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Asghari Alashti F, Goliaei B. Rethinking fat Browning: Uncovering new molecular insights into the synergistic roles of fasting, exercise, and cold exposure. Eur J Pharmacol 2025; 998:177651. [PMID: 40274179 DOI: 10.1016/j.ejphar.2025.177651] [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: 01/28/2025] [Revised: 04/13/2025] [Accepted: 04/17/2025] [Indexed: 04/26/2025]
Abstract
The global obesity epidemic highlights the need to understand the molecular mechanisms that regulate energy metabolism. Among emerging research areas, fat browning-the transformation of white adipose tissue into beige fat-has gained significant attention. This review explores the molecular pathways involved in fat browning triggered by fasting, physical exercise, and cold exposure, emphasizing both shared and distinct regulatory mechanisms. These stimuli consistently induce physiological responses such as lipolysis, mitochondrial biogenesis, and improved insulin sensitivity. Notably, PGC-1α and SIRT3 are upregulated across all three conditions, underscoring their central roles in mitochondrial function and energy metabolism and identifying them as promising therapeutic targets. In contrast, UCP1 and PRDM16 exhibit condition-specific regulation, suggesting they may not be universally essential for fat browning. In addition, the review discusses species-specific differences in brown adipose tissue (BAT) activation, particularly between rodents and humans, highlighting the challenges of translating animal model findings to human therapies. Future research should aim to develop selective pharmacological activators of PGC-1α and SIRT3 to enhance therapeutic outcomes while minimizing adverse effects. This review also proposes that integrating fasting, exercise, and cold exposure could provide innovative strategies to promote metabolic health.
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Affiliation(s)
- Fariborz Asghari Alashti
- Institute of Biochemistry and Biophysics (IBB), Laboratory of Biophysics and Molecular Biology, University of Tehran, Tehran, Iran; Sunnybrook Research Institute, Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, M4N 3M5, Canada.
| | - Bahram Goliaei
- Institute of Biochemistry and Biophysics (IBB), Laboratory of Biophysics and Molecular Biology, University of Tehran, Tehran, Iran.
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Lee C, Kim MJ, Kumar A, Lee HW, Yang Y, Kim Y. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct Target Ther 2025; 10:170. [PMID: 40383803 PMCID: PMC12086256 DOI: 10.1038/s41392-025-02249-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/09/2025] [Accepted: 04/21/2025] [Indexed: 05/20/2025] Open
Abstract
Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.
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Affiliation(s)
- Chunsik Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea.
| | - Myung-Jin Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea
| | - Anil Kumar
- Center for Research and Innovations, Adichunchanagiri University, Mandya, Karnataka, India
| | - Han-Woong Lee
- Department of R&D, GEMCRO Inc, Seoul, Republic of Korea
| | - Yunlong Yang
- Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yonghwan Kim
- Department of Biological Sciences and Research Institute of Women's Health, Sookmyung Women's University, Seoul, Republic of Korea.
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Sousa-Filho CPB, Petrovic N. No UCP1 in the kidney. Mol Metab 2025; 95:102127. [PMID: 40120980 PMCID: PMC11995138 DOI: 10.1016/j.molmet.2025.102127] [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] [Received: 02/19/2025] [Revised: 03/05/2025] [Accepted: 03/15/2025] [Indexed: 03/25/2025] Open
Abstract
OBJECTIVES Several recent studies have indicated the presence of UCP1 in the kidney, challenging the paradigm that UCP1 is only found in brown and beige adipocytes and broadening the (patho)physiological significance of UCP1. The kidney localization has been the direct result of immunohistochemical investigations and an inferred outcome from multiple lines of reporter mice. These findings require confirmation and further physiological characterization. METHODS We examined UCP1 expression in the kidney using immunohistochemistry and qPCR. Transversal sections through or near the kidney hilum, consistently including perirenal brown fat and adjacent kidney tissue, were analyzed with four UCP1 antibodies. RESULTS In addition to detecting UCP1 in perirenal adipose tissue, we observed distinct immunopositive structures in the kidney with our in-house UCP1-antibody, 'C10', in apparent agreement with earlier reports. To corroborate this, we tested the C10-antibody on kidney sections from UCP1-ablated mice but found equal reactivity in these UCP1-negative tissues. We then tested the widely used antibody ab10983, previously employed in kidney studies. Also here, the positive signal persisted in UCP1-ablated mice, clearly invalidating earlier findings. UCP1 qPCR studies also failed to detect UCP1 mRNA above background. Finally, two highly specific antibodies, E9Z2V and EPR20381, accurately detected UCP1 in perirenal adipose tissue but showed no signal in the kidney. CONCLUSIONS When appropriate controls are implemented, there is no evidence for the presence of UCP1 in the kidney. Consequently, this conclusion also implies that the results from UCP1 reporter mice, specifically regarding kidney expression of the UCP1 gene - though possibly applicable to other tissues - require reconfirmation before being accepted as evidence for the presence of UCP1 in non-adipose tissues.
