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1
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Futatsugi M, Miyazaki A, Kanai Y, Kondo N, Temma T. Fluorine-18-Labeled Positron Emission Tomography Probe Targeting Activated p38α: Design, Synthesis, and In Vivo Evaluation in Rodents. Pharmaceuticals (Basel) 2025; 18:600. [PMID: 40284035 PMCID: PMC12030359 DOI: 10.3390/ph18040600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: The kinase p38α, a member of the mitogen-activated protein kinase (MAPK) family, is activated by external stimuli and plays a crucial role in inflammation, tumor growth, and metabolic disorders. In particular, p38α is involved in thermogenesis and the metabolism of glucose in brown adipose tissue (BAT), and it contributes to the suppression of obesity and diabetes. The noninvasive imaging of activated p38α could help elucidate diverse pathological processes, including metabolic and inflammatory conditions. This study aimed to develop and evaluate a novel fluorine-18-labeled positron emission tomography (PET) probe for imaging activated p38α in vivo. Methods: We designed 6-(4-[18F]fluoro-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([18F]R1487) by replacing a fluorine atom in R1487, which is a highly selective p38α inhibitor, with 18F. A tributylstannyl precursor was reacted with [18F]KF in the presence of a copper catalyst to synthesize [18F]R1487. Biodistribution studies and PET/computed tomography (CT) were performed on normal mice to evaluate the in vivo potential of [18F]R1487. Results: [18F]R1487 was obtained with a decay-corrected radiochemical conversion of 30.6 ± 5.6% and a decay-corrected radiochemical yield of 6.9 ± 3.6% with a radiochemical purity of >99% after reversed-phase high-performance liquid chromatography purification. The biodistribution study demonstrated high and rapid radioactivity accumulation in BAT (16.3 ± 2.7 %ID/g at 5 min post-injection), with a consistently high BAT-to-blood ratio (>5 over 2 h post-injection). PET/CT imaging successfully visualized BAT with high contrast. Conclusions: These results suggest that [18F]R1487 is a promising PET probe for imaging activated p38α in vivo, which has potential applications for pathophysiological conditions such as inflammation, cancer, and metabolic disorders.
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Affiliation(s)
- Mikiya Futatsugi
- Department of Biofunctional Analysis, Graduate School of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan; (M.F.); (A.M.); (N.K.)
| | - Anna Miyazaki
- Department of Biofunctional Analysis, Graduate School of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan; (M.F.); (A.M.); (N.K.)
| | - Yasukazu Kanai
- Kansai BNCT Medical Center, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan;
| | - Naoya Kondo
- Department of Biofunctional Analysis, Graduate School of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan; (M.F.); (A.M.); (N.K.)
- Division of Fundamental Technology Development, Near InfraRed Photo-ImmunoTherapy Research Institute, Kansai Medical University, 2-5-1 Shin-machi, Hirakata 573-1010, Osaka, Japan
| | - Takashi Temma
- Department of Biofunctional Analysis, Graduate School of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan; (M.F.); (A.M.); (N.K.)
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Peng Y, Jia L, Hu X, Shi X, Fang X, Qiu Y, Gan Z, Wang Y. Cellular Feimin enhances exercise performance by suppressing muscle thermogenesis. Nat Metab 2025; 7:84-101. [PMID: 39747484 DOI: 10.1038/s42255-024-01176-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 11/05/2024] [Indexed: 01/04/2025]
Abstract
Exercise can rapidly increase core body temperature, and research has indicated that elevated internal body temperature can independently contribute to fatigue during physical activity. However, the precise mechanisms responsible for regulating thermogenesis in muscles during exercise have remained unclear. Here, we demonstrate that cellular Feimin (cFeimin) enhances exercise performance by inhibiting muscle thermogenesis during physical activity. Mechanistically, we found that AMP-activated protein kinase (AMPK) phosphorylates cFeimin and facilitates its translocation into the cell nucleus during exercise. Within the nucleus, cFeimin binds to the forkhead transcription factor FOXC2, leading to the suppressed expression of sarcolipin (Sln), which is a key regulator of muscle thermogenesis. In addition, our results further reveal that short-term AMPK agonist treatments can enhance exercise performance through the activation of the AMPK-cFeimin signalling pathway. In summary, these results underscore the crucial role of cFeimin in enhancing exercise performance by modulating SLN-mediated thermogenesis.
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Affiliation(s)
- Ying Peng
- State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Liangjie Jia
- State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Xiao Hu
- State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Xiaoliu Shi
- State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Xinlei Fang
- State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Yifu Qiu
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Zhenji Gan
- State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, China
| | - Yiguo Wang
- State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
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3
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Vakili S, Cao K. Angiopoietin-2: A Therapeutic Target for Vascular Protection in Hutchinson-Gilford Progeria Syndrome. Int J Mol Sci 2024; 25:13537. [PMID: 39769300 PMCID: PMC11676795 DOI: 10.3390/ijms252413537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a pediatric condition characterized by clinical features that resemble accelerated aging. The abnormal accumulation of a toxic form of the lamin A protein known as progerin disrupts cellular functions, leading to various complications, including growth retardation, loss of subcutaneous fat, abnormal skin, alopecia, osteoporosis, and progressive joint contractures. Death primarily occurs as the result of complications from progressive atherosclerosis, especially from cardiac disease, such as myocardial infarction or heart failure, or cerebrovascular disease like stroke. Despite the availability of lonafarnib, the only US Food and Drug Administration-approved treatment for HGPS, cardiovascular complications remain the leading cause of morbidity and mortality in affected patients. Defective angiogenesis-the process of forming new blood vessels from existing ones-plays a crucial role in the development of cardiovascular disease. A recent study suggests that Angiopoietin-2 (Ang2), a pro-angiogenic growth factor that regulates angiogenesis and vascular stability, may offer therapeutic potential for the treatment of HGPS. In this review, we describe the clinical features and key cellular processes impacted by progerin and discuss the therapeutic potential of Ang2 in addressing these challenges.
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Affiliation(s)
| | - Kan Cao
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA;
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4
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Alur V, Vastrad B, Raju V, Vastrad C, Kotturshetti S. The identification of key genes and pathways in polycystic ovary syndrome by bioinformatics analysis of next-generation sequencing data. MIDDLE EAST FERTILITY SOCIETY JOURNAL 2024; 29:53. [DOI: 10.1186/s43043-024-00212-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/17/2024] [Indexed: 01/02/2025] Open
Abstract
Abstract
Background
Polycystic ovary syndrome (PCOS) is a reproductive endocrine disorder. The specific molecular mechanism of PCOS remains unclear. The aim of this study was to apply a bioinformatics approach to reveal related pathways or genes involved in the development of PCOS.
Methods
The next-generation sequencing (NGS) dataset GSE199225 was downloaded from the gene expression omnibus (GEO) database and NGS dataset analyzed is obtained from in vitro culture of PCOS patients’ muscle cells and muscle cells of healthy lean control women. Differentially expressed gene (DEG) analysis was performed using DESeq2. The g:Profiler was utilized to analyze the gene ontology (GO) and REACTOME pathways of the differentially expressed genes. A protein–protein interaction (PPI) network was constructed and module analysis was performed using HiPPIE and cytoscape. The miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed. The hub genes were validated by using receiver operating characteristic (ROC) curve analysis.
Results
We have identified 957 DEG in total, including 478 upregulated genes and 479 downregulated gene. GO terms and REACTOME pathways illustrated that DEG were significantly enriched in regulation of molecular function, developmental process, interferon signaling and platelet activation, signaling, and aggregation. The top 5 upregulated hub genes including HSPA5, PLK1, RIN3, DBN1, and CCDC85B and top 5 downregulated hub genes including DISC1, AR, MTUS2, LYN, and TCF4 might be associated with PCOS. The hub gens of HSPA5 and KMT2A, together with corresponding predicted miRNAs (e.g., hsa-mir-34b-5p and hsa-mir-378a-5p), and HSPA5 and TCF4 together with corresponding predicted TF (e.g., RCOR3 and TEAD4) were found to be significantly correlated with PCOS.
Conclusions
These study uses of bioinformatics analysis of NGS data to obtain hub genes and key signaling pathways related to PCOS and its associated complications. Also provides novel ideas for finding biomarkers and treatment methods for PCOS and its associated complications.
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Hemat Jouy S, Mohan S, Scichilone G, Mostafa A, Mahmoud AM. Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases. Biomedicines 2024; 12:2129. [PMID: 39335642 PMCID: PMC11428859 DOI: 10.3390/biomedicines12092129] [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: 08/25/2024] [Revised: 09/14/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent decades as a multifunctional organ that plays a significant role in energy metabolism and homeostasis. Currently, it is evident that adipose tissue primarily performs its function by secreting a diverse array of signaling molecules known as adipokines. Apart from their pivotal function in energy expenditure and metabolism regulation, these adipokines exert significant influence over a multitude of biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, and insulin sensitivity. Adipokines are pivotal in regulating numerous biological processes within adipose tissue and facilitating communication between adipose tissue and various organs, including the brain, gut, pancreas, endothelial cells, liver, muscle, and more. Dysregulated adipokines have been implicated in several metabolic diseases, like obesity and diabetes, as well as cardiovascular diseases. In this article, we attempted to describe the significance of adipokines in developing metabolic and cardiovascular diseases and highlight their role in the crosstalk between adipose tissues and other tissues and organs.
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Affiliation(s)
- Shaghayegh Hemat Jouy
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Central Tehran Branch, Islamic Azad University, Tehran 14778-93855, Iran;
| | - Sukrutha Mohan
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (S.M.); (G.S.)
| | - Giorgia Scichilone
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (S.M.); (G.S.)
| | - Amro Mostafa
- Department of Pharmacology, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA;
| | - Abeer M. Mahmoud
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA; (S.M.); (G.S.)
