting NAD+ metabolism in metabolic disease, maps the different strategies for NAD+ boosting, and addresses the challenges and open questions in the field. The health potential of targeting NAD+ homeostasis will inform clinical study design to identify nutraceutical approaches for combating metabolic disease and the unwanted effects of aging.
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Affiliation(s)
- Yasir S. Elhassan
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, United Kingdom
| | - Andrew A. Philp
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Gareth G. Lavery
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, United Kingdom
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24
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Yamaguchi S, Yoshino J. Adipose tissue NAD + biology in obesity and insulin resistance: From mechanism to therapy. Bioessays 2017; 39. [PMID: 28295415 DOI: 10.1002/bies.201600227] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Nicotinamide adenine dinucleotide (NAD+ ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD+ biosynthesis, together with its key downstream mediator, namely the NAD+ -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD+ biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD+ biology.
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Affiliation(s)
- Shintaro Yamaguchi
- Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jun Yoshino
- Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
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AAV-mediated Sirt1 overexpression in skeletal muscle activates oxidative capacity but does not prevent insulin resistance. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2016; 5:16072. [PMID: 27909699 PMCID: PMC5111573 DOI: 10.1038/mtm.2016.72] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 09/15/2016] [Accepted: 09/29/2016] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue, Sirt1 up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation. Here we examined whether Sirt1 overexpression mediated by adeno-associated viral vectors of serotype 1 (AAV1) specifically in skeletal muscle can counteract the development of insulin resistance induced by a high fat diet in mice. AAV1-Sirt1-treated mice showed up-regulated expression of key genes related to β-oxidation together with increased levels of phosphorylated AMP protein kinase. Moreover, SIRT1 overexpression in skeletal muscle also increased basal phosphorylated levels of AKT. However, AAV1-Sirt1 treatment was not enough to prevent high fat diet-induced obesity and insulin resistance. Although Sirt1 gene transfer to skeletal muscle induced changes at the muscular level related with lipid and glucose homeostasis, our data indicate that overexpression of SIRT1 in skeletal muscle is not enough to improve whole-body insulin resistance and that suggests that SIRT1 has to be increased in other metabolic tissues to prevent insulin resistance.
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Hesselink MKC, Schrauwen-Hinderling V, Schrauwen P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol 2016; 12:633-645. [PMID: 27448057 DOI: 10.1038/nrendo.2016.104] [Citation(s) in RCA: 182] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Low levels of physical activity and the presence of obesity are associated with mitochondrial dysfunction. In addition, mitochondrial dysfunction has been associated with the development of insulin resistance and type 2 diabetes mellitus (T2DM). Although the evidence for a causal relationship between mitochondrial function and insulin resistance is still weak, emerging evidence indicates that boosting mitochondrial function might be beneficial to patient health. Exercise training is probably the most recognized promoter of mitochondrial function and insulin sensitivity and hence is still regarded as the best strategy to prevent and treat T2DM. Animal data, however, have revealed several new insights into the regulation of mitochondrial metabolism, and novel targets for interventions to boost mitochondrial function have emerged. Importantly, many of these targets seem to be regulated by factors such as nutrition, ambient temperature and circadian rhythms, which provides a basis for nonpharmacological strategies to prevent or treat T2DM in humans. Here, we will review the current evidence that mitochondrial function can be targeted therapeutically to improve insulin sensitivity and to prevent T2DM, focusing mainly on human intervention studies.
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Affiliation(s)
- Matthijs K C Hesselink
- Department of Human Biology and Human Movement Sciences, Maastricht University Medical Center, Universiteitsingel 50, 6229 ER, Maastricht, Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Universiteitsingel 50, 6229 ER, Maastricht, Netherlands
| | - Vera Schrauwen-Hinderling
- Department of Human Biology and Human Movement Sciences, Maastricht University Medical Center, Universiteitsingel 50, 6229 ER, Maastricht, Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Universiteitsingel 50, 6229 ER, Maastricht, Netherlands
- Department of Radiology, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX, Maastricht, Netherlands
| | - Patrick Schrauwen
- Department of Human Biology and Human Movement Sciences, Maastricht University Medical Center, Universiteitsingel 50, 6229 ER, Maastricht, Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Universiteitsingel 50, 6229 ER, Maastricht, Netherlands
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Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes. Sci Rep 2016; 6:35047. [PMID: 27756900 PMCID: PMC5069469 DOI: 10.1038/srep35047] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 09/15/2016] [Indexed: 12/16/2022] Open
Abstract
Cell and animal studies have demonstrated that circadian rhythm is governed by autonomous rhythmicity of clock genes. Although disturbances in circadian rhythm have been implicated in metabolic disease development, it remains unknown whether muscle circadian rhythm is altered in human models of type 2 diabetes. Here we used human primary myotubes (HPM) to investigate if rhythmicity of clock- and metabolic gene expression is altered in donors with obesity or type 2 diabetes compared to metabolically healthy donors. HPM were obtained from skeletal muscle biopsies of four groups: type 2 diabetic patients and their BMI- and age-matched obese controls and from lean, healthy and young endurance trained athletes and their age-matched sedentary controls. HPM were differentiated for 7 days before synchronization by serum shock followed by gene expression profiling over the next 72 hours. HPM display robust circadian rhythms in clock genes, but REVERBA displayed dampened rhythmicity in type 2 diabetes. Furthermore, rhythmicity in NAMPT and SIRT1 expression was only observed in HPM from trained athletes. Rhythmicity in expression of key-regulators of carbohydrate and lipid metabolism was modest. We demonstrate that in human skeletal muscle REVERBA/B, NAMPT and SIRT1 circadian rhythms are affected in donors of sedentary life style and poor health status.