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Affiliation(s)
| | - Natasa Petrovic
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
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Zhou S, He Y, Lin J, Yang F, Zhou W, Cai J, Liao Y, Lu F. Brown Adipose Tissue Improves Angiogenesis and M2 Macrophage Polarization in Burn Wounds by Activating Interleukin-17 Signaling. Plast Reconstr Surg 2025; 155:649-658. [PMID: 39287625 DOI: 10.1097/prs.0000000000011743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
BACKGROUND Burn wound healing is a complex physiologic process that requires complicated regulation by different cells and tissues. Brown adipose tissue (BAT) plays a key role in the hypermetabolic response to severe burns. However, it is unclear whether BAT contributes to burn wound healing. METHODS Mice were divided into 2 groups: the BAT removal group (BR group) and the control group. Burn wounds were created on the backs of mice (weighing 20 to 25 g) exposed to 100°C hot water for 12 seconds using a homemade burn tube, resulting in a burned area measuring 10 mm in diameter. The treatments were applied once a day for 10 days. Full-thickness wound tissue was collected on days 1, 4, 7, and 10, and analyzed by immunostaining of CD31, α-SMA + , F4/80, and CD206 ( n = 3). RESULTS On days 4, 7, and 10, the wound-healing rate of the control group was significantly higher than that of the BR group. In the histologic analysis, evident inflammatory infiltration and severe collagen denaturation was observed in the BR group. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the interleukin-17 pathway was enriched and related genes were up-regulated in the heat map. Immunostaining and transcriptional analyses revealed that angiogenesis and fibroblasts were enhanced in the control group, and there were fewer CD206 + M2 macrophages and higher levels of inflammatory infiltration in the BR group. CONCLUSION BAT may reduce inflammatory signaling in burn wounds by increasing the interleukin-17A-hypoxia inducible factor-1α axis and driving M2 macrophage polarization. CLINICAL RELEVANCE STATEMENT Patients with severe burn injuries and difficult wounds are encouraged to convert white adipose tissue into beige adipose tissue using drug assistance beneath the wound. Then, browning adipose tissue could improve local angiogenesis and promote the formation of a better microenvironment for wound healing.
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Affiliation(s)
- Shaolong Zhou
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
- Aesthetic Medical School, Yichun University
| | - Yufei He
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Jiayan Lin
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Fei Yang
- Aesthetic Medical School, Yichun University
| | | | - Junrong Cai
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Yunjun Liao
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
| | - Feng Lu
- From the Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University
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Yi T, Wu S, Yang Y, Li X, Yang S, Zhang Y, Zhang L, Hu Y, Zhang G, Li J, Yang D. Single-nucleus RNA sequencing reveals dynamic changes in the microenvironment of visceral adipose tissue and metabolic characteristics after cold exposure. Front Endocrinol (Lausanne) 2025; 16:1562431. [PMID: 40196457 PMCID: PMC11973077 DOI: 10.3389/fendo.2025.1562431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 03/04/2025] [Indexed: 04/09/2025] Open
Abstract
Introduction Visceral adipose tissue (VAT) plays a crucial role in regulating systemic metabolic balance. Excess accumulation of VAT is closely associated with various metabolic disorders, a process that involves the coordinated actions of multiple cell types within the tissue. Cold exposure, as a potential intervention, has been proposed to improve metabolic dysfunction. However, the heterogeneity of VAT and its comprehensive metabolic characteristics under cold exposure remain unclear. Methods We collected epididymal white adipose tissue (eWAT) of C57BL/6J mice after cold exposure at three different time points for single-nucleus RNA sequencing (snRNA-seq) analysis. Results We successfully identified ten major cell types in eWAT, enabling understanding of the dynamic changes in the eWAT microenvironment and its metabolic features during cold exposure. This study revealed that cold exposure for 1 day reduced cellular metabolic activity and intercellular communication in eWAT including receptor-ligand-based cell communication and metabolite-mediated interactions. However, after 14 days of cold acclimation, the metabolic activity of adipocytes was significantly enhanced, and intercellular metabolic communication was restored. Additionally, prolonged cold exposure promoted the formation of a distinct adipocyte subpopulation that may be associated with UCP1-independent thermogenesis. These changes may be a new homeostatic state established by VAT to adapt to the cold environment. The study also identified the importance of adipocytes, adipose stem and progenitor cells, myeloid cells, and endothelial cells in the process of cold adaptation. Discussion This research provides valuable insights into the cellular heterogeneity, adipocyte remodeling, and metabolic reprogramming in eWAT after cold exposure. It highlights the critical role of transcriptional dynamics in eWAT during cold exposure and provides new perspectives on the prevention and treatment of metabolic diseases.
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Affiliation(s)
- Ting Yi
- School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Shuai Wu
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Yusha Yang
- School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Xi Li
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Shuran Yang
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yongqiang Zhang
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Li Zhang
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Yuyu Hu
- School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Guanyu Zhang
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
| | - Jun Li
- School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
| | - Danfeng Yang
- Academy of Military Medical Sciences, Academy of Military Sciences, Tianjin, China
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Wu Y, Wang C, Tian XY. Protocol for inducing beige adipocytes in white adipose tissue of mouse using cold exposure and CL316,243 injection. STAR Protoc 2025; 6:103337. [PMID: 39817914 PMCID: PMC11783104 DOI: 10.1016/j.xpro.2024.103337] [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: 03/25/2024] [Revised: 07/20/2024] [Accepted: 09/03/2024] [Indexed: 01/18/2025] Open
Abstract
White adipose tissue (WAT) beiging holds significant therapeutic potential for combating obesity. Here, we present a protocol for inducing beige WAT in mice using both cold exposure and CL316,243 treatment. We describe steps for intraperitoneal injection, and subcutaneous WAT (sWAT) isolation, dissection, and fixation. We then detail procedures for histology, whole-mount immunofluorescence (IF) staining, and extracting RNA and protein. This protocol can be used for subsequent analysis to explore the mechanisms governing beige WAT induction in experimental settings, particularly the evaluation of angiogenesis. For complete details on the use and execution of this protocol, please refer to Wang et al.1.