- Department of Kinesiology and Nutrition, College of Applied Health Sciences, University of Illinois Chicago, Chicago, IL 60612, USA
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Yang Y, Li M, Zhu Y, Wang X, Chen Q, Lu S. Identification of potential tissue-specific biomarkers involved in pig fat deposition through integrated bioinformatics analysis and machine learning. Heliyon 2024; 10:e31311. [PMID: 38807889 PMCID: PMC11130688 DOI: 10.1016/j.heliyon.2024.e31311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 05/30/2024] Open
Abstract
Backfat thickness (BT) and intramuscular fat (IMF) content are closely appertained to meat production and quality in pig production. Deposition in subcutaneous adipose (SA) and IMF concerns different genes and regulatory mechanisms. And larger studies with rigorous design should be carried to explore the molecular regulation of fat deposition in different tissues. The purpose of this study is to gain a better understanding of the molecular mechanisms underlying differences in fat deposition among different tissues and identify tissue-specific genes involved in regulating fat deposition. The SA-associated datasets (GSE122349 and GSE145956) and IMF-associated datasets (GSE165613 and GSE207279) were downloaded from the Gene Expression Omnibus (GEO) as the BT and IMF group, respectively. Subsequently, the Robust Rank Aggregation (RRA) algorithm identified 27 down- and 29 up-regulated differentially expressed genes (DEGs) in the BT group. Based on bioinformatics and three machine learning algorithms, four SA deposition-related potential biomarkers, namely ACLY, FASN, ME1, and ARVCF were selected. FASN was evaluated as the most valuable biomarker for the SA mechanism. The 18 down- and 34 up-regulated DEGs in the IMF group were identified, and ACTA2 and HMGCL were screened as the IMF deposition-related candidate core genes, especially the ACTA2 may play the critical role in IMF deposition regulation. Moreover, based on the constructed ceRNA network, we postulated that the role of predicted ceRNA interaction network of XIST, NEAT1/miR-15a-5p, miR-16-5p, miR-424-5p, miR-497-5p/FASN were vital in the SA metabolism, XIST, NEAT1/miR-27a/b-3p, 181a/c-5p/ACTA2 might contribute to the regulation to IMF metabolism, which all gave suggestions in molecular mechanism for regulation of fat deposition. These findings may facilitate advancements in porcine quality at the genetic and molecular levels and assist with human obesity-associated diseases.
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Affiliation(s)
| | | | - Yixuan Zhu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, 650201, Yunnan, China
| | - Xiaoyi Wang
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, 650201, Yunnan, China
| | - Qiang Chen
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, 650201, Yunnan, China
| | - Shaoxiong Lu
- Faculty of Animal Science and Technology, Yunnan Agricultural University, Kunming, 650201, Yunnan, China
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7
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Holman CD, Sakers AP, Calhoun RP, Cheng L, Fein EC, Jacobs C, Tsai L, Rosen ED, Seale P. Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming. eLife 2024; 12:RP87756. [PMID: 38775132 PMCID: PMC11111218 DOI: 10.7554/elife.87756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2024] Open
Abstract
The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process in mice. We found that aging increases the expression of Cd9 and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro, suggesting that environmental factors suppress adipogenesis in vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with aging and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified Npr3, which encodes the natriuretic peptide clearance receptor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a resource for identifying cold and aging-regulated pathways in adipose tissue.
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Affiliation(s)
- Corey D Holman
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Alexander P Sakers
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Ryan P Calhoun
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Lan Cheng
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Ethan C Fein
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
| | - Christopher Jacobs
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Broad Institute of MIT and HarvardCambridgeUnited States
| | - Linus Tsai
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Broad Institute of MIT and HarvardCambridgeUnited States
- Harvard Medical SchoolBostonUnited States
| | - Evan D Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Broad Institute of MIT and HarvardCambridgeUnited States
- Harvard Medical SchoolBostonUnited States
| | - Patrick Seale
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUnited States
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8
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Khan AQ, Hasan A, Mir SS, Rashid K, Uddin S, Steinhoff M. Exploiting transcription factors to target EMT and cancer stem cells for tumor modulation and therapy. Semin Cancer Biol 2024; 100:1-16. [PMID: 38503384 DOI: 10.1016/j.semcancer.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024]
Abstract
Transcription factors (TFs) are essential in controlling gene regulatory networks that determine cellular fate during embryogenesis and tumor development. TFs are the major players in promoting cancer stemness by regulating the function of cancer stem cells (CSCs). Understanding how TFs interact with their downstream targets for determining cell fate during embryogenesis and tumor development is a critical area of research. CSCs are increasingly recognized for their significance in tumorigenesis and patient prognosis, as they play a significant role in cancer initiation, progression, metastasis, and treatment resistance. However, traditional therapies have limited effectiveness in eliminating this subset of cells, allowing CSCs to persist and potentially form secondary tumors. Recent studies have revealed that cancer cells and tumors with CSC-like features also exhibit genes related to the epithelial-to-mesenchymal transition (EMT). EMT-associated transcription factors (EMT-TFs) like TWIST and Snail/Slug can upregulate EMT-related genes and reprogram cancer cells into a stem-like phenotype. Importantly, the regulation of EMT-TFs, particularly through post-translational modifications (PTMs), plays a significant role in cancer metastasis and the acquisition of stem cell-like features. PTMs, including phosphorylation, ubiquitination, and SUMOylation, can alter the stability, localization, and activity of EMT-TFs, thereby modulating their ability to drive EMT and stemness properties in cancer cells. Although targeting EMT-TFs holds potential in tackling CSCs, current pharmacological approaches to do so directly are unavailable. Therefore, this review aims to explore the role of EMT- and CSC-TFs, their connection and impact in cellular development and cancer, emphasizing the potential of TF networks as targets for therapeutic intervention.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow 226026, India
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India
| | - Khalid Rashid
- Department of Urology,Feinberg School of Medicine, Northwestern University, 303 E Superior Street, Chicago, IL 60611, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India; Laboratory Animal Research Center, Qatar University, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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Holman CD, Sakers AP, Calhoun RP, Cheng L, Fein EC, Jacobs C, Tsai L, Rosen ED, Seale P. Aging impairs cold-induced beige adipogenesis and adipocyte metabolic reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.03.20.533514. [PMID: 36993336 PMCID: PMC10055201 DOI: 10.1101/2023.03.20.533514] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
The energy-burning capability of beige adipose tissue is a potential therapeutic tool for reducing obesity and metabolic disease, but this capacity is decreased by aging. Here, we evaluate the impact of aging on the profile and activity of adipocyte stem and progenitor cells (ASPCs) and adipocytes during the beiging process. We found that aging increases the expression of Cd9 and other fibro-inflammatory genes in fibroblastic ASPCs and blocks their differentiation into beige adipocytes. Fibroblastic ASPC populations from young and aged mice were equally competent for beige differentiation in vitro, suggesting that environmental factors suppress adipogenesis in vivo. Examination of adipocytes by single nucleus RNA-sequencing identified compositional and transcriptional differences in adipocyte populations with age and cold exposure. Notably, cold exposure induced an adipocyte population expressing high levels of de novo lipogenesis (DNL) genes, and this response was severely blunted in aged animals. We further identified natriuretic peptide clearance receptor Npr3, a beige fat repressor, as a marker gene for a subset of white adipocytes and an aging-upregulated gene in adipocytes. In summary, this study indicates that aging blocks beige adipogenesis and dysregulates adipocyte responses to cold exposure and provides a unique resource for identifying cold and aging-regulated pathways in adipose tissue.
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Affiliation(s)
- Corey D. Holman
- Institute for Diabetes, Obesity & Metabolism; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Alexander P. Sakers
- Institute for Diabetes, Obesity & Metabolism; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Ryan P. Calhoun
- Institute for Diabetes, Obesity & Metabolism; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Lan Cheng
- Institute for Diabetes, Obesity & Metabolism; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Ethan C. Fein
- Institute for Diabetes, Obesity & Metabolism; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher Jacobs
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Linus Tsai
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Evan D. Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Patrick Seale
- Institute for Diabetes, Obesity & Metabolism; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology; Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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Huang J, Zhang Y, Zhou X, Song J, Feng Y, Qiu T, Sheng S, Zhang M, Zhang X, Hao J, Zhang L, Zhang Y, Li X, Liu M, Chang Y. Foxj3 Regulates Thermogenesis of Brown and Beige Fat Via Induction of PGC-1α. Diabetes 2024; 73:178-196. [PMID: 37939221 DOI: 10.2337/db23-0454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 10/29/2023] [Indexed: 11/10/2023]
Abstract
Enhancing the development of and thermogenesis in brown and beige fat represents a potential treatment for obesity. In this study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impaired the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice displayed increased fasting blood glucose levels and hepatic steatosis while on a chow diet. Foxj3 deficiency inhibited the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduced the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhanced the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and iWAT increased energy expenditure and improved systemic metabolism on either a chow or high-fat diet. Finally, Foxj3 deletion in fat inhibited the β3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulated the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. This study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Jincan Huang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Yujie Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Xuenan Zhou
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jiani Song
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Yueyao Feng
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Tongtong Qiu
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Sufang Sheng
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Menglin Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Xi Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jingran Hao
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Lei Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Yinliang Zhang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Ming Liu
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
| | - Yongsheng Chang
- Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
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11
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Matsumura Y, Osborne TF, Ito R, Takahashi H, Sakai J. β-Adrenergic Signal and Epigenomic Regulatory Process for Adaptive Thermogenesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1461:213-227. [PMID: 39289284 DOI: 10.1007/978-981-97-4584-5_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Activation of β-adrenergic (β-AR) signaling induces fight-or-flight stress responses which include enhancement of cardiopulmonary function, metabolic regulation, and muscle contraction. Classical dogma for β-AR signaling has dictated that the receptor-mediated response results in an acute and transient signal. However, more recent studies support more wide-ranging roles for β-AR signaling with long-term effects including cell differentiation that requires precisely timed and coordinated integration of many signaling pathways that culminate in precise epigenomic chromatin modifications. In this chapter, we discuss cold stress/β-AR signaling-induced epigenomic changes in adipose tissues that influence adaptive thermogenesis. We highlight recent studies showing dual roles for the histone demethylase JMJD1A as a mediator of both acute and chronic thermogenic responses to cold stress, in two distinct thermogenic tissues, and through two distinct molecular mechanisms. β-AR signaling not only functions through transient signals during acute stress responses but also relays a more sustained signal to long-term adaptation to environmental changes.
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Affiliation(s)
- Yoshihiro Matsumura
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, Akita, Japan
| | - Timothy F Osborne
- Institute for Fundamental Biomedical Research Division of Endocrinology, Diabetes and Metabolism Johns Hopkins University School of Medicine, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA
| | - Ryo Ito
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroki Takahashi
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Juro Sakai
- Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
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12
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Kang Q, Zhu X, Ren D, Ky A, MacDougald OA, O'Rourke RW, Rui L. Adipose METTL14-Elicited N 6 -Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing β Adrenergic Signaling and Lipolysis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301645. [PMID: 37526326 PMCID: PMC10558699 DOI: 10.1002/advs.202301645] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/08/2023] [Indexed: 08/02/2023]
Abstract
White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N6 -methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts' m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.