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Dimauro I, Scalabrin M, Fantini C, Grazioli E, Beltran Valls MR, Mercatelli N, Parisi A, Sabatini S, Di Luigi L, Caporossi D. Resistance training and redox homeostasis: Correlation with age-associated genomic changes. Redox Biol 2016; 10:34-44. [PMID: 27687219 PMCID: PMC5040637 DOI: 10.1016/j.redox.2016.09.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 09/19/2016] [Accepted: 09/20/2016] [Indexed: 01/15/2023] Open
Abstract
Regular physical activity is effective as prevention and treatment for different chronic conditions related to the ageing processes. In fact, a sedentary lifestyle has been linked to a worsening of cellular ageing biomarkers such as telomere length (TL) and/or specific epigenetic changes (e.g. DNA methylation), with increase of the propensity to aging-related diseases and premature death. Extending our previous findings, we aimed to test the hypothesis that 12 weeks of low frequency, moderate intensity, explosive-type resistance training (EMRT) may attenuate age-associated genomic changes. To this aim, TL, global DNA methylation, TRF2, Ku80, SIRT1, SIRT2 and global protein acetylation, as well as other proteins involved in apoptotic pathway (Bcl-2, Bax and Caspase-3), antioxidant response (TrxR1 and MnSOD) and oxidative damage (myeloperoxidase) were evaluated before and after EMRT in whole blood or peripheral mononuclear cells (PBMCs) of elderly subjects. Our findings confirm the potential of EMRT to induce an adaptive change in the antioxidant protein systems at systemic level and suggest a putative role of resistance training in the reduction of global DNA methylation. Moreover, we observed that EMRT counteracts the telomeres' shortening in a manner that proved to be directly correlated with the amelioration of redox homeostasis and efficacy of training regime, evaluated as improvement of both muscle's power/strength and functional parameters.
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Affiliation(s)
- Ivan Dimauro
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Mattia Scalabrin
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Cristina Fantini
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Elisa Grazioli
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Maria Reyes Beltran Valls
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Neri Mercatelli
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Attilio Parisi
- Unit of Sport Medicine, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
| | - Stefania Sabatini
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
| | - Luigi Di Luigi
- Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
| | - Daniela Caporossi
- Unit of Biology, Genetics and Biochemistry, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 15, 00135 Rome, Italy.
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Yang F, Du X, Wang Y, Wang C, Huang C, Xiao Q, Bai X, Wang H. Characterization and functional analysis of porcine estrogen-related receptors and their alternative splicing variants. J Anim Sci 2016; 93:4258-66. [PMID: 26440325 DOI: 10.2527/jas.2015-9188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Estrogen-related receptors (ESRR) are orphan nuclear hormone receptors with unidentified ligands; they play important roles in tissue regulation and development and maintenance of pluripotent cell identity. The splicer variant, genomic organization, and physiological roles of ESRR have been elucidated in the human and the mouse. However, in livestock, they remain elusive. In this study, we cloned porcine ESRR family members , , and . Two alternative splicing variants, and , and a novel were identified. To determine the domain function, we constructed vectors with sequential deletions of the ESRRB coding sequence. The functional analysis showed that the C domain of ESRR plays a core role in promoting the activation of estrogen response elements that are found in all kinds of ESRR-targeting genes, whereas the E domain is not essential for transcription regulation of ESRR unless a specific and identified ligand is applied.
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Abd El-Haleim EA, Bahgat AK, Saleh S. Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression. World J Gastroenterol 2016; 22:2931-2948. [PMID: 26973390 PMCID: PMC4779917 DOI: 10.3748/wjg.v22.i10.2931] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 12/04/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of resveratrol, alone and in combination with fenofibrate, on fructose-induced metabolic genes abnormalities in rats.
METHODS: Giving a fructose-enriched diet (FED) to rats for 12 wk was used as a model for inducing hepatic dyslipidemia and insulin resistance. Adult male albino rats (150-200 g) were divided into a control group and a FED group which was subdivided into 4 groups, a control FED, fenofibrate (FENO) (100 mg/kg), resveratrol (RES) (70 mg/kg) and combined treatment (FENO + RES) (half the doses). All treatments were given orally from the 9th week till the end of experimental period. Body weight, oral glucose tolerance test (OGTT), liver index, glucose, insulin, insulin resistance (HOMA), serum and liver triglycerides (TGs), oxidative stress (liver MDA, GSH and SOD), serum AST, ALT, AST/ALT ratio and tumor necrosis factor-α (TNF-α) were measured. Additionally, hepatic gene expression of suppressor of cytokine signaling-3 (SOCS-3), sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), malonyl CoA decarboxylase (MCD), transforming growth factor-β1 (TGF-β1) and adipose tissue genes expression of leptin and adiponectin were investigated. Liver sections were taken for histopathological examination and steatosis area were determined.
RESULTS: Rats fed FED showed damaged liver, impairment of glucose tolerance, insulin resistance, oxidative stress and dyslipidemia. As for gene expression, there was a change in favor of dyslipidemia and nonalcoholic steatohepatitis (NASH) development. All treatment regimens showed some benefit in reversing the described deviations. Fructose caused deterioration in hepatic gene expression of SOCS-3, SREBP-1c, FAS, MDA and TGF-β1 and in adipose tissue gene expression of leptin and adiponectin. Fructose showed also an increase in body weight, insulin resistance (OGTT, HOMA), serum and liver TGs, hepatic MDA, serum AST, AST/ALT ratio and TNF-α compared to control. All treatments improved SOCS-3, FAS, MCD, TGF-β1 and leptin genes expression while only RES and FENO + RES groups showed an improvement in SREBP-1c expression. Adiponectin gene expression was improved only by RES. A decrease in body weight, HOMA, liver TGs, AST/ALT ratio and TNF-α were observed in all treatment groups. Liver index was increased in FENO and FENO + RES groups. Serum TGs was improved only by FENO treatment. Liver MDA was improved by RES and FENO + RES treatments. FENO + RES group showed an increase in liver GSH content.
CONCLUSION: When resveratrol was given with half the dose of fenofibrate it improved NASH-related fructose-induced disturbances in gene expression similar to a full dose of fenofibrate.