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Affiliation(s)
- Yalan Wu
- School of Biomedical Sciences, Heart and Vascular Institute, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
| | - Chenguang Wang
- School of Biomedical Sciences, Heart and Vascular Institute, The Chinese University of Hong Kong, Hong Kong SAR, China; Department of Hematology and Oncology, Shenzhen University General Hospital, Shenzhen University, Shenzhen 518071, China
| | - Xiao Yu Tian
- School of Biomedical Sciences, Heart and Vascular Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Festuccia WT. mTORC1 and 2 Adrenergic Regulation and Function in Brown Adipose Tissue. Physiology (Bethesda) 2025; 40:0. [PMID: 39470603 DOI: 10.1152/physiol.00023.2024] [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: 05/07/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 10/30/2024] Open
Abstract
Brown adipose tissue (BAT) thermogenesis results from the uncoupling of mitochondrial inner membrane proton gradient mediated by uncoupling protein 1 (UCP-1), which is activated by lipolysis-derived fatty acids. Norepinephrine (NE) secreted by sympathetic innervation not only activates BAT lipolysis and UCP-1 but, uniquely in brown adipocytes, promotes "futile" metabolic cycles and enhances BAT thermogenic capacity by increasing UCP-1 content, mitochondrial biogenesis, and brown adipocyte hyperplasia. NE exerts these actions by triggering signaling in the canonical G protein-coupled β-adrenergic receptors, cAMP, and protein kinase A (PKA) pathway, which in brown adipocytes is under a complex and intricate cross talk with important growth-promoting signaling pathways such as those of mechanistic target of rapamycin (mTOR) complexes 1 (mTORC1) and 2 (mTORC2). This article reviews evidence suggesting that mTOR complexes are modulated by and participate in the thermogenic, metabolic, and growth-promoting effects elicited by NE in BAT and discusses current gaps and future directions in this field of research.
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Rauchenwald T, Benedikt-Kühnast P, Eder S, Grabner GF, Forstreiter S, Lang M, Sango R, Eisenberg T, Rattei T, Haschemi A, Wolinski H, Schweiger M. Clearing the path for whole-mount labeling and quantification of neuron and vessel density in adipose tissue. J Cell Sci 2025; 138:JCS263438. [PMID: 39878039 PMCID: PMC11832183 DOI: 10.1242/jcs.263438] [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: 07/16/2024] [Accepted: 12/29/2024] [Indexed: 01/31/2025] Open
Abstract
White adipose tissue (WAT) comprises a plethora of cell types beyond adipocytes forming a regulatory network that ensures systemic energy homeostasis. Intertissue communication is facilitated by metabolites and signaling molecules that are spread by vasculature and nerves. Previous works have indicated that WAT responds to environmental cues by adapting the abundance of these 'communication routes'; however, the high intra-tissue heterogeneity questions the informative value of bulk or single-cell analyses and underscores the necessity of whole-mount imaging. The applicability of whole-mount WAT-imaging is currently limited by two factors - (1) methanol-based tissue clearing protocols restrict the usable antibody portfolio to methanol-resistant antibodies and (2) the vast amounts of data resulting from 3D imaging of whole-tissue samples require high computational expertise and advanced equipment. Here, we present a protocol for whole-mount WAT clearing, overcoming the constraints of antibody-methanol sensitivity. Additionally, we introduce TiNeQuant (for 'tissue network quantifier') a Fiji tool for automated 3D quantification of neuron or vascular network density, which we have made freely available. Given TiNeQuants versatility beyond WAT, it simplifies future efforts studying neuronal or vascular alterations in numerous pathologies.
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Affiliation(s)
- Thomas Rauchenwald
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Pia Benedikt-Kühnast
- Institute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany
| | - Sandra Eder
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Gernot F. Grabner
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria
| | | | - Michaela Lang
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Roko Sango
- Centre for Pathobiochemistry and Genetics, Medical University of Vienna, 1090 Vienna, Austria
- Centre for Microbiology and Environmental Systems’ Science, University of Vienna, 1030 Vienna, Austria
- Doctoral School in Microbiology and Environmental Science, University of Vienna, 1030 Vienna, Austria
| | - Tobias Eisenberg
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
- Field of Excellence BioHealth - University of Graz, 8010 Graz, Austria
- BioTechMed-Graz, 8010 Graz, Austria
| | - Thomas Rattei
- Centre for Microbiology and Environmental Systems’ Science, University of Vienna, 1030 Vienna, Austria
| | - Arvand Haschemi
- Department of Laboratory Medicine (KILM), Medical University of Vienna, 1090 Vienna, Austria
| | - Heimo Wolinski
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
- Field of Excellence BioHealth - University of Graz, 8010 Graz, Austria
| | - Martina Schweiger
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
- Field of Excellence BioHealth - University of Graz, 8010 Graz, Austria
- BioTechMed-Graz, 8010 Graz, Austria
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Huynh PM, Wang F, An YA. Hypoxia signaling in the adipose tissue. J Mol Cell Biol 2025; 16:mjae039. [PMID: 39363240 PMCID: PMC11892559 DOI: 10.1093/jmcb/mjae039] [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: 01/03/2024] [Revised: 03/12/2024] [Accepted: 10/01/2024] [Indexed: 10/05/2024] Open
Abstract
Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in humans and rodent models with obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.