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Affiliation(s)
- Qianqian Kang
- Department of Molecular and Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Elizabeth Weiser Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| | - Xiaorong Zhu
- Department of Molecular and Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Department of EndocrinologyBeijing Tongren HospitalCapital Medical UniversityBeijing Diabetes InstituteBeijing100730China
| | - Decheng Ren
- Department of MedicineUniversity of ChicagoChicagoIL60637USA
| | - Alexander Ky
- Department of SurgeryUniversity of Michigan Medical SchoolAnn ArborMI48109USA
| | - Ormond A. MacDougald
- Department of Molecular and Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Elizabeth Weiser Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
- Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMI48109USA
| | - Robert W. O'Rourke
- Department of SurgeryUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Department of SurgeryVeterans Affairs Ann Arbor Healthcare SystemAn ArborMI48105USA
| | - Liangyou Rui
- Department of Molecular and Integrative PhysiologyUniversity of Michigan Medical SchoolAnn ArborMI48109USA
- Elizabeth Weiser Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
- Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMI48109USA
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13
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Merli GJ, Yenser H, Orapallo D. Approach to the Patient with Non-cardiac Leg Swelling. Med Clin North Am 2023; 107:945-961. [PMID: 37541718 DOI: 10.1016/j.mcna.2023.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/06/2023]
Abstract
One of the most common reasons for patient visits in the outpatient practice is lower extremity swelling. Non-cardiac etiologies are the most frequent reason for these encounters. The approach to this patient population will focus on the 7 key questions to initiate the gathering of historical information on the etiology of leg swelling. Figures and tables will complement the text for diagnosing lower extremity swelling. In this article, the common non-cardiac etiologies will be reviewed which include medications, chronic venous insufficiency, lymphatic disease, lipedema, venous thrombosis, and musculoskeletal etiologies.
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Affiliation(s)
- Geno J Merli
- Division Vascular Medicine, Jefferson Vascular Center, Sidney Kimmel Medical College, Thomas Jefferson University Hospitals, Suite 6210, Gibbon Building, 111 South 11th Street, Philadelphia, PA 19107, USA.
| | - Heather Yenser
- Division of Vascular Medicine, Department of Surgery, Jefferson Vascular Center, Sidney Kimmel Medical College, Thomas Jefferson University Hospitals, Suite 6210, Gibbon Building, 111 South 11th Street, Philadelphia, PA 19107, USA
| | - Dina Orapallo
- Division of Vascular Medicine, Department of Surgery, Jefferson Vascular Center, Sidney Kimmel Medical College, Thomas Jefferson University Hospitals, Suite 6210, Gibbon Building, 111 South 11th Street, Philadelphia, PA 19107, USA
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14
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Hu AJ, Li W, Pathak A, Hu GF, Hou X, Farmer SR, Hu MG. CDK6 is essential for mesenchymal stem cell proliferation and adipocyte differentiation. Front Mol Biosci 2023; 10:1146047. [PMID: 37664186 PMCID: PMC10469316 DOI: 10.3389/fmolb.2023.1146047] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 08/08/2023] [Indexed: 09/05/2023] Open
Abstract
Background: Overweight or obesity poses a significant risk of many obesity-related metabolic diseases. Among all the potential new therapies, stem cell-based treatments hold great promise for treating many obesity-related metabolic diseases. However, the mechanisms regulating adipocyte stem cells/progenitors (precursors) are unknown. The aim of this study is to investigate if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation. Methods: Cyclin-dependent kinase 6 (Cdk6) mouse models together with stem cells derived from stromal vascular fraction (SVF) or mouse embryonic fibroblasts (MEFs) of Cdk6 mutant mice were used to determine if CDK6 is required for mesenchymal stem cell proliferation and adipocyte differentiation. Results: We found that mice with a kinase inactive CDK6 mutants (K43M) had fewer precursor residents in the SVF of adult white adipose tissue (WAT). Stem cells from the SVF or MEFs of K43M mice had defects in proliferation and differentiation into the functional fat cells. In contrast, mice with a constitutively active kinase CDK6 mutant (R31C) had the opposite traits. Ablation of RUNX1 in both mature and precursor K43M cells, reversed the phenotypes. Conclusion: These results represent a novel role of CDK6 in regulating precursor numbers, proliferation, and differentiation, suggesting a potential pharmacological intervention for using CDK6 inhibitors in the treatment of obesity-related metabolic diseases.
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Affiliation(s)
- Alexander J. Hu
- Division of Hematology and Oncology, Tufts Medical Center, Department of Medicine, Boston, MA, United States
- Department of Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, United States
| | - Wei Li
- Division of Hematology and Oncology, Tufts Medical Center, Department of Medicine, Boston, MA, United States
- National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Apana Pathak
- Division of Hematology and Oncology, Tufts Medical Center, Department of Medicine, Boston, MA, United States
- Assay Research and Development Department, GRAIL LLC, Menlo Park, CA, United States
| | - Guo-Fu Hu
- Division of Hematology and Oncology, Tufts Medical Center, Department of Medicine, Boston, MA, United States
| | - Xiaoli Hou
- Division of Hematology and Oncology, Tufts Medical Center, Department of Medicine, Boston, MA, United States
- Center for Analysis and Testing, Zhejiang Chinese Medical University, Hangzhou, China
| | - Stephen R. Farmer
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, United States
| | - Miaofen G. Hu
- Division of Hematology and Oncology, Tufts Medical Center, Department of Medicine, Boston, MA, United States
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15
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Shu H, Zhang J, Cheng D, Zhao X, Ma Y, Zhang C, Zhang Y, Jia Z, Liu Z. The Role of Proton-Coupled Amino Acid Transporter 2 (SLC36A2) in Cold-Induced Thermogenesis of Mice. Nutrients 2023; 15:3552. [PMID: 37630739 PMCID: PMC10458080 DOI: 10.3390/nu15163552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Brown adipocytes mainly utilize glucose and fatty acids to produce energy, which play key roles in thermogenesis. Furthermore, brown adipocytes also utilize other substrates, such as amino acids, for energy expenditure in various conditions. Here, we report the new physiological roles of proton-coupled amino acid transporters, SLC36A2 and SLC36A3, on global energy metabolism. The relative mRNA expression levels of both Slc36a2 and Slc36a3 were all highest in brown adipose tissue. We then generated global Slc36a2 and Slc36a3 knockout mice to investigate their functions in metabolism. Neither loss of Slc36a2 nor Slc36a3 affected the body weight and body composition of the mice. Slc36a2 knockout mice exhibited increased oxygen consumption during the daytime. After cold treatment, inhibition of Slc36a2 significantly decreased the mass of brown adipose tissue compared to wildtype mice, while it lowered the expression level of Cpt1a. Moreover, the serum lipid levels and liver mass were also decreased in Slc36a2 knockout mice after cold treatment. On the contrary, Slc36a3 knockout impaired glucose tolerance and up-regulated serum LDL-cholesterol concentration. Thus, SLC36A2 and SLC36A3 play central and different roles in the energy metabolism of the mice.
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Affiliation(s)
| | | | | | | | | | | | | | - Zhihao Jia
- Cambridge-Suda Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou 215123, China; (H.S.); (J.Z.); (Y.M.); (Y.Z.)
| | - Zhiwei Liu
- Cambridge-Suda Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou 215123, China; (H.S.); (J.Z.); (Y.M.); (Y.Z.)
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16
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Gupta A, Efthymiou V, Kodani SD, Shamsi F, Patti ME, Tseng YH, Streets A. Mapping the transcriptional landscape of human white and brown adipogenesis using single-nuclei RNA-seq. Mol Metab 2023; 74:101746. [PMID: 37286033 PMCID: PMC10338377 DOI: 10.1016/j.molmet.2023.101746] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 05/24/2023] [Accepted: 05/30/2023] [Indexed: 06/09/2023] Open
Abstract
Adipogenesis is key to maintaining organism-wide energy balance and healthy metabolic phenotype, making it critical to thoroughly comprehend its molecular regulation in humans. By single-nuclei RNA-sequencing (snRNA-seq) of over 20,000 differentiating white and brown preadipocytes, we constructed a high-resolution temporal transcriptional landscape of human white and brown adipogenesis. White and brown preadipocytes were isolated from a single individual's neck region, thereby eliminating inter-subject variability across two distinct lineages. These preadipocytes were also immortalized to allow for controlled, in vitro differentiation, allowing sampling of distinct cellular states across the spectrum of adipogenic progression. Pseudotemporal cellular ordering revealed the dynamics of ECM remodeling during early adipogenesis, and lipogenic/thermogenic response during late white/brown adipogenesis. Comparison with adipogenic regulation in murine models Identified several novel transcription factors as potential targets for adipogenic/thermogenic drivers in humans. Among these novel candidates, we explored the role of TRPS1 in adipocyte differentiation and showed that its knockdown impairs white adipogenesis in vitro. Key adipogenic and lipogenic markers revealed in our analysis were applied to analyze publicly available scRNA-seq datasets; these confirmed unique cell maturation features in recently discovered murine preadipocytes, and revealed inhibition of adipogenic expansion in humans with obesity. Overall, our study presents a comprehensive molecular description of both white and brown adipogenesis in humans and provides an important resource for future studies of adipose tissue development and function in both health and metabolic disease state.
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Affiliation(s)
- Anushka Gupta
- University of California at Berkeley, University of California at San Francisco Graduate Program in Bioengineering, Berkeley, CA 94720, USA
| | - Vissarion Efthymiou
- Department of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA
| | - Sean D Kodani
- Department of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA
| | - Farnaz Shamsi
- Department of Molecular Pathobiology, New York University, New York, NY 10010, USA
| | - Mary Elizabeth Patti
- Department of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA
| | - Yu-Hua Tseng
- Department of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Aaron Streets
- University of California at Berkeley, University of California at San Francisco Graduate Program in Bioengineering, Berkeley, CA 94720, USA; Biophysics Graduate Group, University of California at Berkeley, Berkeley, CA 94720, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
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17
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Li X, McPherson M, Hager M, Lee M, Chang P, Miller RA. Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice. GeroScience 2023; 45:2495-2510. [PMID: 36920743 PMCID: PMC10651632 DOI: 10.1007/s11357-023-00770-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 03/06/2023] [Indexed: 03/16/2023] Open
Abstract
Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug.
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Affiliation(s)
- Xinna Li
- Department of Pathology, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, RoomAnn Arbor, MI, 316048109-2200, USA.
| | - Madaline McPherson
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Mary Hager
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Michael Lee
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Peter Chang
- College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Richard A Miller
- Department of Pathology, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, RoomAnn Arbor, MI, 316048109-2200, USA
- University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA
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18
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Wang C, Wang X, Hu W. Molecular and cellular regulation of thermogenic fat. Front Endocrinol (Lausanne) 2023; 14:1215772. [PMID: 37465124 PMCID: PMC10351381 DOI: 10.3389/fendo.2023.1215772] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 06/14/2023] [Indexed: 07/20/2023] Open
Abstract
Thermogenic fat, consisting of brown and beige adipocytes, dissipates energy in the form of heat, in contrast to the characteristics of white adipocytes that store energy. Increasing energy expenditure by activating brown adipocytes or inducing beige adipocytes is a potential therapeutic strategy for treating obesity and type 2 diabetes. Thus, a better understanding of the underlying mechanisms of thermogenesis provides novel therapeutic interventions for metabolic diseases. In this review, we summarize the recent advances in the molecular regulation of thermogenesis, focusing on transcription factors, epigenetic regulators, metabolites, and non-coding RNAs. We further discuss the intercellular and inter-organ crosstalk that regulate thermogenesis, considering the heterogeneity and complex tissue microenvironment of thermogenic fat.