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Rappou E, Jukarainen S, Rinnankoski-Tuikka R, Kaye S, Heinonen S, Hakkarainen A, Lundbom J, Lundbom N, Saunavaara V, Rissanen A, Virtanen KA, Pirinen E, Pietiläinen KH. Weight Loss Is Associated With Increased NAD(+)/SIRT1 Expression But Reduced PARP Activity in White Adipose Tissue. J Clin Endocrinol Metab 2016; 101:1263-73. [PMID: 26760174 DOI: 10.1210/jc.2015-3054] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) are 2 important nicotinamide adenine dinucleotide (NAD)(+)-dependent enzyme families with opposing metabolic effects. Energy shortage increases NAD(+) biosynthesis and SIRT activity but reduces PARP activity in animals. Effects of energy balance on these pathways in humans are unknown. OBJECTIVE We compared NAD(+)/SIRT pathway expressions and PARP activities in sc adipose tissue (SAT) between lean and obese subjects and investigated their change in the obese subjects during a 12-month weight loss. DESIGN, SETTING AND PARTICIPANTS SAT biopsies were obtained from 19 clinically healthy obese subjects (mean ± SE body mass index, 34.6 ± 2.7 kg/m(2)) during a weight-loss intervention (0, 5, and 12 mo) and from 19 lean reference subjects (body mass index, 22.7 ± 1.1 kg/m(2)) at baseline. MAIN OUTCOME MEASURES SAT mRNA expressions of SIRTs 1-7 and the rate-limiting gene in NAD(+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) were measured by Affymetrix, and total PARP activity by ELISA kit. RESULTS SIRT1, SIRT3, SIRT7, and NAMPT expressions were significantly lower, whereas total PARP activity was increased in obese compared with lean subjects. SIRT1 and NAMPT expressions increased in obese subjects between 0 and 5 months, after a mean weight loss of 11.7%. In subjects who continued to lose weight between 5 and 12 months, SIRT1 expression increased progressively, whereas in subjects with weight regain, SIRT1 reverted to baseline levels. PARP activity significantly decreased in all subjects upon weight loss. CONCLUSIONS Calorie restriction is an attractive strategy to improve the NAD(+)/SIRT pathway and decrease PARPs in SAT in human obesity.
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Affiliation(s)
- Elisabeth Rappou
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Sakari Jukarainen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Rita Rinnankoski-Tuikka
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Sanna Kaye
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Sini Heinonen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Antti Hakkarainen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Jesper Lundbom
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Nina Lundbom
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Virva Saunavaara
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Aila Rissanen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Kirsi A Virtanen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Eija Pirinen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit (E.R., S.J., S.K., S.H., A.R., K.H.P.), Research Programs Unit, University of Helsinki, 00014 Helsinki, Finland; Research Program for Molecular Neurology (R.R.-T., E.P.), University of Helsinki, 00014 Helsinki, Finland; Helsinki Medical Imaging Center (A.H., J.L., N.L.), Radiology, University of Helsinki, 00290 Helsinki, Finland; Institute for Clinical Diabetology (J.L.), German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225 Düsseldorf, Germany; Turku Positron Emission Tomography Center (V.S., K.A.V.), Turku University Hospital and University of Turku, 20521 Turku, Finland; Institute for Molecular Medicine Finland (K.H.P.), Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Endocrinology (K.H.P.), Abdominal Center, Helsinki University Hospital, University of Helsinki, 00014 Helsinki, Finland
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Li Y, Wei H, Li F, Chen S, Duan Y, Guo Q, Liu Y, Yin Y. Supplementation of branched-chain amino acids in protein-restricted diets modulates the expression levels of amino acid transporters and energy metabolism associated regulators in the adipose tissue of growing pigs. ACTA ACUST UNITED AC 2016; 2:24-32. [PMID: 29767034 PMCID: PMC5940986 DOI: 10.1016/j.aninu.2016.01.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 01/29/2016] [Accepted: 01/31/2016] [Indexed: 12/17/2022]
Abstract
This experiment was conducted to investigate the effects of branched-chain amino acids (BCAA) supplemented in protein-restricted diets on the growth performance and the expression profile of amino acid transporters and energy metabolism related regulators in the white adipose tissue (WAT) of different regional depots including dorsal subcutaneous adipose (DSA) and abdominal subcutaneous adipose (ASA). A total of 24 crossbred barrows (7.40 ± 0.70 kg) were randomly divided into 4 groups and were fed the following isocaloric diets for 33 days: 1) a recommended adequate protein diet (AP, 20% CP, as a positive control); 2) a low protein diet (LP, 17% CP); 3) the LP diet supplemented with BCAA (LP + B, 17% CP) to reach the same level of the AP diet group; 4) the LP diet supplemented with 2 times the amount of BCAA (LP + 2B, 17% CP). The daily gain and daily feed intake of the LP diet group were the lowest among all the treatments (P < 0.01). The feed conversion was improved markedly in the group of LP + B compared with the LP diet group (P < 0.05). No significant difference was noted for the serum biochemical parameter concentrations of glucose, triglyceride, nonesterified fatty acid and insulin among the groups (P > 0.05). Moreover, BCAA supplementation down-regulated the expression levels of amino acid transporters including L-type amino acid transporter 1 and sodium-coupled neutral amino acid transporter 2 in DSA, but up-regulated the expression level of L-type amino acid transporter 4 in ASA (P < 0.05). Meanwhile, the energy sensor AMP-activated protein kinase α was activated in the DSA of pigs fed LP diet and in the ASA of the pigs fed AP or LP + 2B diets (P < 0.05). The mRNA expression profile of the selected mitochondrial component and mitochondrial biogenesis associated regulators in DSA and ASA also responded differently to dietary BCAA supplementation. These results suggested that the growth performance of growing pigs fed protein restricted diets supplemented with BCAA could catch up to that of the pigs fed AP diets. The results also partly demonstrated that the regulation mechanisms of BCAA are different in the adipose tissues of different depots.
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Affiliation(s)
- Yinghui Li
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Hongkui Wei
- College of Animal Sciences, Huazhong Agricultural University, Wuhan 430070, China
| | - Fengna Li
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- Hunan Co-Innovation Center of Animal Production Safety (CICAPS), Changsha 410128, China
- Corresponding authors.
| | - Shuai Chen
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yehui Duan
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Qiuping Guo
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yingying Liu
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- University of Chinese Academy of Sciences, Beijing 100039, China
| | - Yulong Yin
- Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- Changsha Lvye Biotechnology Limited Company Academician Expert Workstation, Changsha 410126, China
- Hang Zhou King Techina Limited Company Academician Expert Workstation, Hangzhou 311107, China
- Corresponding authors.