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Affiliation(s)
- Phu M Huynh
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Fenfen Wang
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yu A An
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
- Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
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Lv Y, Zheng Y, Su S, Xiao J, Yang J, Xiong L, Guo Y, Zhou X, Guo N, Lei P. CD14 loCD301b + macrophages gathering as a proangiogenic marker in adipose tissues. J Lipid Res 2025; 66:100720. [PMID: 39645040 PMCID: PMC11745947 DOI: 10.1016/j.jlr.2024.100720] [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: 02/06/2024] [Revised: 11/19/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024] Open
Abstract
The role of the monocyte marker CD14 in the regulation of obesity is increasingly recognized. Our observations indicated that Cd14-/- mice exhibited a leaner body shape compared to their wild-type (WT) counterparts. And the loss of CD14 alleviated high-fat diet-induced obesity in mice. In human subjects, CD14 level was tested to be positively correlated with overweight and obesity. However, the relationship between CD14 and the development of obesity remains only partially understood. To investigate the underlying mechanisms, adipose tissues (ATs) from Cd14-/- and WT mice were subjected to deep RNA sequencing. Gene Ontology enrichment analysis revealed a significant enhancement of angiogenesis-related function in the Cd14-/- epididymal adipose tissues compared to WT counterpart, which was accompanied by an upregulation of Cd301b. Subsequent assays confirmed the enhanced angiogenesis and more accumulation of CD301b+ macrophages in Cd14-/- epididymal adipose tissues. Because Igf1 expression has been suggested to be associated with Cd301b expression through pseudotime analysis, we found it was insulin-like growth factor 1 secreted from Cd14-/- macrophages that mediated the angiogenesis enhancement. Collectively, our findings indicate that CD14 deficiency increased the accumulation of CD14loCD301b+ macrophages in ATs, which may serve as a proangiogenic marker, providing novel insights into the relationship between CD14 and obesity development.
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Affiliation(s)
- Yibing Lv
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Henan Provincial Key Laboratory of Genetic Diseases and Functional Genomics, Medical Genetic Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Yidan Zheng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shanshan Su
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junyi Xiao
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Yang
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingyun Xiong
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanyan Guo
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqi Zhou
- Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Nengqiang Guo
- Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ping Lei
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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11
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Shen C, Li J, She W, Liu A, Meng Q. Temperature-responsive hydrogel-grafted vessel-on-a-chip: Exploring cold-induced endothelial injury. Biotechnol Bioeng 2024; 121:3239-3251. [PMID: 38946677 DOI: 10.1002/bit.28779] [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: 07/13/2023] [Revised: 06/03/2024] [Accepted: 06/10/2024] [Indexed: 07/02/2024]
Abstract
Cold-induced vasoconstriction is a significant contributor that leads to chilblains and hypothermia in humans. However, current animal models have limitations in replicating cold-induced acral injury due to their low sensitivity to cold. Moreover, existing in vitro vascular chips composed of endothelial cells and perfusion systems lack temperature responsiveness, failing to simulate the vasoconstriction observed under cold stress. This study presents a novel approach where a microfluidic bioreactor of vessel-on-a-chip was developed by grafting the inner microchannel surface of polydimethylsiloxane with a thermosensitive hydrogel skin composed of N-isopropyl acrylamide and gelatin methacrylamide. With a lower critical solution temperature set at 30°C, the gel layer exhibited swelling at low temperatures, reducing the flow rate inside the channel by 10% when the temperature dropped from 37°C to 4°C. This well mimicked the blood stasis observed in capillary vessels in vivo. The vessel-on-a-chip was further constructed by culturing endothelial cells on the surface of the thermosensitive hydrogel layer, and a perfused medium was introduced to the cells to provide a physiological shear stress. Notably, cold stimulation of the vessel-on-a-chip led to cell necrosis, mitochondrial membrane potential (ΔΨm) collapse, cytoskeleton disaggregation, and increased levels of reactive oxygen species. In contrast, the static culture of endothelial cells showed limited response to cold exposure. By faithfully replicating cold-induced endothelial injury, this groundbreaking thermosensitive vessel-on-a-chip technology offers promising advancements in the study of cold-induced cardiovascular diseases, including pathogenesis and therapeutic drug screening.
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Affiliation(s)
- Chong Shen
- Key Laboratory of Smart Biomaterials of Zhejiang Province, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
- Center for Membrane and Water Science & Technology, Institute of Oceanic and Environmental Chemical Engineering, State Key Lab Base of Green Chemical Synthesis Technology, Zhejiang University of Technology, Hangzhou, China
| | - Jiajie Li
- Key Laboratory of Smart Biomaterials of Zhejiang Province, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Wenqi She
- Key Laboratory of Smart Biomaterials of Zhejiang Province, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Aiping Liu
- Key Laboratory of Smart Biomaterials of Zhejiang Province, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
| | - Qin Meng
- Key Laboratory of Smart Biomaterials of Zhejiang Province, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China
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12
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Duarte Afonso Serdan T, Cervantes H, Frank B, Tian Q, Choi CHJ, Hoffmann A, Cohen P, Blüher M, Schwartz GJ, Shamsi F. Slit3 Fragments Orchestrate Neurovascular Expansion and Thermogenesis in Brown Adipose Tissue. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.24.613949. [PMID: 39386533 PMCID: PMC11463466 DOI: 10.1101/2024.09.24.613949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Abstract
Brown adipose tissue (BAT) represents an evolutionary innovation enabling placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are surrounded by a dense network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure stimulates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we identify Slit guidance ligand 3 (Slit3) as a new niche factor that mediates the crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We show that adipocyte progenitors secrete Slit3 which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which activate distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. Moreover, we introduce bone morphogenetic protein-1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this study underscores the essential role of Slit3-mediated neurovascular network expansion in enabling cold-induced BAT adaptation. The co-regulation of neurovascular expansion by Slit3 fragments provides a bifurcated yet harmonized approach to ensure a synchronized response of BAT to environmental challenges. This study presents the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.