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Affiliation(s)
- Cuihua Wang
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangdong, China
| | - Xianju Wang
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
| | - Wenxiang Hu
- GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou, China
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19
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Li W, Hu JK, Hu MG. CDK6: an attractive therapeutic target for T-ALL/LBL. Expert Opin Ther Targets 2023; 27:1087-1096. [PMID: 37975616 DOI: 10.1080/14728222.2023.2285775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 11/16/2023] [Indexed: 11/19/2023]
Abstract
INTRODUCTION Human T-cell acute lymphoblastic leukemia/T-cell lymphoblastic lymphoma (T-ALL/LBL) is a type of cancer that originates from the bone marrow and spreads quickly to other organs. Long-term survival rate with current available chemotherapy is less than 20%. Despite the potentially huge market, a truly effective and safe therapy for T-ALL/LBL is elusive. Thus, it is imperative to identify new therapeutic ways to target essential pathways in T-ALL that regulate the proliferation and survival of these cancer cells. AREAS COVERED The role of the Cyclin-dependent kinase 6 (CDK6) pathway in human T-ALL is of significant interest with major clinical/translational relevance. This review covers the recent advances in elucidating the essential roles of CDK6 and its closely regulated networks in proliferation, survival, and metabolism of T-ALL cells, with new insight into its mechanisms of action which hopefully could trigger the identification of new therapeutic avenues. EXPERT OPINION Animal models showed that inhibition of CDK6 and its related networks blocked initiation, growth, and survival of T-ALL in vivo. Numerous clinical trials of CDK4/6 inhibitors are ongoing in T-ALL. Specific CDK6 inhibitors alone or novel combination regimens may hopefully delay the progression, or even reverse the symptoms of T-ALL, leading to disease eradication and cure.
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Affiliation(s)
- Wei Li
- Department of Medicine, Division of Hematology and Oncology, Tufts Medical Center, Boston, USA
| | - Jamie Katy Hu
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Miaofen G Hu
- Department of Medicine, Division of Hematology and Oncology, Tufts Medical Center, Boston, USA
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20
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Poláková N, Lederer KA, Richter B, Panáková L. A Case Report of Presumptive Primary Lymphedema Localized to the Face of a Dog. Vet Sci 2023; 10:409. [PMID: 37505815 PMCID: PMC10385117 DOI: 10.3390/vetsci10070409] [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: 05/01/2023] [Revised: 06/09/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023] Open
Abstract
Primary lymphedema (PLE) is an uncommon diagnosis in veterinary medicine, with most of the previously described cases showing lower limb edema associated with a guarded long-term prognosis. To the authors' knowledge, this case report describes the first case of lymphedema localized unilaterally to the facial region of one-year-old German Shorthair Pointer, in which indirect CT-lymphography, combined with histopathologic examination of the skin, resulted in a tentative diagnosis of PLE.
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Affiliation(s)
- Nina Poláková
- Clinical Department for Small Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Kristina Anna Lederer
- Clinical Unit of Diagnostic Imaging, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Barbara Richter
- Institute of Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
| | - Lucia Panáková
- Clinical Department for Small Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
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21
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Eljalby M, Huang X, Becher T, Wibmer AG, Jiang CS, Vaughan R, Schöder H, Cohen P. Brown adipose tissue is not associated with cachexia or increased mortality in a retrospective study of patients with cancer. Am J Physiol Endocrinol Metab 2023; 324:E144-E153. [PMID: 36576355 PMCID: PMC9902220 DOI: 10.1152/ajpendo.00187.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/28/2022] [Accepted: 12/19/2022] [Indexed: 12/29/2022]
Abstract
Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and β-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia.NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.
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Affiliation(s)
- Mahmoud Eljalby
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Xiaojing Huang
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Tobias Becher
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
- DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany
- First Department of Medicine (Division of Cardiology), University Medical Center Mannheim, Mannheim, Germany
| | - Andreas G Wibmer
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Caroline S Jiang
- Center for Clinical and Translational Science, The Rockefeller University, New York City, New York
| | - Roger Vaughan
- Center for Clinical and Translational Science, The Rockefeller University, New York City, New York
- Graduate School of Medical Sciences, Weill Cornell Medicine, New York City, New York
| | - Heiko Schöder
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York
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22
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Chen Q, Huang L, Pan D, Hu K, Li R, Friedline RH, Kim JK, Zhu LJ, Guertin DA, Wang YX. A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis. Nat Commun 2022; 13:7633. [PMID: 36496438 PMCID: PMC9741603 DOI: 10.1038/s41467-022-35335-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
The signaling mechanisms underlying adipose thermogenesis have not been fully elucidated. Particularly, the involvement of adipokines that are selectively expressed in brown adipose tissue (BAT) and beige adipocytes remains to be investigated. Here we show that a previously uncharacterized adipokine (UPF0687 protein / human C20orf27 homolog) we named as Adissp (Adipose-secreted signaling protein) is a key regulator for white adipose tissue (WAT) thermogenesis and glucose homeostasis. Adissp expression is adipose-specific and highly BAT-enriched, and its secretion is stimulated by β3-adrenergic activation. Gain-of-functional studies collectively showed that secreted Adissp promotes WAT thermogenesis, improves glucose homeostasis, and protects against obesity. Adipose-specific Adissp knockout mice are defective in WAT browning, and are susceptible to high fat diet-induced obesity and hyperglycemia. Mechanistically, Adissp binds to a putative receptor on adipocyte surface and activates protein kinase A independently of β-adrenergic signaling. These results establish BAT-enriched Adissp as a major upstream signaling component in thermogenesis and offer a potential avenue for the treatment of obesity and diabetes.
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Affiliation(s)
- Qingbo Chen
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lei Huang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Dongning Pan
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China
| | - Kai Hu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Rui Li
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Randall H Friedline
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jason K Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Lihua Julie Zhu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - David A Guertin
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Yong-Xu Wang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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23
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Hargadon KM, Goodloe TB, Lloyd ND. Oncogenic functions of the FOXC2 transcription factor: a hallmarks of cancer perspective. Cancer Metastasis Rev 2022; 41:833-852. [PMID: 35701636 DOI: 10.1007/s10555-022-10045-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/06/2022] [Indexed: 01/25/2023]
Abstract
Epigenetic regulation of gene expression is a fundamental determinant of molecular and cellular function, and epigenetic reprogramming in the context of cancer has emerged as one of the key enabling characteristics associated with acquisition of the core hallmarks of this disease. As such, there has been renewed interest in studying the role of transcription factors as epigenetic regulators of gene expression in cancer. In this review, we discuss the current state of knowledge surrounding the oncogenic functions of FOXC2, a transcription factor that frequently becomes dysregulated in a variety of cancer types. In addition to highlighting the clinical impact of aberrant FOXC2 activity in cancer, we discuss mechanisms by which this transcription factor becomes dysregulated in both tumor and tumor-associated cells, placing particular emphasis on the ways in which FOXC2 promotes key hallmarks of cancer progression. Finally, we bring attention to important issues related to the oncogenic dysregulation of FOXC2 that must be addressed going forward in order to improve our understanding of FOXC2-mediated cancer progression and to guide prognostic and therapeutic applications of this knowledge in clinical settings.
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Affiliation(s)
- Kristian M Hargadon
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA.
| | - Travis B Goodloe
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA
| | - Nathaniel D Lloyd
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA
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24
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Zhang L, He Y, Tu X, Wang C, Ding X, Ye R, Shi J, Xie Y, Jiang Y, Deng X. FOXC2 as a prognostic marker and a potential molecular target in patients with human solid tumors. Front Surg 2022; 9:960698. [PMID: 36425886 PMCID: PMC9679010 DOI: 10.3389/fsurg.2022.960698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 10/17/2022] [Indexed: 10/18/2024] Open
Abstract
BACKGROUND Forkhead Box Protein C2 (FOXC2) belongs to the Forkhead/Wing-helix family. The regulatory role of this transcription factor in physiological function and carcinogenic activity has been proven in subsequent investigations. However, there is still scarcity of evidence on the relationship between FOXC2 expression and prognosis in human solid tumors. We conducted this meta-analysis to evaluate the role of FOXC2 as a prognosis factor and a possible target marker in human solid tumors. METHODS PubMed, Web of Science, Embase, and the Cochrane library database were all searched methodically. Eligible publications on FOXC2 in human solid tumors were gathered and reviewed. The effect sizes were calculated using pooled hazard ratios (HRs) or odds ratios (ORs) with the corresponding 95% confidence interval (CI). Statistical analysis was conducted with Stata SE12.0. RESULTS This meta-analysis comprised 3,267 patients from 20 studies covering a variety of solid tumors. Increased FOXC2 expression was related to shorter overall survival (OS) (HR = 2.05, 95% CI: 1.73-2.42). High expression of FOXC2 is associated with lymph node metastases (OR = 3.33, 95% CI: 2.65-4.19), TNM stage (OR = 3.09, 95% CI: 2.00-4.78), and age (OR = 1.26, 95% CI: 1.06-1.50), according to the pooled ORs. However, no significant association was observed between the high expression of FOXC2 and sex, tumor size or tumor differentiation. CONCLUSION Increased expression of FOXC2 is associated with unfavored OS, lymph node metastases, TNM stage, and age. FOXC2 is a promising prognostic marker and a novel target marker in human solid tumors.
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Affiliation(s)
- Long Zhang
- Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital of Jiangxi Province (Ganzhou Hospital Affiliated to Nanchang University), Ganzhou, China
| | - Yong He
- Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital of Jiangxi Province (Ganzhou Hospital Affiliated to Nanchang University), Ganzhou, China
| | - Xiaohong Tu
- Department of Physical Education, Ganzhou Teachers College, Ganzhou, China
| | - Chao Wang
- Hepatic Surgery Center, Institute of Hepato-pancreato-biliary Surgery, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojun Ding
- Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital of Jiangxi Province (Ganzhou Hospital Affiliated to Nanchang University), Ganzhou, China
| | - Rongqiang Ye
- Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital of Jiangxi Province (Ganzhou Hospital Affiliated to Nanchang University), Ganzhou, China
| | - Jiayu Shi
- Hepatic Surgery Center, Institute of Hepato-pancreato-biliary Surgery, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Hepato-pancreato-biliary Surgery, Wuhan University of Science and Technology, Wuhan, China
| | - Yuancai Xie
- Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital of Jiangxi Province (Ganzhou Hospital Affiliated to Nanchang University), Ganzhou, China
| | - Yufen Jiang
- Department of Gastroenterology, Kezhou People’s Hospital, Atushi, China
| | - Xiaohong Deng
- Department of Hepatopancreatobiliary Surgery, Ganzhou People's Hospital of Jiangxi Province (Ganzhou Hospital Affiliated to Nanchang University), Ganzhou, China
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25
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Recouvreux MS, Miao J, Gozo MC, Wu J, Walts AE, Karlan BY, Orsulic S. FOXC2 Promotes Vasculogenic Mimicry in Ovarian Cancer. Cancers (Basel) 2022; 14:4851. [PMID: 36230774 PMCID: PMC9564305 DOI: 10.3390/cancers14194851] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 09/27/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
FOXC2 is a forkhead family transcription factor that plays a critical role in specifying mesenchymal cell fate during embryogenesis. FOXC2 expression is associated with increased metastasis and poor survival in various solid malignancies. Using in vitro and in vivo assays in mouse ovarian cancer cell lines, we confirmed the previously reported mechanisms by which FOXC2 could promote cancer growth, metastasis, and drug resistance, including epithelial-mesenchymal transition, stem cell-like differentiation, and resistance to anoikis. In addition, we showed that FOXC2 expression is associated with vasculogenic mimicry in mouse and human ovarian cancers. FOXC2 overexpression increased the ability of human ovarian cancer cells to form vascular-like structures in vitro, while inhibition of FOXC2 had the opposite effect. Thus, we present a novel mechanism by which FOXC2 might contribute to cancer aggressiveness and poor patient survival.