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Park SK, Seong RK, Kim JA, Son SJ, Kim Y, Yokozawa T, Shin OS. Oligonol promotes anti-aging pathways via modulation of SIRT1-AMPK-Autophagy Pathway. Nutr Res Pract 2016; 10:3-10. [PMID: 26865910 PMCID: PMC4742308 DOI: 10.4162/nrp.2016.10.1.3] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 08/05/2015] [Accepted: 08/26/2015] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND/OBJECTIVES Oligonol, mainly found in lychee fruit, is an antioxidant polyphenolic compound which has been shown to have anti-inflammatory and anti-cancer properties. The detailed mechanisms by which oligonol may act as an anti-aging molecule have not been determined. MATERIALS/METHODS In this study, we evaluated the ability of oligonol to modulate sirtuin (SIRT) expression in human lung epithelial (A549) cells. Oligonol was added to A549 cells and reactive oxygen species production, mitochondrial superoxide formation, and p21 protein levels were measured. Signaling pathways activated upon oligonol treatment were also determined by western blotting. Furthermore, the anti-aging effect of oligonol was evaluated ex vivo in mouse splenocytes and in vivo in Caenorhabditis elegans. RESULTS Oligonol specifically induced the expression of SIRT1, whose activity is linked to gene expression, metabolic control, and healthy aging. In response to influenza virus infection of A549 cells, oligonol treatment significantly up-regulated SIRT1 expression and down-regulated viral hemagglutinin expression. Oligonol treatment also resulted in the activation of autophagy pathways and the phosphorylation of AMP-activated protein kinase (AMPK). Furthermore, oligonol-treated spleen lymphocytes from old mice showed increased cell proliferation, and mRNA levels of SIRT1 in the lungs of old mice were significantly lower than those in the lungs of young mice. Additionally, in vivo lethality assay revealed that oligonol extended the lifespan of C. elegans infected with lethal Vibrio cholerae. CONCLUSIONS These data demonstrated that oligonol may act as an anti-aging molecule by modulating SIRT1/autophagy/AMPK pathways.
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Affiliation(s)
- Seul-Ki Park
- Department of Biomedical Sciences, College of Medicine, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
| | - Rak-Kyun Seong
- Department of Biomedical Sciences, College of Medicine, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
| | - Ji-Ae Kim
- Department of Biomedical Sciences, College of Medicine, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea
| | - Seok-Jun Son
- BK21 Plus Graduate Program, Department of Animal Science and Institute of Rare Earth for Biological Application , Chonbuk National University, Jeonju 54896, Korea
| | - Younghoon Kim
- BK21 Plus Graduate Program, Department of Animal Science and Institute of Rare Earth for Biological Application , Chonbuk National University, Jeonju 54896, Korea
| | - Takako Yokozawa
- Institute of Natural Medicine, University of Toyama, Toyama, Japan
| | - Ok Sarah Shin
- Department of Biomedical Sciences, College of Medicine, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Korea.; Department of Microbiology, College of Medicine, Korea University, Seoul 02841, Korea
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Moreno-Navarrete JM, Moreno M, Ortega F, Sabater M, Xifra G, Ricart W, Fernández-Real JM. CISD1 in association with obesity-associated dysfunctional adipogenesis in human visceral adipose tissue. Obesity (Silver Spring) 2016; 24:139-47. [PMID: 26692580 DOI: 10.1002/oby.21334] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 08/05/2015] [Accepted: 08/14/2015] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To investigate CISD1 mRNA and protein in human adipose tissue in association with obesity and adipogenesis. METHODS Subcutaneous (SAT) and visceral (VAT) adipose tissue CISD1 gene expression (real-time PCR) and protein (Western blot) levels were investigated in human adipose tissue and during human adipocyte differentiation. RESULTS SAT and VAT CISD1 mRNA and protein levels were significantly decreased in subjects with obesity and negatively correlated with BMI after controlling for age and sex. In participants with morbid obesity, VAT CISD1 gene expression was positively correlated with insulin sensitivity (r = 0.47, P = 0.01), and bariatric surgery-induced weight loss led to increased SAT CISD1 mRNA levels. In both VAT and SAT, CISD1 gene expression was significantly associated with SIRT1, ISCA2, and mitochondrial biogenesis-related (PPARGC1A, TFAM, and MT-CO3) and browning-related (PRDM16 and UCP1) gene expression. In addition, VAT CISD1 gene expression was significantly associated with adipogenic and iron metabolism-related genes. Importantly, these correlations were replicated in a second cohort. At the cellular level, CISD1 gene expression increased during human adipocyte differentiation in correlation with adipogenic genes (r > 0.60, P < 0.005). CONCLUSIONS These data suggest a possible role of CISD1 in obesity-associated dysfunctional adipogenesis in human VAT.
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Affiliation(s)
- José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
| | - María Moreno
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
| | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
| | - Mònica Sabater
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
| | - Gemma Xifra
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut D'investigació Biomèdica De Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto De Salud Carlos III (ISCIII), Girona, Spain
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Rabadan-Chávez G, Quevedo-Corona L, Garcia AM, Reyes-Maldonado E, Jaramillo-Flores ME. Cocoa powder, cocoa extract and epicatechin attenuate hypercaloric diet-induced obesity through enhanced β-oxidation and energy expenditure in white adipose tissue. J Funct Foods 2016. [DOI: 10.1016/j.jff.2015.10.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Fang M, Fan Z, Tian W, Zhao Y, Li P, Xu H, Zhou B, Zhang L, Wu X, Xu Y. HDAC4 mediates IFN-γ induced disruption of energy expenditure-related gene expression by repressing SIRT1 transcription in skeletal muscle cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2015; 1859:294-305. [PMID: 26619800 DOI: 10.1016/j.bbagrm.2015.11.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 11/13/2015] [Accepted: 11/23/2015] [Indexed: 01/08/2023]
Abstract
Metabolic homeostasis is achieved through balanced energy storage and output. Impairment of energy expenditure is a hallmark event in patients with obesity and type 2 diabetes. Previously we have shown that the pro-inflammatory cytokine interferon gamma (IFN-γ) disrupts energy expenditure in skeletal muscle cells via hypermethylated in cancer 1 (HIC1)-class II transactivator (CIITA) dependent repression of SIRT1 transcription. Here we report that repression of SIRT1 transcription by IFN-γ paralleled loss of histone acetylation on the SIRT1 promoter region with simultaneous recruitment of histone deacetylase 4 (HDAC4). IFN-γ activated HDAC4 in vitro and in vivo by up-regulating its expression and stimulating its nuclear accumulation. HIC1 and CIITA recruited HDAC4 to the SIRT1 promoter and cooperated with HDAC4 to repress SIRT1 transcription. HDAC4 depletion by small interfering RNA or pharmaceutical inhibition normalized histone acetylation on the SIRT1 promoter and restored SIRT1 expression in the presence of IFN-γ. Over-expression of HDAC4 suppressed the transcription of genes involved in energy expenditure in a SIRT1-dependent manner. In contrast, HDAC4 knockdown/inhibition neutralized the effect of IFN-γ on cellular metabolism by normalizing SIRT1 expression. Therefore, our data reveal a role for HDAC4 in regulating cellular energy output and as such provide insights into rationalized design of novel anti-diabetic therapeutics.