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Affiliation(s)
| | - Heidi Cervantes
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
| | - Benjamin Frank
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
| | - Qiyu Tian
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
| | - Chan Hee J Choi
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
| | - Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, Leipzig, 04103, Germany
| | - Paul Cohen
- Laboratory of Molecular Metabolism, The Rockefeller University, New York, NY, USA
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, Leipzig, 04103, Germany
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig 04103, Germany
| | - Gary J Schwartz
- Departments of Medicine and Neuroscience, Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Farnaz Shamsi
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA
- Departments of Cell Biology and Medicine, Grossman School of Medicine, New York University, New York, NY, USA
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13
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Zakaria M, Matta J, Honjol Y, Schupbach D, Mwale F, Harvey E, Merle G. Decoding Cold Therapy Mechanisms of Enhanced Bone Repair through Sensory Receptors and Molecular Pathways. Biomedicines 2024; 12:2045. [PMID: 39335558 PMCID: PMC11429201 DOI: 10.3390/biomedicines12092045] [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: 08/01/2024] [Revised: 08/22/2024] [Accepted: 08/30/2024] [Indexed: 09/30/2024] Open
Abstract
Applying cold to a bone injury can aid healing, though its mechanisms are complex. This study investigates how cold therapy impacts bone repair to optimize healing. Cold was applied to a rodent bone model, with the physiological responses analyzed. Vasoconstriction was mediated by an increase in the transient receptor protein channels (TRPs), transient receptor potential ankyrin 1 (TRPA1; p = 0.012), and transient receptor potential melastatin 8 (TRPM8; p < 0.001), within cortical defects, enhancing the sensory response and blood flow regulation. Cold exposure also elevated hypoxia (p < 0.01) and vascular endothelial growth factor expression (VEGF; p < 0.001), promoting angiogenesis, vital for bone regeneration. The increased expression of osteogenic proteins peroxisome proliferator-activated receptor gamma coactivator (PGC-1α; p = 0.039) and RNA-binding motif protein 3 (RBM3; p < 0.008) suggests that the reparative processes have been stimulated. Enhanced osteoblast differentiation and the presence of alkaline phosphatase (ALP) at day 5 (three-fold, p = 0.021) and 10 (two-fold, p < 0.001) were observed, along with increased osteocalcin (OCN) at day 10 (two-fold, p = 0.019), indicating the presence of mature osteoblasts capable of mineralization. These findings highlight cold therapy's multifaceted effects on bone repair, offering insights for therapeutic strategies.
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Affiliation(s)
- Matthew Zakaria
- Surgical and Interventional Sciences Division, Faculty of Medicine, McGill University, Montreal, QC H3A 2B2, Canada; (M.Z.); (J.M.); (Y.H.); (D.S.); (E.H.)
| | - Justin Matta
- Surgical and Interventional Sciences Division, Faculty of Medicine, McGill University, Montreal, QC H3A 2B2, Canada; (M.Z.); (J.M.); (Y.H.); (D.S.); (E.H.)
| | - Yazan Honjol
- Surgical and Interventional Sciences Division, Faculty of Medicine, McGill University, Montreal, QC H3A 2B2, Canada; (M.Z.); (J.M.); (Y.H.); (D.S.); (E.H.)
| | - Drew Schupbach
- Surgical and Interventional Sciences Division, Faculty of Medicine, McGill University, Montreal, QC H3A 2B2, Canada; (M.Z.); (J.M.); (Y.H.); (D.S.); (E.H.)
- Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC H3A 0C5, Canada
| | - Fackson Mwale
- Lady Davis Institute for Medical Research, Lady Davies Institute Jewish General Hospital, 3755 Cote-St. Catherine Road, Room 602, Montréal, QC H3T 1E2, Canada;
| | - Edward Harvey
- Surgical and Interventional Sciences Division, Faculty of Medicine, McGill University, Montreal, QC H3A 2B2, Canada; (M.Z.); (J.M.); (Y.H.); (D.S.); (E.H.)
- Department of Surgery, Faculty of Medicine, McGill University, Montreal, QC H3A 0C5, Canada
| | - Geraldine Merle
- Surgical and Interventional Sciences Division, Faculty of Medicine, McGill University, Montreal, QC H3A 2B2, Canada; (M.Z.); (J.M.); (Y.H.); (D.S.); (E.H.)
- Department of Chemical Engineering, École Polytechnique de Montréal, Montreal, QC H3T 1J4, Canada
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14
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Wang T, Sharma AK, Wu C, Maushart CI, Ghosh A, Yang W, Stefanicka P, Kovanicova Z, Ukropec J, Zhang J, Arnold M, Klug M, De Bock K, Schneider U, Popescu C, Zheng B, Ding L, Long F, Dewal RS, Moser C, Sun W, Dong H, Takes M, Suelberg D, Mameghani A, Nocito A, Zech CJ, Chirindel A, Wild D, Burger IA, Schön MR, Dietrich A, Gao M, Heine M, Sun Y, Vargas-Castillo A, Søberg S, Scheele C, Balaz M, Blüher M, Betz MJ, Spiegelman BM, Wolfrum C. Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes. Cell Metab 2024; 36:2130-2145.e7. [PMID: 39084216 DOI: 10.1016/j.cmet.2024.07.005] [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] [Received: 12/26/2023] [Revised: 04/22/2024] [Accepted: 07/08/2024] [Indexed: 08/02/2024]
Abstract
Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.