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Affiliation(s)
- Maria Sol Recouvreux
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Jiangyong Miao
- Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Maricel C. Gozo
- Women’s Cancer Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jingni Wu
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Ann E. Walts
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Beth Y. Karlan
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Sandra Orsulic
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
- Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA
- Veterans Administration Greater Los Angeles Healthcare System, Los Angeles, CA 90095, USA
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26
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Manrique OJ, Bustos SS, Ciudad P, Adabi K, Chen WF, Forte AJ, Cheville AL, Jakub JW, McLaughlin SA, Chen HC. Overview of Lymphedema for Physicians and Other Clinicians: A Review of Fundamental Concepts. Mayo Clin Proc 2022; 97:1920-1935. [PMID: 32829905 DOI: 10.1016/j.mayocp.2020.01.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 10/17/2019] [Accepted: 01/06/2020] [Indexed: 12/16/2022]
Abstract
Lymphedema has historically been underrated in clinical practice, education, and scholarship to the detriment of many patients with this chronic, debilitating condition. The mechanical insufficiency of the lymphatic system causes the abnormal accumulation of protein-rich fluid in the interstitium, which triggers a cascade of adverse consequences such as fat deposition and fibrosis. As the condition progresses, patients present with extremity heaviness, itchiness, skin infections, and, in later stages, dermal fibrosis, skin papillomas, acanthosis, and other trophic skin changes. Correspondingly, lymphedema results in psychological morbidity, including anxiety, depression, social avoidance, and a decreased quality of life, encompassing emotional, functional, physical, and social domains. For this review, we conducted a literature search using PubMed and EMBASE and herein summarize the evidence related to the fundamental concepts of lymphedema. This article aims to raise awareness of this serious condition and outline and review the fundamental concepts of lymphedema.
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Affiliation(s)
- Oscar J Manrique
- Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN.
| | - Samyd S Bustos
- Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN
| | - Pedro Ciudad
- Department of Plastic, Reconstructive and Burn Surgery, Arzobispo Loayza National Hospital, Lima, Peru
| | - Kian Adabi
- Division of Plastic and Reconstructive Surgery, Mayo Clinic, Rochester, MN
| | - Wei F Chen
- Division of Plastic and Reconstructive Surgery, University of Iowa, Iowa City
| | | | - Andrea L Cheville
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN
| | | | | | - Hung-Chi Chen
- Department of Plastic and Reconstructive Surgery, China Medical University Hospital, Taichung, Taiwan
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27
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Davis MJ, Kim HJ, Nichols CG. K ATP channels in lymphatic function. Am J Physiol Cell Physiol 2022; 323:C1018-C1035. [PMID: 35785984 PMCID: PMC9550566 DOI: 10.1152/ajpcell.00137.2022] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/22/2022]
Abstract
KATP channels function as negative regulators of active lymphatic pumping and lymph transport. This review summarizes and critiques the evidence for the expression of specific KATP channel subunits in lymphatic smooth muscle and endothelium, the roles that they play in normal lymphatic function, and their possible involvement in multiple diseases, including metabolic syndrome, lymphedema, and Cantú syndrome. For each of these topics, suggestions are made for directions for future research.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Hae Jin Kim
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri
| | - Colin G Nichols
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
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28
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Abstract
While most tissues exhibit their greatest growth during development, adipose tissue is capable of additional massive expansion in adults. Adipose tissue expandability is advantageous when temporarily storing fuel for use during fasting, but becomes pathological upon continuous food intake, leading to obesity and its many comorbidities. The dense vasculature of adipose tissue provides necessary oxygen and nutrients, and supports delivery of fuel to and from adipocytes under fed or fasting conditions. Moreover, the vasculature of adipose tissue comprises a major niche for multipotent progenitor cells, which give rise to new adipocytes and are necessary for tissue repair. Given the multiple, pivotal roles of the adipose tissue vasculature, impairments in angiogenic capacity may underlie obesity-associated diseases such as diabetes and cardiometabolic disease. Exciting new studies on the single-cell and single-nuclei composition of adipose tissues in mouse and humans are providing new insights into mechanisms of adipose tissue angiogenesis. Moreover, new modes of intercellular communication involving micro vesicle and exosome transfer of proteins, nucleic acids and organelles are also being recognized to play key roles. This review focuses on new insights on the cellular and signaling mechanisms underlying adipose tissue angiogenesis, and on their impact on obesity and its pathophysiological consequences.
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29
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Ku HC, Cheng CF. Role of adipocyte browning in prostate and breast tumor microenvironment. Tzu Chi Med J 2022; 34:359-366. [PMID: 36578640 PMCID: PMC9791856 DOI: 10.4103/tcmj.tcmj_62_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/06/2022] [Accepted: 04/15/2022] [Indexed: 12/31/2022] Open
Abstract
Prostate cancer (PC) and breast cancer (BC) are the most common cancers in men and women, respectively, in developed countries. The increased incidence of PC and BC largely reflects an increase in the prevalence of obesity and metabolic syndrome. In pathological conditions involving the development and progression of PC and BC, adipose tissue plays an important role via paracrine and endocrine signaling. The increase in the amount of local adipose tissue, specifically periprostatic adipose tissue, may be a key contributor to the PC pathobiology. Similarly, breast adipose tissue secretion affects various aspects of BC by influencing tumor progression, angiogenesis, metastasis, and microenvironment. In this context, the role of white adipose tissue (WAT) has been extensively studied. However, the influence of browning of the WAT on the development and progression of PC and BC is unclear and has received less attention. In this review, we highlight that adipose tissue plays a vital role in the regulation of the tumor microenvironment in PC or BC and highlight the probable underlying mechanisms linking adipose tissue with PC or BC. We further discuss whether the browning of WAT could be a therapeutic strategy for the treatment of PC and BC.
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Affiliation(s)
- Hui-Chen Ku
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
| | - Ching-Feng Cheng
- Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan,Department of Pediatrics, School of Medicine, Tzu Chi University, Hualien, Taiwan,Address for correspondence: Dr. Ching-Feng Cheng, Department of Pediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289, Jianguo Road, Xindian District, New Taipei, Taiwan. E-mail:
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30
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Labusca L. Adipose tissue in bone regeneration - stem cell source and beyond. World J Stem Cells 2022; 14:372-392. [PMID: 35949397 PMCID: PMC9244952 DOI: 10.4252/wjsc.v14.i6.372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/30/2021] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
Adipose tissue (AT) is recognized as a complex organ involved in major home-ostatic body functions, such as food intake, energy balance, immunomodulation, development and growth, and functioning of the reproductive organs. The role of AT in tissue and organ homeostasis, repair and regeneration is increasingly recognized. Different AT compartments (white AT, brown AT and bone marrow AT) and their interrelation with bone metabolism will be presented. AT-derived stem cell populations - adipose-derived mesenchymal stem cells and pluripotent-like stem cells. Multilineage differentiating stress-enduring and dedifferentiated fat cells can be obtained in relatively high quantities compared to other sources. Their role in different strategies of bone and fracture healing tissue engineering and cell therapy will be described. The current use of AT- or AT-derived stem cell populations for fracture healing and bone regenerative strategies will be presented, as well as major challenges in furthering bone regenerative strategies to clinical settings.
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Affiliation(s)
- Luminita Labusca
- Magnetic Materials and Sensors, National Institute of Research and Development for Technical Physics, Iasi 700050, Romania
- Orthopedics and Traumatology, County Emergency Hospital Saint Spiridon Iasi, Iasi 700050, Romania.
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31
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Guo F, Zhu Y, Han Y, Feng X, Pan Z, He Y, Li Y, Jin L. DEPP Deficiency Contributes to Browning of White Adipose Tissue. Int J Mol Sci 2022; 23:ijms23126563. [PMID: 35743009 PMCID: PMC9223522 DOI: 10.3390/ijms23126563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/06/2022] [Accepted: 06/09/2022] [Indexed: 11/23/2022] Open
Abstract
Decidual protein induced by progesterone (DEPP) was originally identified as a modulator in the process of decidualization in the endometrium. Here, we define that DEPP is involved in adipose tissue thermogenesis, which contributes to metabolic regulation. Knockdown of DEPP suppressed adipocyte differentiation and lipid accumulation in 3T3-L1 cells, induced expression of brown adipose tissue (BAT) markers in primary brown adipocyte and induced mouse embryonic fibroblasts (MEFs) differentiation to brown adipocytes. Moreover, DEPP deficiency in mice induced white adipocyte browning and enhanced BAT activity. Cold exposure stimulated more browning of white adipose tissue (WAT) and maintained higher body temperature in DEPP knockout mice compared to that in wild-type control mice. DEPP deficiency also protected mice against high-fat-diet-induced insulin resistance. Mechanistic studies demonstrated that DEPP competitively binds SIRT1, inhibiting the interaction between peroxisome proliferator-activated receptor gamma (PPARγ) and Sirtuin 1 (SIRT1). Collectively, these findings suggest that DEPP plays a crucial role in orchestrating thermogenesis through regulating adipocyte programs and thus might be a potential target for the treatment of metabolic disorders.
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Affiliation(s)
- Fusheng Guo
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
| | - Yanlin Zhu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
| | - Yaping Han
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
| | - Xuhui Feng
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
| | - Zhifu Pan
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
| | - Ying He
- Laboratory Animal Center, Xiamen University, Xiamen 361102, China;
| | - Yong Li
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
- Correspondence: (Y.L.); (L.J.)
| | - Lihua Jin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, China; (F.G.); (Y.Z.); (Y.H.); (X.F.); (Z.P.)
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
- Correspondence: (Y.L.); (L.J.)