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Affiliation(s)
- Mingming Fang
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China
| | - Zhiwen Fan
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Wenfang Tian
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Yuhao Zhao
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Ping Li
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Huihui Xu
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Bisheng Zhou
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Liping Zhang
- Department of Biochemistry, Xinjiang Medical University, Urumqi, China
| | - Xiaoyan Wu
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
| | - Yong Xu
- Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
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Luo S, Yang X, Wang D, Ni J, Wu J, Xu Z, Xuan D, Zhang J. Periodontitis contributes to aberrant metabolism in type 2 diabetes mellitus rats by stimulating the expression of adipokines. J Periodontal Res 2015; 51:453-61. [PMID: 26456152 DOI: 10.1111/jre.12322] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2015] [Indexed: 12/16/2022]
Affiliation(s)
- S. Luo
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - X. Yang
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - D. Wang
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - J. Ni
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - J. Wu
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - Z. Xu
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - D. Xuan
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
| | - J. Zhang
- Department of Periodontology; Guangdong Provincial Stomatological Hospital; Southern Medical University; Haizhu District Guangzhou China
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Abente EJ, Subramanian M, Ramachandran V, Najafi-Shoushtari SH. MicroRNAs in obesity-associated disorders. Arch Biochem Biophys 2015; 589:108-19. [PMID: 26416722 DOI: 10.1016/j.abb.2015.09.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/17/2015] [Accepted: 09/18/2015] [Indexed: 02/08/2023]
Abstract
The emergence of a worldwide obesity epidemic has dramatically increased the prevalence of insulin resistance and metabolic syndrome, predisposing individuals to a greater risk for the development of non-alcoholic fatty liver disease, type II diabetes and atherosclerotic cardiovascular diseases. Current available pharmacological interventions combined with diet and exercise-based managements are still poorly effective for weight management, likely in part due to an incomplete understanding of regulatory mechanisms and pathways contributing to the systemic metabolic abnormalities under disturbed energy homeostasis. MicroRNAs, small non-coding RNAs that regulate posttranscriptional gene expression, have been increasingly described to influence shifts in metabolic pathways under various obesity-related disease settings. Here we review recent discoveries of the mechanistic role that microRNAs play in regulating metabolic functions in liver and adipose tissues involved in obesity associated disorders, and briefly discusses the potential candidates that are being pursued as viable therapeutic targets.
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Affiliation(s)
- Eugenio J Abente
- Department of Cell and Developmental Biology, Weill Cornell Medical College, Cornell University, New York 10021, NY, USA; Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | - Murugan Subramanian
- Department of Cell and Developmental Biology, Weill Cornell Medical College, Cornell University, New York 10021, NY, USA; Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | - Vimal Ramachandran
- Department of Cell and Developmental Biology, Weill Cornell Medical College, Cornell University, New York 10021, NY, USA; Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar
| | - S Hani Najafi-Shoushtari
- Department of Cell and Developmental Biology, Weill Cornell Medical College, Cornell University, New York 10021, NY, USA; Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, P.O. Box 24144, Doha, Qatar.
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Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J 2015; 36:3404-12. [PMID: 26112889 PMCID: PMC4685177 DOI: 10.1093/eurheartj/ehv290] [Citation(s) in RCA: 340] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 06/08/2015] [Indexed: 12/21/2022] Open
Abstract
Sirtuins (Sirt1–Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation—all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFκB, Pcsk9, low-density lipoprotein-receptor, PPARγ, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD+, we anticipate that this field will move quickly from bench to bedside.
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Affiliation(s)
- Stephan Winnik
- Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland
| | - Johan Auwerx
- Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - David A Sinclair
- Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Genetics Department, Harvard Medical School, Boston, MA, USA
| | - Christian M Matter
- Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
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Moreno-Navarrete JM, Ortega F, Moreno M, Xifra G, Ricart W, Fernández-Real JM. PRDM16 sustains white fat gene expression profile in human adipocytes in direct relation with insulin action. Mol Cell Endocrinol 2015; 405:84-93. [PMID: 25662275 DOI: 10.1016/j.mce.2015.01.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 01/22/2015] [Accepted: 01/29/2015] [Indexed: 01/08/2023]
Abstract
In the present study, we aimed to evaluate the possible role of PRDM16 in human adipocytes and in whole adipose tissue according to obesity and insulin sensitivity. PRDM16 knockdown (KD) had a dual behavior. While KD in preadipocytes led to enhanced gene expression markers of adipocyte differentiation, PRDM16 KD in fully differentiated adipocytes resulted in decreased adipogenic gene expression and insulin action. In line with KD in adipocytes, PRDM16 was positively associated with the expression of several genes involved in adipogenesis, insulin signaling, mitochondrial function and brown adipocyte-related markers in whole adipose tissue from two independent cohorts. PRDM16 was decreased in obese subjects in relation with the decrease of insulin sensitivity [HOM(AIR) (cohort 1) and M clamp value (cohort 2)]. Rosiglitazone (5 µmol/l) and metformin (5 mmol/l) led to increased PRDM16 mRNA and protein levels in isolated human adipocytes and in whole adipose tissue. In conclusion, PRDM16 might contribute to maintain adipose tissue "white fat" gene expression profile and systemic metabolic homeostasis.