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Affiliation(s)
- Tongtong Wang
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Anand Kumar Sharma
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Chunyan Wu
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Claudia Irene Maushart
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Basel and University of Basel, Basel, Switzerland
| | - Adhideb Ghosh
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Wu Yang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Patrik Stefanicka
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University in Bratislava, Bratislava, Slovakia
| | - Zuzana Kovanicova
- Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jozef Ukropec
- Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jing Zhang
- Laboratory of Exercise and Health, Health Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland
| | - Myrtha Arnold
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Manuel Klug
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Katrien De Bock
- Laboratory of Exercise and Health, Health Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland
| | - Ulrich Schneider
- Department of Surgery, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland
| | - Cristina Popescu
- Department of Nuclear Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland
| | - Bo Zheng
- School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China
| | - Lianggong Ding
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Fen Long
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Revati Sumukh Dewal
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Caroline Moser
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Wenfei Sun
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Hua Dong
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland
| | - Martin Takes
- Department of Radiology and Nuclear Medicine, University Hospital of Basel, Basel, Switzerland
| | - Dominique Suelberg
- Department of Surgery, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland
| | - Alexander Mameghani
- Department of Surgery, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland
| | - Antonio Nocito
- Department of Surgery, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland
| | - Christoph Johannes Zech
- Department of Radiology and Nuclear Medicine, University Hospital of Basel, Basel, Switzerland
| | - Alin Chirindel
- Department of Radiology and Nuclear Medicine, University Hospital of Basel, Basel, Switzerland
| | - Damian Wild
- Department of Radiology and Nuclear Medicine, University Hospital of Basel, Basel, Switzerland
| | - Irene A Burger
- Department of Nuclear Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland; Department of Nuclear Medicine, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Michael R Schön
- Städtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, Karlsruhe, Germany
| | - Arne Dietrich
- Clinic for Visceral, Transplant and Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany
| | - Min Gao
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Markus Heine
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
| | - Yizhi Sun
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Ariana Vargas-Castillo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Susanna Søberg
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; The Center of Inflammation and Metabolism and the Center for Physical Activity Research, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Camilla Scheele
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; The Center of Inflammation and Metabolism and the Center for Physical Activity Research, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Miroslav Balaz
- Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia; Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia
| | - Matthias Blüher
- Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Germany & Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital, Leipzig, Germany.
| | - Matthias Johannes Betz
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Basel and University of Basel, Basel, Switzerland.
| | - Bruce M Spiegelman
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA
| | - Christian Wolfrum
- Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland.
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15
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Wang R, Gomez Salazar M, Pruñonosa Cervera I, Coutts A, French K, Pinto MM, Gohlke S, García-Martín R, Blüher M, Schofield CJ, Kourtzelis I, Stimson RH, Bénézech C, Christian M, Schulz TJ, Gudmundsson EF, Jennings LL, Gudnason VG, Chavakis T, Morton NM, Emilsson V, Michailidou Z. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality. Nat Commun 2024; 15:7483. [PMID: 39209825 PMCID: PMC11362468 DOI: 10.1038/s41467-024-51718-7] [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: 04/09/2022] [Accepted: 08/14/2024] [Indexed: 09/04/2024] Open
Abstract
Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
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Affiliation(s)
- Rongling Wang
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mario Gomez Salazar
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Iris Pruñonosa Cervera
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Amanda Coutts
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Karen French
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Marlene Magalhaes Pinto
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Sabrina Gohlke
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany
| | - Ruben García-Martín
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC (CNB-CSIC), Campus-UAM, Madrid, Spain
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Christopher J Schofield
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research University of Oxford, Oxford, UK
| | - Ioannis Kourtzelis
- Hull York Medical School, York Biomedical Research Institute, University of York, York, UK
| | - Roland H Stimson
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Cécile Bénézech
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mark Christian
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Nuthetal, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | | | - Lori L Jennings
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Vilmundur G Gudnason
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Triantafyllos Chavakis
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, Helmholtz Zentrum München, University Hospital and Faculty of Medicine Technische Universität Dresden, Dresden, Germany
| | - Nicholas M Morton
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK
| | - Valur Emilsson
- Icelandic Heart Association, Kopavogur, Iceland
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Zoi Michailidou
- Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Clifton, Nottingham, UK.
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16
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Davidsen LI, Hagberg CE, Goitea V, Lundby SM, Larsen S, Ebbesen MF, Stanic N, Topel H, Kornfeld JW. Mouse vascularized adipose spheroids: an organotypic model for thermogenic adipocytes. Front Endocrinol (Lausanne) 2024; 15:1396965. [PMID: 38982992 PMCID: PMC11231189 DOI: 10.3389/fendo.2024.1396965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/30/2024] [Indexed: 07/11/2024] Open
Abstract
Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues' thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by environmental factors like cold exposure or by pharmacology, share metabolic mechanisms that drive non-shivering thermogenesis. Understanding these two cell types requires advanced, yet broadly applicable in vitro models that reflect the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue, a tissue with 'beiging' capacity in mice and humans. We show that adding a scaffold improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers, thus reflecting increased adipocyte maturity. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to classical 2D cultures, which was enhanced by β-adrenergic receptor stimulation correlating with elevated β-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.