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32
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Yang J, Liu F, Li Y, Wu D, Zhang Z, Chen S, Deng M, Yang C, Yang J. Forkhead box C2 is associated with insulin resistance in gestational diabetes mellitus. Gynecol Endocrinol 2022; 38:499-502. [PMID: 35532201 DOI: 10.1080/09513590.2022.2072485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Abstract
OBJECTIVE This study aimed to investigate serum levels of adiponectin, and the mRNA expression of forkhead box C2 (FOXC2) and glucose transporter-4 (GLUT4) in visceral adipose tissue obtained from patients with gestational diabetes mellitus (GDM) and healthy pregnant women. METHODS Venous blood samples were obtained from 60 pregnant women with gestational normal glucose tolerance (GNGT) and 21 patients with GDM. Visceral adipose tissues were obtained from 11 women with GDM and 30 with GNGT. Serum adiponectin levels were detected by enzyme-linked immunosorbent assay, and FOXC2 and GLUT4 mRNA expression were detected by quantitative polymerase chain reaction. RESULTS Serum adiponectin concentrations were lower in the women with GDM than in the controls (p < .05). FOXC2 and GLUT4 mRNA expression were decreased in visceral adipose tissue of GDM women than in the controls (p < .05). Correlation analyses showed that FOXC2 tended to have a positive correlation with GLUT4 in GDM patients' visceral adipose tissue (p =.0564). CONCLUSION Our results revealed that decreased adiponectin, FOXC2, and GLUT4 expression were associated with increased risk of GDM and the regulation mechanism of GLUT4 mediated by FOXC2 would be the focus of further studies.
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Affiliation(s)
- Jing Yang
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Fen Liu
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Yi Li
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Dongbo Wu
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Zhenhui Zhang
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Sicen Chen
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Mandan Deng
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Chengying Yang
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
| | - Jing Yang
- Department of Obstetrics and Gynecology, The First hospital of Changsha, Changsha, China
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Role of Distinct Fat Depots in Metabolic Regulation and Pathological Implications. Rev Physiol Biochem Pharmacol 2022; 186:135-176. [PMID: 35915363 DOI: 10.1007/112_2022_73] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
People suffering from obesity and associated metabolic disorders including diabetes are increasing exponentially around the world. Adipose tissue (AT) distribution and alteration in their biochemical properties play a major role in the pathogenesis of these diseases. Emerging evidence suggests that AT heterogeneity and depot-specific physiological changes are vital in the development of insulin resistance in peripheral tissues like muscle and liver. Classically, AT depots are classified into white adipose tissue (WAT) and brown adipose tissue (BAT); WAT is the site of fatty acid storage, while BAT is a dedicated organ of metabolic heat production. The discovery of beige adipocyte clusters in WAT depots indicates AT heterogeneity has a more central role than hither to ascribed. Therefore, we have discussed in detail the current state of understanding on cellular and molecular origin of different AT depots and their relevance toward physiological metabolic homeostasis. A major focus is to highlight the correlation between altered WAT distribution in the body and metabolic pathogenesis in animal models and humans. We have also underscored the disparity in the molecular (including signaling) changes in various WAT tissues during diabetic pathogenesis. Exercise-mediated beneficial alteration in WAT physiology/distribution that protects against metabolic disorders is evolving. Here we have discussed the depot-specific biochemical adjustments induced by different forms of exercise. A detailed understanding of the molecular details of inter-organ crosstalk via substrate utilization/storage and signaling through chemokines provide strategies to target selected WAT depots to pharmacologically mimic the benefits of exercise countering metabolic diseases including diabetes.
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Abstract
Adipose tissue, once thought to be an inert receptacle for energy storage, is now recognized as a complex tissue with multiple resident cell populations that actively collaborate in response to diverse local and systemic metabolic, thermal, and inflammatory signals. A key participant in adipose tissue homeostasis that has only recently captured broad scientific attention is the lymphatic vasculature. The lymphatic system's role in lipid trafficking and mediating inflammation makes it a natural partner in regulating adipose tissue, and evidence supporting a bidirectional relationship between lymphatics and adipose tissue has accumulated in recent years. Obesity is now understood to impair lymphatic function, whereas altered lymphatic function results in aberrant adipose tissue deposition, though the molecular mechanisms governing these phenomena have yet to be fully elucidated. We will review our current understanding of the relationship between adipose tissue and the lymphatic system here, focusing on known mechanisms of lymphatic-adipose crosstalk.
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Affiliation(s)
- Gregory P Westcott
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Joslin Diabetes Center, Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
| | - Evan D Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
- Harvard Medical School, Boston, MA 02215, USA
- Broad Institute, Cambridge, MA 02142, USA
- Correspondence: Evan D. Rosen, MD, PhD, Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
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35
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miR-21 mimic blocks obesity in mice: A novel therapeutic option. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:401-416. [PMID: 34552821 PMCID: PMC8426473 DOI: 10.1016/j.omtn.2021.06.019] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/25/2021] [Indexed: 12/14/2022]
Abstract
MicroRNAs (miRNAs) are promising drug targets for obesity and metabolic disorders. Recently, miRNA mimics are providing a unique mechanism of action that guides the process for drug development and sets out the context of their therapeutic application. miRNA (miR)-21 expression in white adipose tissue (WAT) has been associated with obesity. We aimed to analyze miR-21 expression levels in relation to diabetes and obesity to determine the effect that miR-21 mimic has on processes involved in WAT functionality, to dissect the underlying molecular mechanisms, and to study the potential therapeutic application of the miR-21 mimic against obesity. We found higher miR-21 levels in WAT from non-diabetic obese compared to normoweight humans and mice. Moreover, in 3T3-L1 adipocytes, miR-21 mimic affect genes involved in WAT functionality regulation and significantly increase the expression of genes involved in browning and thermogenesis. Interestingly, in vivo treatment with the miR-21 mimic blocked weight gain induced by a high-fat diet in obese mice, without modifying food intake or physical activity. This was associated with metabolic enhancement, WAT browning, and brown adipose tissue (AT) thermogenic programming through vascular endothelial growth factor A (VEGF-A), p53, and transforming growth factor β1 (TGF-β1) signaling pathways. Our findings suggest that miR-21 mimic-based therapy may provide a new opportunity to therapeutically manage obesity and consequently, its associated alterations.
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36
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Augmented CCL5/CCR5 signaling in brown adipose tissue inhibits adaptive thermogenesis and worsens insulin resistance in obesity. Clin Sci (Lond) 2021; 136:121-137. [PMID: 34821367 DOI: 10.1042/cs20210959] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 11/17/2022]
Abstract
Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than wild-type (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than wild-type mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 siRNA. Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further upregulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved HFD-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of AT CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance.
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37
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Imodoye SO, Adedokun KA, Muhammed AO, Bello IO, Muhibi MA, Oduola T, Oyenike MA. Understanding the Complex Milieu of Epithelial-Mesenchymal Transition in Cancer Metastasis: New Insight Into the Roles of Transcription Factors. Front Oncol 2021; 11:762817. [PMID: 34868979 PMCID: PMC8636732 DOI: 10.3389/fonc.2021.762817] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs via a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but also resistant to several cytotoxic agents during treatment, owing to their anatomically diffuse localisation in the body system. As the quest to find an effective method of addressing metastasis in cancer intervention heightens, understanding the molecular interplay involving the signalling pathways, downstream effectors, and their interactions with the EMT would be an important requisite while the challenges of metastasis continue to punctuate. Unfortunately, the molecular underpinnings that govern this process remain to be completely illuminated. However, it is becoming increasingly clear that EMT, which initiates every episode of metastasis, significantly requires some master regulators called EMT transcription factors (EMT-TFs). Thus, this review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation. In addition, it discusses the interaction of various signalling molecules and effector proteins with these factors. It also provides insight into promising therapeutic targets that may inhibit the metastatic process to overcome the limitation of "undruggable" cancer targets in therapeutic design and upturn the current spate of drug resistance. More so, it extends the discussion from the basic understanding of the EMT binary switch model, and ultimately unveiling the E/M cellular plasticity along a phenotypic spectrum via multiple trans-differentiations. It wraps up on how this knowledge update shapes the diagnostic and clinical approaches that may demand a potential shift in investigative paradigm using novel technologies such as single-cell analyses to improve overall patient survival.
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Affiliation(s)
- Sikiru O. Imodoye
- Department of Medical Laboratory Science, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Kamoru A. Adedokun
- Department of Oral Pathology, Dental University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Abdurrasheed Ola Muhammed
- Department of Histopathology, School of Medical Laboratory Science, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Ibrahim O. Bello
- Department of Biological Sciences, Southern Illinois University, Edwardsville, IL, United States
| | - Musa A. Muhibi
- Department of Medical Laboratory Science, Faculty of Applied Sciences, Edo State University, Uzairue, Nigeria
| | - Taofeeq Oduola
- Department of Chemical Pathology, School of Medical Laboratory Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria
| | - Musiliu A. Oyenike
- Department of Medical Laboratory Science, Ladoke Akintola University of Technology, Ogbomosho, Nigeria
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38
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Yan S, Kumari M, Xiao H, Jacobs C, Kochumon S, Jedrychowski M, Chouchani E, Ahmad R, Rosen ED. IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis. J Clin Invest 2021; 131:144888. [PMID: 33571167 DOI: 10.1172/jci144888] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 02/10/2021] [Indexed: 12/21/2022] Open
Abstract
Adipose thermogenesis is repressed in obesity, reducing the homeostatic capacity to compensate for chronic overnutrition. Inflammation inhibits adipose thermogenesis, but little is known about how this occurs. Here we showed that the innate immune transcription factor IRF3 is a strong repressor of thermogenic gene expression and oxygen consumption in adipocytes. IRF3 achieved this by driving expression of the ubiquitin-like modifier ISG15, which became covalently attached to glycolytic enzymes, thus reducing their function and decreasing lactate production. Lactate repletion was able to restore thermogenic gene expression, even when the IRF3/ISG15 axis was activated. Mice lacking ISG15 phenocopied mice lacking IRF3 in adipocytes, as both had elevated energy expenditure and were resistant to diet-induced obesity. These studies provide a deep mechanistic understanding of how the chronic inflammatory milieu of adipose tissue in obesity prevents thermogenic compensation for overnutrition.