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Affiliation(s)
- José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), Instituto de Salud Carlos III (ISCIII), Girona 17007, Spain.
| | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), Instituto de Salud Carlos III (ISCIII), Girona 17007, Spain
| | - María Moreno
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), Instituto de Salud Carlos III (ISCIII), Girona 17007, Spain
| | - Gemma Xifra
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), Instituto de Salud Carlos III (ISCIII), Girona 17007, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), Instituto de Salud Carlos III (ISCIII), Girona 17007, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), Instituto de Salud Carlos III (ISCIII), Girona 17007, Spain.
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Zeng HL, Huang SL, Xie FC, Zeng LM, Hu YH, Leng Y. Yhhu981, a novel compound, stimulates fatty acid oxidation via the activation of AMPK and ameliorates lipid metabolism disorder in ob/ob mice. Acta Pharmacol Sin 2015; 36:343-52. [PMID: 25732571 DOI: 10.1038/aps.2014.147] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 12/08/2014] [Indexed: 02/07/2023]
Abstract
AIM Defects in fatty acid metabolism contribute to the pathogenesis of insulin resistance and obesity. In this study, we investigated the effects of a novel compound yhhu981 on fatty acid metabolism in vitro and in vivo. METHODS The capacity to stimulate fatty acid oxidation was assessed in C2C12 myotubes. The fatty acid synthesis was studied in HepG2 cells using isotope tracing. The phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) was examined with Western blot analysis. For in vivo experiments, ob/ob mice were orally treated with yhhu981 acutely (300 mg/kg) or chronically (150 or 300 mg·kg(-1)·d(-1) for 22 d). On the last day of treatment, serum and tissue samples were collected for analysis. RESULTS Yhhu981 (12.5-25 μmol/L) significantly increased fatty acid oxidation and the expression of related genes (Sirt1, Pgc1α and Mcad) in C2C12 myotubes, and inhibited fatty acid synthesis in HepG2 cells. Furthermore, yhhu981 dose-dependently increased the phosphorylation of AMPK and ACC in both C2C12 myotubes and HepG2 cells. Compound C, an AMPK inhibitor, blocked fatty acid oxidation in yhhu981-treated C2C12 myotubes and fatty acid synthesis decrease in yhhu981-treated HepG2 cells. Acute administration of yhhu981 decreased the respiratory exchange ratio in ob/ob mice, whereas chronic treatment with yhhu981 ameliorated the lipid abnormalities and ectopic lipid deposition in skeletal muscle and liver of ob/ob mice. CONCLUSION Yhhu981 is a potent compound that stimulates fatty acid oxidation, and exerts pleiotropic effects on lipid metabolism by activating AMPK.
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Di-(2-ethylhexyl) phthalate inhibits DNA replication leading to hyperPARylation, SIRT1 attenuation, and mitochondrial dysfunction in the testis. Sci Rep 2014; 4:6434. [PMID: 25242624 PMCID: PMC4170195 DOI: 10.1038/srep06434] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 08/19/2014] [Indexed: 01/13/2023] Open
Abstract
Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitously used endocrine disruptor.There is widespread exposure to DEHP in the general population which has raised substantial public concern due to its potential detrimental health effects. It is particularly pertinent to investigate the molecular mechanisms of its testicular toxicity which are largely unknown. By feeding male rats DEHP for 2 weeks, rat spermatogenesis became disrupted, resulting in a decreased number of spermatocytes and spermatids. Since rapidly dividing tissues appeared to be particularly vulnerable to DEHP toxicity we investigated the effect of DEHP on DNA replication. Intriguingly, DEHP appeared to inhibit DNA replication as evidenced by results of fiber tract analysis. This led to induction of the mitochondrial apoptotic pathways and increased ROS production. Furthermore, the toxicity of DEHP led to respiratory chain defects and attenuation of ATP level probably brought about by hyperPARylation and undermined SIRT1 activity. Our findings reveal a previously unknown mitochondrial dysfunction in DEHP-induced testicular toxicity and highlight the importance of SIRT1 in male reproduction.
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Hypoxia in diabetic kidneys. BIOMED RESEARCH INTERNATIONAL 2014; 2014:837421. [PMID: 25054148 PMCID: PMC4094876 DOI: 10.1155/2014/837421] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/02/2014] [Indexed: 12/20/2022]
Abstract
Diabetic nephropathy (DN) is now a leading cause of end-stage renal disease. In addition, DN accounts for the increased mortality in type 1 and type 2 diabetes, and then patients without DN achieve long-term survival compatible with general population. Hypoxia represents an early event in the development and progression of DN, and hypoxia-inducible factor- (HIF-) 1 mediates the metabolic responses to renal hypoxia. Diabetes induces the "fraternal twins" of hypoxia, that is, pseudohypoxia and hypoxia. The kidneys are susceptible to hyperoxia because they accept 20% of the cardiac output. Therefore, the kidneys have specific vasculature to avoid hyperoxia, that is, AV oxygen shunting. The NAD-dependent histone deacetylases (HDACs) sirtuins are seven mammalian proteins, SIRTs 1-7, which are known to modulate longevity and metabolism. Recent studies demonstrated that some isoforms of sirtuins inhibit the activation of HIF by deacetylation or noncatalyzing effects. The kidneys, which have a vascular system that protects them against hyperoxia, unfortunately experience extraordinary hypernutrition today. Then, an unexpected overload of glucose augments the oxygen consumption, which ironically results in hypoxia. This review highlights the primary role of HIF in diabetic kidneys for the metabolic adaptation to diabetes-induced hypoxia.