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Affiliation(s)
- Laura Ingeborg Davidsen
- Functional Genomics and Metabolism Research Unit, Institute of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark
| | - Carolina E. Hagberg
- Division of Cardiovascular Medicine, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Victor Goitea
- Functional Genomics and Metabolism Research Unit, Institute of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark
- Novo Nordisk Foundation Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, Denmark
| | - Stine Meinild Lundby
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Steen Larsen
- Xlab, Center for Healthy Aging, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Morten Frendø Ebbesen
- Danish Molecular Biomedical Imaging Center (DaMBIC), Institute of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark
| | - Natasha Stanic
- Functional Genomics and Metabolism Research Unit, Institute of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark
| | - Hande Topel
- Functional Genomics and Metabolism Research Unit, Institute of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark
- Novo Nordisk Foundation Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, Denmark
| | - Jan-Wilhelm Kornfeld
- Functional Genomics and Metabolism Research Unit, Institute of Biochemistry and Molecular Biology, Faculty of Science, University of Southern Denmark, Odense, Denmark
- Novo Nordisk Foundation Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, Denmark
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17
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Luo Y, Ma W, Cheng S, Yuan T, Li J, Hao H, Liu K, Zeng M, Pan Y. Transplantation of Cold-Stimulated Subcutaneous Adipose Tissue Improves Fat Retention and Recipient Metabolism. Aesthet Surg J 2024; 44:NP486-NP500. [PMID: 38518754 DOI: 10.1093/asj/sjae070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 03/24/2024] Open
Abstract
BACKGROUND Induction of beige fat for grafting is an emerging transplantation strategy. However, safety concerns associated with pharmaceutical interventions limit its wider application. Moreover, because beige fat is a special type of fat with strong metabolic functions, its effect on the metabolism of recipients after grafting has not been explored in the plastic surgery domain. OBJECTIVES The aim of this study was to explore whether cold-induced inguinal white adipose tissue (iWAT) transplantation has a higher retention rate and beneficial effects on recipient metabolism. METHODS C57/BL6 mice were subjected to cold stimulation for 48 hours to induce the browning of iWAT and harvested immediately. Subsequently, each mouse received a transplant of 0.2 mL cold-induced iWAT or normal iWAT. Fat grafts and recipients' iWAT, epididymal adipose tissue, and brown adipose tissue were harvested at 8 weeks after operation. Immunofluorescence staining, real-time polymerase chain reaction, and western blot were used for histological and molecular analysis. RESULTS Cold-induced iWAT grafting had a higher mean [standard error of the mean] retention rate (67.33% [1.74%] vs 55.83% [2.94%], P < .01) and more satisfactory structural integrity than normal iWAT. Histological changes identified improved adipose tissue homeostasis after cold challenge, including abundant smaller adipocytes, higher levels of adipogenesis, angiogenesis, and proliferation, but lower levels of fibrosis. More importantly, cold-induced iWAT grafting suppressed the inflammation of epididymal adipose tissue caused by conventional fat grafting, and activated the glucose metabolism and thermogenic activity of recipients' adipose tissues. CONCLUSIONS Cold-induced iWAT grafting is an effective nonpharmacological intervention strategy to improve the retention rate and homeostasis of grafts. Furthermore, it improves the adverse effects caused by traditional fat grafting, while also conferring metabolic benefits.
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18
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Luengo-Pérez LM, Fernández-Bueso M, Guzmán-Carmona C, López-Navia A, García-Lobato C. Morphofunctional Assessment beyond Malnutrition: Fat Mass Assessment in Adult Patients with Phenylketonuria-Systematic Review. Nutrients 2024; 16:1833. [PMID: 38931188 PMCID: PMC11206948 DOI: 10.3390/nu16121833] [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: 05/12/2024] [Revised: 06/04/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Morphofunctional assessment was developed to evaluate disease-related malnutrition. However, it can also be used to assess cardiometabolic risk, as excess adiposity increases this risk. Phenylketonuria (PKU) is the most prevalent inherited metabolic disease among adults, and obesity in PKU has recently gained interest, although fat mass correlates better with cardiometabolic risk than body mass index. In this systematic review, the objective was to assess whether adult patients with PKU have higher fat mass than healthy controls. Studies of adult PKU patients undergoing dietary treatment in a metabolic clinic reporting fat mass were included. The PubMed and EMBASE databases were searched. Relevance of articles, data collection, and risk of bias were evaluated by two independent reviewers. Ten articles were evaluated, six with a control group, including 310 subjects with PKU, 62 with mild hyperphenylalaninemia, and 157 controls. One study reported a significant and four a tendency towards an increased fat mass in all patients or only females with PKU. Limitations included not having a healthy control group, not reporting sex-specific results and using different techniques to assess fat mass. Evaluation of fat mass should be included in the morphofunctional assessment of cardiometabolic risk in adult patients with PKU.
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Affiliation(s)
- Luis M. Luengo-Pérez
- Medical Sciences Department, Faculty of Medicine and Health Sciences, University of Extremadura, 06006 Badajoz, Spain
- Clinical Nutrition and Dietetics Unit, Endocrinology and Nutrition Section, Badajoz University Hospital, 06008 Badajoz, Spain; (M.F.-B.); (C.G.-L.)
| | - Mercedes Fernández-Bueso
- Clinical Nutrition and Dietetics Unit, Endocrinology and Nutrition Section, Badajoz University Hospital, 06008 Badajoz, Spain; (M.F.-B.); (C.G.-L.)
| | - Carlos Guzmán-Carmona
- Endocrinology and Nutrition, Don Benito-Villanueva de la Serena Hospital Complex, 06400 Don Benito, Spain; (C.G.-C.); (A.L.-N.)
| | - Ana López-Navia
- Endocrinology and Nutrition, Don Benito-Villanueva de la Serena Hospital Complex, 06400 Don Benito, Spain; (C.G.-C.); (A.L.-N.)
| | - Claudia García-Lobato
- Clinical Nutrition and Dietetics Unit, Endocrinology and Nutrition Section, Badajoz University Hospital, 06008 Badajoz, Spain; (M.F.-B.); (C.G.-L.)