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Affiliation(s)
- Shuai Yan
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Manju Kumari
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.,Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Haopeng Xiao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Christopher Jacobs
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.,Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Shihab Kochumon
- Immunology and Microbiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Mark Jedrychowski
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Edward Chouchani
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Rasheed Ahmad
- Immunology and Microbiology Department, Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Evan D Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
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39
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McClung JA, Levy L, Garcia V, Stec DE, Peterson SJ, Abraham NG. Heme-oxygenase and lipid mediators in obesity and associated cardiometabolic diseases: Therapeutic implications. Pharmacol Ther 2021; 231:107975. [PMID: 34499923 DOI: 10.1016/j.pharmthera.2021.107975] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/08/2021] [Accepted: 07/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity-mediated metabolic syndrome remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves the heme oxygenase (HO) system, specifically its inducible form, HO-1. This review collects and updates much of the current knowledge relevant to pharmacology and clinical medicine concerning HO-1 in metabolic diseases and its effect on lipid metabolism. HO-1 has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin and leptin sensitivity. Recent reports indicate that HO-1 with its antioxidants via the effect of bilirubin increases formation of biologically active lipid metabolites such as epoxyeicosatrienoic acid (EET), omega-3 and other polyunsaturated fatty acids (PUFAs). Similarly, HO-1and bilirubin are potential therapeutic targets in the treatment of fat-induced liver diseases. HO-1-mediated upregulation of EET is capable not only of reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, a hallmark of the metabolic syndrome. This process involves browning of white fat tissue (i.e. formation of healthy adipocytes) and reduced lipotoxicity, which otherwise will be toxic to the heart. More importantly, this review examines the activity of EET in biological systems and a series of pathways that explain its mechanism of action and discusses how these might be exploited for potential therapeutic use. We also discuss the link between cardiac ectopic fat deposition and cardiac function in humans, which is similar to that described in obese mice and is regulated by HO-1-EET-PGC1α signaling, a potent negative regulator of the inflammatory adipokine NOV.
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Affiliation(s)
- John A McClung
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America
| | - Lior Levy
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America
| | - Victor Garcia
- Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, United States of America.
| | - Stephen J Peterson
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, United States of America; New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY 11215, United States of America
| | - Nader G Abraham
- Department of Medicine, New York Medical College, Valhalla, NY 10595, United States of America; Department of Pharmacology, New York Medical College, Valhalla, NY 10595, United States of America.
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40
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Yamamoto-Fukuda T, Akiyama N, Kojima H. Super-enhancer Acquisition Drives FOXC2 Expression in Middle Ear Cholesteatoma. J Assoc Res Otolaryngol 2021; 22:405-424. [PMID: 33861394 PMCID: PMC8329101 DOI: 10.1007/s10162-021-00801-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/29/2021] [Indexed: 12/21/2022] Open
Abstract
Distinct histone modifications regulate gene expression in certain diseases, but little is known about histone epigenetics in middle ear cholesteatoma. It is known that histone acetylation destabilizes the nucleosome and chromatin structure and induces gene activation. The association of histone acetylation with chronic inflammatory diseases has been indicated in recent studies. In this study, we examined the localization of variously modified histone H3 acetylation at lysine 9, 14, 18, 23, and 27 in paraffin-embedded sections of human middle ear cholesteatoma (cholesteatoma) tissues and the temporal bones of an animal model of cholesteatoma immunohistochemically. As a result, we found that there was a significant increase of the expression levels of H3K27ac both in human cholesteatoma tissues and the animal model. In genetics, super-enhancers are clusters of enhancers that drive the transcription of genes involved in cell identity. Super-enhancers were originally defined using the H3K27ac signal, and then we used H3K27ac chromatin immunoprecipitation followed by sequencing to map the active cis-regulatory landscape in human cholesteatoma. Based on the results, we identified increased H3K27ac signals as super-enhancers of the FOXC2 loci, as well as increased protein of FOXC2 in cholesteatoma. Recent studies have indicated that menin-MLL inhibitor could suppress tumor growth through the control of histone H3 modification. In this study, we demonstrated that the expression of FOXC2 was inhibited by menin-MLL inhibitor in vivo. These findings indicate that FOXC2 expression under histone modifications promoted the pathogenesis of cholesteatoma and suggest that it may be a therapeutic target of cholesteatoma.
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Affiliation(s)
- Tomomi Yamamoto-Fukuda
- Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan.
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Naotaro Akiyama
- Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Otorhinolaryngology, Toho University School of Medicine, Tokyo, Japan
| | - Hiromi Kojima
- Department of Otorhinolaryngology, Jikei University School of Medicine, Tokyo, Japan
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41
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Brandão BB, Poojari A, Rabiee A. Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential. Int J Mol Sci 2021; 22:5906. [PMID: 34072788 PMCID: PMC8198523 DOI: 10.3390/ijms22115906] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 04/30/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022] Open
Abstract
The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.
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Affiliation(s)
- Bruna B. Brandão
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA;
| | - Ankita Poojari
- Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, USA;
| | - Atefeh Rabiee
- Department of Physiology & Pharmacology, Thomas J. Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, CA 95211, USA;
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42
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Bast-Habersbrunner A, Kiefer C, Weber P, Fromme T, Schießl A, Schwalie PC, Deplancke B, Li Y, Klingenspor M. LncRNA Ctcflos orchestrates transcription and alternative splicing in thermogenic adipogenesis. EMBO Rep 2021; 22:e51289. [PMID: 34056831 PMCID: PMC8256291 DOI: 10.15252/embr.202051289] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 12/12/2022] Open
Abstract
The recruitment of thermogenic brite adipocytes within white adipose tissue attenuates obesity and metabolic comorbidities, arousing interest in understanding the underlying regulatory mechanisms. The molecular network of brite adipogenesis, however, remains largely unresolved. In this light, long noncoding RNAs (lncRNAs) emerged as a versatile class of modulators that control many steps within the differentiation machinery. Leveraging the naturally varying propensities of different inbred mouse strains for white adipose tissue browning, we identify the nuclear lncRNA Ctcflos as a pivotal orchestrator of thermogenic gene expression during brite adipocyte differentiation. Mechanistically, Ctcflos acts as a pleiotropic regulator, being essential for the transcriptional recruitment of the early core thermogenic regulatory program and the modulation of alternative splicing to drive brite adipogenesis. This is showcased by Ctcflos‐regulated gene transcription and splicing of the key browning factor Prdm16 toward the isoform that is specific for the thermogenic gene program. Conclusively, our findings emphasize the mechanistic versatility of lncRNAs acting at several independent levels of gene expression for effective regulation of key differentiation factors to direct cell fate and function.
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Affiliation(s)
- Andrea Bast-Habersbrunner
- Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany
| | - Christoph Kiefer
- Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Peter Weber
- Research Unit Radiation Cytogenetics, Helmholtz Center Munich Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Tobias Fromme
- Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Anna Schießl
- Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Petra C Schwalie
- School of Life Sciences, EPFL and Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Bart Deplancke
- School of Life Sciences, EPFL and Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Yongguo Li
- Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany
| | - Martin Klingenspor
- Chair for Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.,EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany
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43
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Roth CL, Molica F, Kwak BR. Browning of White Adipose Tissue as a Therapeutic Tool in the Fight against Atherosclerosis. Metabolites 2021; 11:319. [PMID: 34069148 PMCID: PMC8156962 DOI: 10.3390/metabo11050319] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/05/2021] [Accepted: 05/13/2021] [Indexed: 02/07/2023] Open
Abstract
Despite continuous medical advances, atherosclerosis remains the prime cause of mortality worldwide. Emerging findings on brown and beige adipocytes highlighted that these fat cells share the specific ability of non-shivering thermogenesis due to the expression of uncoupling protein 1. Brown fat is established during embryogenesis, and beige cells emerge from white adipose tissue exposed to specific stimuli like cold exposure into a process called browning. The consecutive energy expenditure of both thermogenic adipose tissues has shown therapeutic potential in metabolic disorders like obesity and diabetes. The latest data suggest promising effects on atherosclerosis development as well. Upon cold exposure, mice and humans have a physiological increase in brown adipose tissue activation and browning of white adipocytes is promoted. The use of drugs like β3-adrenergic agonists in murine models induces similar effects. With respect to atheroprotection, thermogenic adipose tissue activation has beneficial outcomes in mice by decreasing plasma triglycerides, total cholesterol and low-density lipoproteins, by increasing high-density lipoproteins, and by inducing secretion of atheroprotective adipokines. Atheroprotective effects involve an unaffected hepatic clearance. Latest clinical data tend to find thinner atherosclerotic lesions in patients with higher brown adipose tissue activity. Strategies for preserving healthy arteries are a major concern for public health.
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Affiliation(s)
| | - Filippo Molica
- Department of Pathology and Immunology, University of Geneva, CH-1211 Geneva, Switzerland; (C.L.R.); (B.R.K.)
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44
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Ke H, Luan Y, Wu S, Zhu Y, Tong X. The Role of Mondo Family Transcription Factors in Nutrient-Sensing and Obesity. Front Endocrinol (Lausanne) 2021; 12:653972. [PMID: 33868181 PMCID: PMC8044463 DOI: 10.3389/fendo.2021.653972] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/15/2021] [Indexed: 12/20/2022] Open
Abstract
In the past several decades obesity has become one of the greatest health burdens worldwide. Diet high in fats and fructose is one of the main causes for the prevalence of metabolic disorders including obesity. Promoting brown or beige adipocyte development and activity is regarded as a potential treatment of obesity. Mondo family transcription factors including MondoA and carbohydrate response element binding protein (ChREBP) are critical for nutrient-sensing in multiple metabolic organs including the skeletal muscle, liver, adipose tissue and pancreas. Under normal nutrient conditions, MondoA and ChREBP contribute to maintaining metabolic homeostasis. When nutrient is overloaded, Mondo family transcription factors directly regulate glucose and lipid metabolism in brown and beige adipocytes or modulate the crosstalk between metabolic organs. In this review, we aim to provide an overview of recent advances in the understanding of MondoA and ChREBP in sensing nutrients and regulating obesity or related pathological conditions.
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Affiliation(s)
| | | | | | | | - Xuemei Tong
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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45
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Hargadon KM, Győrffy B, Strong EW. The prognostic significance of FOXC2 gene expression in cancer: A comprehensive analysis of RNA-seq data from the cancer genome atlas. Cancer Genet 2021; 254-255:58-64. [PMID: 33636524 DOI: 10.1016/j.cancergen.2021.02.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 11/29/2022]
Abstract
The FOXC2 transcription factor is a key regulator of tumor progression in many cancer types. Known to exhibit an array of oncogenic functions when dysregulated, FOXC2 has emerged as a useful biomarker for predicting disease aggression and patient outcome. In this regard, increased expression and nuclear localization of FOXC2 protein in tumor tissue have become well-established as poor prognostic factors for many cancer types. However, whether FOXC2 gene expression can serve as a similarly useful RNA-level biomarker has remained largely unexplored. Therefore, we conducted a comprehensive analysis of TCGA RNA-seq data to evaluate whether FOXC2 gene expression levels in primary tumor biopsies correlate with patient outcome. We report herein that increased expression of FOXC2 RNA in tumor tissue is a poor prognostic factor for patient survival in many cancer types. Moreover, we also found that FOXC2 gene expression predicts cancer patient response to several commonly prescribed chemotherapeutics. Together, these data highlight FOXC2 RNA expression in tumor tissue as an important biomarker with prognostic significance for solid tumors of diverse origin.