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Wang X, Sundquist J, Zöller B, Memon AA, Palmér K, Sundquist K, Bennet L. Determination of 14 circulating microRNAs in Swedes and Iraqis with and without diabetes mellitus type 2. PLoS One 2014; 9:e86792. [PMID: 24497980 PMCID: PMC3907562 DOI: 10.1371/journal.pone.0086792] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 12/14/2013] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Recent reports suggest that immigrants from Middle Eastern countries are a high-risk group for type 2 diabetes (T2D) compared with Swedes, and that the pathogenesis of T2D may be ethnicity-specific. Deregulation of microRNA (miRNA) expression has been demonstrated to be associated with T2D but ethnic differences in miRNA have not been investigated. The aim of this study was to explore the ethnic specific expression (Swedish and Iraqi) of a panel of 14 previously identified miRNAs in patients without T2D (including those with prediabetes) and T2D. METHODS A total of 152 individuals were included in the study (84 Iraqis and 68 Swedes). Nineteen Iraqis and 14 Swedes were diagnosed with T2D. Expression of the 14 selected miRNAs (miR-15a, miR-20, miR-21, miR-24, miR-29b, miR-126, miR-144, miR-150, miR-197, miR-223, miR-191, miR-320a, miR-486-5p, and miR-28-3p) in plasma samples was measured by real-time PCR. RESULTS In the whole study population, the expression of miR-24 and miR-29b was significantly different between T2D patients and controls after adjustment for age, sex, waist circumference, family history of T2D, and a sedentary lifestyle. Interestingly, when stratifying the study population according to country of birth, we found that higher expression of miR-144 was significantly associated with T2D in Swedes (OR = 2.43, p = 0.035), but not in Iraqis (OR = 0.54, p = 0.169). The interaction test was significant (p = 0.017). CONCLUSION This study suggests that the association between plasma miR-144 expression and T2D differs between Swedes and Iraqis.
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Affiliation(s)
- Xiao Wang
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
- Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California, United States of America
| | - Bengt Zöller
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Ashfaque A. Memon
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Karolina Palmér
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
- Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California, United States of America
| | - Louise Bennet
- Center for Primary Health Care Research, Lund University/Region Skåne, Sweden
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Ions LJ, Wakeling LA, Bosomworth HJ, Hardyman JEJ, Escolme SM, Swan DC, Valentine RA, Mathers JC, Ford D. Effects of Sirt1 on DNA methylation and expression of genes affected by dietary restriction. AGE (DORDRECHT, NETHERLANDS) 2013; 35:1835-1849. [PMID: 23229445 PMCID: PMC3776097 DOI: 10.1007/s11357-012-9485-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Accepted: 10/23/2012] [Indexed: 05/30/2023]
Abstract
Changes in DNA methylation across the life course may contribute to the ageing process. We hypothesised that some effects of dietary restriction to extend lifespan and/or mitigate against features of ageing result from changes in DNA methylation, so we determined if genes that respond to dietary restriction also show age-related changes in DNA methylation. In support of our hypothesis, the intersection of lists of genes compiled from published sources that (1) were differentially expressed in response to dietary restriction and (2) showed altered methylation with increased age was greater than expected. We also hypothesised that some effects of Sirt1, which may play a pivotal role in beneficial effects of dietary restriction, are mediated through DNA methylation. We thus measured effects of Sirt1 overexpression and knockdown in a human cell line on DNA methylation and expression of a panel of eight genes that respond to dietary restriction and show altered methylation with age. Six genes were affected at the level of DNA methylation, and for six expressions were affected. In further support of our hypothesis, we observed by DNA microarray analysis that genes showing differential expression in response to Sirt1 knockdown were over-represented in the complied list of genes that respond to dietary restriction. The findings reveal that Sirt1 has effects on DNA methylation across the genome and affects, in particular, the expression of genes that respond to dietary restriction. Sirt1-mediated effects on DNA methylation and, consequently, gene expression may thus be one of the mechanisms underlying the response to dietary restriction.
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Affiliation(s)
- Laura J Ions
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
| | - Luisa A Wakeling
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
| | - Helen J Bosomworth
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
- />School of Dental Sciences, Newcastle University, Newcastle upon Tyne, NE2 4BW UK
| | - Joy EJ Hardyman
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
| | - Suzanne M Escolme
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
| | - Daniel C Swan
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
| | - Ruth A Valentine
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
- />School of Dental Sciences, Newcastle University, Newcastle upon Tyne, NE2 4BW UK
| | - John C Mathers
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
| | - Dianne Ford
- />Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, NE2 4NN UK
- />Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL UK
- />Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH UK
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Tzika AA, Constantinou C, Bandyopadhaya A, Psychogios N, Lee S, Mindrinos M, Martyn JAJ, Tompkins RG, Rahme LG. A small volatile bacterial molecule triggers mitochondrial dysfunction in murine skeletal muscle. PLoS One 2013; 8:e74528. [PMID: 24098655 PMCID: PMC3787027 DOI: 10.1371/journal.pone.0074528] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Accepted: 08/03/2013] [Indexed: 01/06/2023] Open
Abstract
Mitochondria integrate distinct signals that reflect specific threats to the host, including infection, tissue damage, and metabolic dysfunction; and play a key role in insulin resistance. We have found that the Pseudomonas aeruginosa quorum sensing infochemical, 2-amino acetophenone (2-AA), produced during acute and chronic infection in human tissues, including in the lungs of cystic fibrosis (CF) patients, acts as an interkingdom immunomodulatory signal that facilitates pathogen persistence, and host tolerance to infection. Transcriptome results have led to the hypothesis that 2-AA causes further harm to the host by triggering mitochondrial dysfunction in skeletal muscle. As normal skeletal muscle function is essential to survival, and is compromised in many chronic illnesses, including infections and CF-associated muscle wasting, we here determine the global effects of 2-AA on skeletal muscle using high-resolution magic-angle-spinning (HRMAS), proton (1H) nuclear magnetic resonance (NMR) metabolomics, in vivo31P NMR, whole-genome expression analysis and functional studies. Our results show that 2-AA when injected into mice, induced a biological signature of insulin resistance as determined by 1H NMR analysis-, and dramatically altered insulin signaling, glucose transport, and mitochondrial function. Genes including Glut4, IRS1, PPAR-γ, PGC1 and Sirt1 were downregulated, whereas uncoupling protein UCP3 was up-regulated, in accordance with mitochondrial dysfunction. Although 2-AA did not alter high-energy phosphates or pH by in vivo31P NMR analysis, it significantly reduced the rate of ATP synthesis. This affect was corroborated by results demonstrating down-regulation of the expression of genes involved in energy production and muscle function, and was further validated by muscle function studies. Together, these results further demonstrate that 2-AA, acts as a mediator of interkingdom modulation, and likely effects insulin resistance associated with a molecular signature of mitochondrial dysfunction in skeletal muscle. Reduced energy production and mitochondrial dysfunctional may further favor infection, and be an important step in the establishment of chronic and persistent infections.
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Affiliation(s)
- A. Aria Tzika
- Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Athinoula A. Martinos Center of Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
- * E-mail: (AAT); (LGR)
| | - Caterina Constantinou
- Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
| | - Arunava Bandyopadhaya
- Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
| | - Nikolaos Psychogios
- Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Athinoula A. Martinos Center of Biomedical Imaging, Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
| | - Sangseok Lee
- Department of Anesthesiology and Critical Care, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
| | - Michael Mindrinos
- Department of Biochemistry, Stanford University School of Medicine, Stanford, California, United States of America
| | - J. A. Jeevendra Martyn
- Department of Anesthesiology and Critical Care, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
| | - Ronald G. Tompkins
- Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Laurence G. Rahme
- Department of Surgery, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, United States of America
- Shriners Hospitals for Children Boston, Boston, Massachusetts, United States of America
- * E-mail: (AAT); (LGR)
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Song YS, Lee SK, Jang YJ, Park HS, Kim JH, Lee YJ, Heo YS. Association between low SIRT1 expression in visceral and subcutaneous adipose tissues and metabolic abnormalities in women with obesity and type 2 diabetes. Diabetes Res Clin Pract 2013; 101:341-8. [PMID: 23876548 DOI: 10.1016/j.diabres.2013.07.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 05/20/2013] [Accepted: 07/01/2013] [Indexed: 01/02/2023]
Abstract
AIMS To assess the importance of adipose tissue sirtuin 1 (SIRT1) in the regulation of whole-body metabolism in humans with obesity and type 2 diabetes. METHODS In total, 19 non-diabetic obese women, 19 type 2 diabetic women undergoing gastric bypass surgery, and 27 normal-weight women undergoing gynecological surgery (total 65 women) were enrolled. Their anthropometric variables, abdominal fat distribution and metabolic parameters, serum adiponectin concentrations, and SIRT1 mRNA and protein and adiponectin mRNA expressions in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured. RESULTS SIRT1 mRNA levels in VAT and SAT were similar and these levels were suppressed in obese and type 2 diabetic women compared to normal-weight subjects. These decreases in SIRT1 expression were observed in both adipocytes and non-fat cells. There was a strong association between adipose tissue SIRT1 mRNA and protein levels. Adipose SIRT1 expression correlated inversely with HOMA-IR and other insulin resistance-related parameters. Adipose SIRT1 and adiponectin mRNA expression correlated very strongly and positively. SIRT1 mRNA level in VAT correlated inversely with visceral obesity whereas its expression in SAT correlated negatively with body mass index. CONCLUSIONS Adipose tissue SIRT1 may play a key role in the regulation of whole body metabolic homeostasis in humans. Downregulation of SIRT1 in VAT may contribute to the metabolic abnormalities that are associated with visceral obesity.
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Affiliation(s)
- Young Sook Song
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
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Timmers S, Hesselink MK, Schrauwen P. Therapeutic potential of resveratrol in obesity and type 2 diabetes: new avenues for health benefits? Ann N Y Acad Sci 2013; 1290:83-9. [DOI: 10.1111/nyas.12185] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
| | - Matthijs K.C. Hesselink
- Department of Human Movement Sciences; NUTRIM School for Nutrition; Toxicology and Metabolism; Maastricht University Medical Center; Maastricht the Netherlands
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Chen YR, Lai YL, Lin SD, Li XT, Fu YC, Xu WC. SIRT1 interacts with metabolic transcriptional factors in the pancreas of insulin-resistant and calorie-restricted rats. Mol Biol Rep 2013; 40:3373-80. [PMID: 23292098 DOI: 10.1007/s11033-012-2412-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2012] [Accepted: 12/18/2012] [Indexed: 02/05/2023]
Abstract
Sirtuin 1 (SIRT1) is one member of the silent information regulator 2 (Sir2)-like family of proteins involved in glucose homeostasis in mammals. It has been reported that SIRT1 modulates endocrine signaling of glucose and fat homeostasis by regulating transcription factors such as forkhead transcription factor 3a (FOXO3a), glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and PPARγ coactivator (PGC-1α). However, it is still not clear how SIRT1 is involved in the development of insulin resistance. To determine the location and expression of SIRT1 and its target proteins in rats and analyze the interactions and functions of these proteins in insulin resistance. Forty-eight male Sprague-Dawley rats were randomly divided into four regimen groups: normal control (NC), calorie restriction (CR), high-fat (HFa), and high-fructose (HFr). Animals were fed for 12 weeks and blood samples collected from tail veins at weeks 2, 4, 6, 8 and 12 after fasting for 16 h. Baseline metabolic parameters such as fasting blood sugar, insulin, cholesterol and triglycerides were analyzed. A glucose tolerance test was carried out at the end of the study. Visceral fat, consisting of epididymis and perirenal fat, was isolated and weighed. The pancreas from each animal was also immediately removed. Immunohistochemical staining was performed to detect the locations of SIRT1, FOXO3a, GLUT4, PPARγ and PGC-1α in the β-cell of the rat pancreas. Expression in the pancreas was analyzed by western blotting. Blood biochemical analysis indicated that the HFa and HFr groups were insulin-resistant. Immunohistochemical staining showed that GLUT4 was a nuclear protein. SIRT1, FOXO3a, PPARγ and PGC-1α were present in both the nucleus and the cytoplasm of β-cells of pancreatic islets. The expression of SIRT1, GLUT4 and PGC-1α increased significantly in response to CR, but decreased in the HFr and HFa groups. FOXO3a was similar in the CR and the NC groups, whereas it declined in the HFa and HFr groups. PPARγ was elevated in the HFa group, but dropped in the CR and HFr groups. These data suggest that SIRT1 and its regulators are involved in the development of insulin resistance.
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Affiliation(s)
- Yong-Ru Chen
- Intensive Care Unit (ICU), The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
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Hwang YP, Choi JH, Kim HG, Khanal T, Song GY, Nam MS, Lee HS, Chung YC, Lee YC, Jeong HG. Saponins, especially platycodin D, from Platycodon grandiflorum modulate hepatic lipogenesis in high-fat diet-fed rats and high glucose-exposed HepG2 cells. Toxicol Appl Pharmacol 2013; 267:174-83. [DOI: 10.1016/j.taap.2013.01.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 12/21/2012] [Accepted: 01/02/2013] [Indexed: 11/28/2022]
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