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Affiliation(s)
- Kristian M Hargadon
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Brown Student Center, Box 837, Hampden-Sydney, VA 23943, USA.
| | - Balázs Győrffy
- TTK Cancer Biomarker Research Group, Magyar Tudósok körútja 2., H-1117 Budapest, Hungary; Department of Bioinformatics and 2nd Department of Pediatrics, Semmelweis University, Tuzolto u. 7-9, H-1094 Budapest, Hungary
| | - Elijah W Strong
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Brown Student Center, Box 837, Hampden-Sydney, VA 23943, USA
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Okla M, Kassem M. Thermogenic potentials of bone marrow adipocytes. Bone 2021; 143:115658. [PMID: 32979539 DOI: 10.1016/j.bone.2020.115658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/18/2020] [Accepted: 09/19/2020] [Indexed: 12/31/2022]
Abstract
Bone marrow adipose tissue (MAT) is a unique fat depot located in proximity to bone surfaces and exerts regulatory functions in the skeleton. Recent studies have demonstrated that MAT responds to changes in whole-body energy metabolism, such as in obesity and anorexia nervosa, where MAT expands, resulting in deleterious effects on the skeleton. Interestingly, MAT shares properties with both brown and white adipose tissues but exhibits distinct features with regard to lipid metabolism and insulin sensitivity. Recent reports have addressed the capacity of MAT to undergo browning, which could be an attractive strategy for preventing excessive MAT accumulation within the skeleton. In this review, we summarize studies addressing the browning phenomenon of MAT and its regulation by a number of pathophysiological conditions. Moreover, we discuss the relationship between adaptive thermogenesis and bone health. Understanding the thermogenic potentials of MAT will delineate the biological importance of this organ and unravel its potential for improving bone health and whole-body energy metabolism.
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Affiliation(s)
- Meshail Okla
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia; Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
| | - Moustapha Kassem
- Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Molecular Endocrinology, KMEB, University of Southern Denmark, Odense University Hospital, 5000 Odense C, Denmark; Department of Cellular and Molecular Medicine, The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Panum Institute, University of Copenhagen, Copenhagen, Denmark
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Shen X, Zhao K, Xu L, Cheng G, Zhu J, Gan L, Wu Y, Zhuang Z. YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway. Front Genet 2021; 11:592042. [PMID: 33505426 PMCID: PMC7831514 DOI: 10.3389/fgene.2020.592042] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022] Open
Abstract
Background Gastric cancer (GC) is one of the most common malignancies in the world, and the fourth most frequent malignancy worldwide. YTHDF2 (YTH domain family 2, YTHDF2) binds to mRNA containing m6A, thereby regulating the localization and stability of the bound mRNA. YTHDF2 was shown to be associated with some cancer patient prognosis. However, the effect of YTHDF2 on gastric cancer and the molecular mechanism of this effect have not been documented. Methods To conduct this research, YTHDF2 expression levels in public databases and gastric cancer patient samples were analyzed. The effects of YTHDF2 on the growth of gastric cancer cells were detected in vivo and in vitro. RNA-seq was used to analyze the signal pathways regulated by YTHDF2, and experiments were carried out for verification. Results In our study, we found that YTHDF2 has lower expression in GC tissues and GC cells, and inhibits the growth of GC cells. In addition, the analysis of clinical data found that the expression level of YTHDF2 is closely related to the stage of GC and the survival of patients with GC. RNA sequencing results showed that overexpression of YTHDF2 significantly reduced protein expression in the FOXC2 (Forkhead box protein C2, FOXC2) signaling pathway. Finally, we found that knockout of FOXC2 reversed the inhibitory effect of YTHDF2 on GC cells. Conclusion In summary, YTHDF2 inhibits the growth of GC cells by negatively regulating FOXC2 and may serve as a prognostic marker in GC.
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Affiliation(s)
- Xudong Shen
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Kui Zhao
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Liming Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Guilian Cheng
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jianhong Zhu
- Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Gan
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yongyou Wu
- Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhixiang Zhuang
- Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Giardullo L, Corrado A, Maruotti N, Cici D, Mansueto N, Cantatore FP. Adipokine role in physiopathology of inflammatory and degenerative musculoskeletal diseases. Int J Immunopathol Pharmacol 2021; 35:20587384211015034. [PMID: 33983056 PMCID: PMC8127732 DOI: 10.1177/20587384211015034] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/05/2021] [Indexed: 12/16/2022] Open
Abstract
We performed a systematic literature review to summarize the underlying pathogenic mechanisms by which adipokines influence rheumatological diseases and the resulting clinical manifestations. Increasing evidence display that numerous adipokines may significantly influence the development or clinical course of various rheumatological diseases. Despite the normal anti- or pro-inflammatory role of the cytokines, the serum level varies enormously in various rheumatological diseases. The expression of high levels of pro-inflammatory cytokines such as leptin or visfatin, respectively in systemic lupus erythematosus and in rheumatoid arthritis, represents a negative prognostic factor; other adipokines such as adiponectin, broadly known for their anti-inflammatory effects, showed a correlation with disease activity in rheumatoid arthritis. In the near future pro-inflammatory cytokines may represent a potential therapeutic target to restrain the severity of rheumatological diseases. Further studies on adipokines may provide important information on the pathogenesis of these diseases, which are not yet fully understood. The mechanisms by which adipokines induce, worsen, or suppress inflammatory and degenerative musculoskeletal pathologies and their clinical significance will be discussed in this review.
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Affiliation(s)
- Liberato Giardullo
- Rheumatology Clinic “Mario Carrozzo”, Department of Medical and Surgical Sciences, University of Foggia, “Policlinico Riuniti” University Hospital, Foggia, Italy
| | - Addolorata Corrado
- Rheumatology Clinic “Mario Carrozzo”, Department of Medical and Surgical Sciences, University of Foggia, “Policlinico Riuniti” University Hospital, Foggia, Italy
| | - Nicola Maruotti
- Rheumatology Clinic “Mario Carrozzo”, Department of Medical and Surgical Sciences, University of Foggia, “Policlinico Riuniti” University Hospital, Foggia, Italy
| | - Daniela Cici
- Rheumatology Clinic “Mario Carrozzo”, Department of Medical and Surgical Sciences, University of Foggia, “Policlinico Riuniti” University Hospital, Foggia, Italy
| | - Natalia Mansueto
- Rheumatology Clinic “Mario Carrozzo”, Department of Medical and Surgical Sciences, University of Foggia, “Policlinico Riuniti” University Hospital, Foggia, Italy
| | - Francesco Paolo Cantatore
- Rheumatology Clinic “Mario Carrozzo”, Department of Medical and Surgical Sciences, University of Foggia, “Policlinico Riuniti” University Hospital, Foggia, Italy
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The Intricate Role of p53 in Adipocyte Differentiation and Function. Cells 2020; 9:cells9122621. [PMID: 33297294 PMCID: PMC7762213 DOI: 10.3390/cells9122621] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/14/2022] Open
Abstract
For more than three decades, numerous studies have demonstrated the function of p53 in cell cycle, cellular senescence, autophagy, apoptosis, and metabolism. Among diverse functions, the essential role of p53 is to maintain cellular homeostatic response to stress by regulating proliferation and apoptosis. Recently, adipocytes have been studied with increasing intensity owing to the increased prevalence of metabolic diseases posing a serious public health concern and because metabolic dysfunction can directly induce tumorigenesis. The prevalence of metabolic diseases has steadily increased worldwide, and a growing interest in these diseases has led to the focus on the role of p53 in metabolism and adipocyte differentiation with or without metabolic stress. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. Therefore, this review focuses on the newly discovered roles of p53 in adipocyte differentiation and function.
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Heenan KA, Carrillo AE, Fulton JL, Ryan EJ, Edsall JR, Rigopoulos D, Markofski MM, Flouris AD, Dinas PC. Effects of Nutrition/Diet on Brown Adipose Tissue in Humans: A Systematic Review and Meta-Analysis. Nutrients 2020; 12:E2752. [PMID: 32927664 PMCID: PMC7551565 DOI: 10.3390/nu12092752] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/29/2020] [Accepted: 09/08/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Brown adipose tissue (BAT) provides a minor contribution to diet-induced thermogenesis (DIT)-the metabolic response to food consumption. Increased BAT activity is generally considered beneficial for mammalian metabolism and has been associated with favorable health outcomes. The aim of the current systematic review was to explore whether nutritional factors and/or diet affect human BAT activity. METHODS We searched PubMed Central, Embase and Cochrane Library (trials) to conduct this systematic review (PROSPERO protocol: CRD42018082323). RESULTS We included 24 eligible papers that studied a total of 2785 participants. We found no mean differences in standardized uptake value of BAT following a single meal or after 6 weeks of L-Arginine supplementation. Resting energy expenditure (REE), however, was increased following a single meal and after supplementation of capsinoid and catechin when compared to a control condition (Z = 2.41, p = 0.02; mean difference = 102.47 (95% CI = 19.28-185.67)). CONCLUSIONS Human BAT activity was not significantly affected by nutrition/diet. Moreover, REE was only increased in response to a single meal, but it is unlikely that this was due to increased BAT activity. BAT activity assessments in response to the chronic effect of food should be considered along with other factors such as body composition and/or environmental temperature.
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Affiliation(s)
- Kelsey A. Heenan
- Department of Movement Science, Chatham University, Pittsburgh, PA 15232, USA; (K.A.H.); (A.E.C.); (J.L.F.); (E.J.R.); (J.R.E.)
| | - Andres E. Carrillo
- Department of Movement Science, Chatham University, Pittsburgh, PA 15232, USA; (K.A.H.); (A.E.C.); (J.L.F.); (E.J.R.); (J.R.E.)
- FAME Laboratory, Department of Exercise Science, University of Thessaly, GR42100 Trikala, Greece; (D.R.); (A.D.F.)
| | - Jacob L. Fulton
- Department of Movement Science, Chatham University, Pittsburgh, PA 15232, USA; (K.A.H.); (A.E.C.); (J.L.F.); (E.J.R.); (J.R.E.)
| | - Edward J. Ryan
- Department of Movement Science, Chatham University, Pittsburgh, PA 15232, USA; (K.A.H.); (A.E.C.); (J.L.F.); (E.J.R.); (J.R.E.)
| | - Jason R. Edsall
- Department of Movement Science, Chatham University, Pittsburgh, PA 15232, USA; (K.A.H.); (A.E.C.); (J.L.F.); (E.J.R.); (J.R.E.)
| | - Dimitrios Rigopoulos
- FAME Laboratory, Department of Exercise Science, University of Thessaly, GR42100 Trikala, Greece; (D.R.); (A.D.F.)
| | - Melissa M. Markofski
- Department of Health and Human Performance, University of Houston, Houston, TX 77204, USA;
| | - Andreas D. Flouris
- FAME Laboratory, Department of Exercise Science, University of Thessaly, GR42100 Trikala, Greece; (D.R.); (A.D.F.)
| | - Petros C. Dinas
- FAME Laboratory, Department of Exercise Science, University of Thessaly, GR42100 Trikala, Greece; (D.R.); (A.D.F.)
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