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19
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Han J, Chen Y, Xu X, Li Q, Xiang X, Shen J, Ma X. Development of Recombinant High-Density Lipoprotein Platform with Innate Adipose Tissue-Targeting Abilities for Regional Fat Reduction. ACS NANO 2024; 18:13635-13651. [PMID: 38753978 DOI: 10.1021/acsnano.4c00403] [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: 05/18/2024]
Abstract
As an escalating public health issue, obesity and overweight conditions are predispositions to various diseases and are exacerbated by concurrent chronic inflammation. Nonetheless, extant antiobesity pharmaceuticals (quercetin, capsaicin, catecholamine, etc.) manifest constrained efficacy alongside systemic toxic effects. Effective therapeutic approaches that selectively target adipose tissue, thereby enhancing local energy expenditure, surmounting the limitations of prevailing antiobesity modalities are highly expected. In this context, we developed a temperature-sensitive hydrogel loaded with recombinant high-density lipoprotein (rHDL) to achieve targeted delivery of resveratrol, an adipose browning activator, to adipose tissue. rHDL exhibits self-regulation on fat cell metabolism and demonstrates natural targeting toward scavenger receptor class B type I (SR-BI), which is highly expressed by fat cells, thereby achieving a synergistic effect for the treatment of obesity. Additionally, the dispersion of rHDL@Res in temperature-sensitive hydrogels, coupled with the regulation of their degradation and drug release rate, facilitated sustainable drug release at local adipose tissues over an extended period. Following 24 days' treatment regimen, obese mice exhibited improved metabolic status, resulting in a reduction of 68.2% of their inguinal white adipose tissue (ingWAT). Specifically, rHDL@Res/gel facilitated the conversion of fatty acids to phospholipids (PA, PC), expediting fat mobilization, mitigating triglyceride accumulation, and therefore facilitating adipose tissue reduction. Furthermore, rHDL@Res/gel demonstrated efficacy in attenuating obesity-induced inflammation and fostering angiogenesis in ingWAT. Collectively, this engineered local fat reduction platform demonstrated heightened effectiveness and safety through simultaneously targeting adipocytes, promoting WAT browning, regulating lipid metabolism, and controlling inflammation, showing promise for adipose-targeted therapy.
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Affiliation(s)
- Junhua Han
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Yingxian Chen
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Xiaolong Xu
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Qingmeng Li
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Xin Xiang
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Jianzhong Shen
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
| | - Xiaowei Ma
- National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China
- Sanya Institute of China Agricultural University, Sanya, Hainan 572025, P. R. China
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20
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Zheng Y, Li H, Bao Q, Tu Y, Ye Y, Jia W, Cao D. Brown Adipose Tissue Promotes Autologous Fat Grafts Retention Possibly Through Inhibiting Wnt/β-Catenin Pathway. Aesthetic Plast Surg 2024; 48:1817-1824. [PMID: 38409345 DOI: 10.1007/s00266-024-03888-4] [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: 08/25/2023] [Accepted: 01/30/2024] [Indexed: 02/28/2024]
Abstract
BACKGROUND In plastic surgery, autologous fat grafts (AFG) play an important role because of their abundant supply, biocompatibility, and low rejection rate. However, the lower retention rate of fat grafts limits their widespread use. Brown adipose tissue (BAT) can promote angiogenesis and regulate the level of associated inflammation. This study explored whether BAT has a facilitative effect on fat graft retention. METHODS We obtained white adipose tissue (WAT) from c57 mice and combined it with either BAT from c57 mice or phosphate-buffered saline (PBS) as a control. These mixtures were injected subcutaneously into the back of thymus-free nude mice. After 12 weeks, fat grafts were harvested, weighed, and analyzed. RESULTS We found that the BAT-grafted group had higher mass retention, more mature adipocytes, and higher vascularity than the other group. Further analysis revealed that BAT inhibited M1 macrophages; down-regulated IL-6, IL-1β, and TNF-β; upregulated M2 macrophages and Vascular endothelial growth factor-A (VEGFA); and promoted adipocyte regeneration by inhibiting the Wnt/β-catenin pathway, which together promoted adipose graft retention. CONCLUSION The study demonstrated that BAT improved adipose graft retention by promoting angiogenesis, inhibiting tissue inflammation levels and the Wnt/β-catenin pathway. LEVEL OF EVIDENCE III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
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Affiliation(s)
- Yunfeng Zheng
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China
| | - Honghong Li
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China
| | - Qiong Bao
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China
| | - Yiqian Tu
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China
| | - Yujie Ye
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China
| | - Wenjun Jia
- Department of Breast Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China.
| | - Dongsheng Cao
- Department of Plastic and Reconstructive Surgery, The Second Affiliated Hospital of Anhui Medical University, 678, FuRong Road, Hefei, 230601, Anhui, China.
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21
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Zhang Y, Zhang B, Sun X. The molecular mechanism of macrophage-adipocyte crosstalk in maintaining energy homeostasis. Front Immunol 2024; 15:1378202. [PMID: 38650945 PMCID: PMC11033412 DOI: 10.3389/fimmu.2024.1378202] [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: 01/29/2024] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
Interactions between macrophages and adipocytes in adipose tissue are critical for the regulation of energy metabolism and obesity. Macrophage polarization induced by cold or other stimulations can drive metabolic reprogramming of adipocytes, browning, and thermogenesis. Accordingly, investigating the roles of macrophages and adipocytes in the maintenance of energy homeostasis is critical for the development of novel therapeutic approaches specifically targeting macrophages in metabolic disorders such as obesity. Current review outlines macrophage polarization not only regulates the release of central nervous system and inflammatory factors, but controls mitochondrial function, and other factor that induce metabolic reprogramming of adipocytes and maintain energy homeostasis. We also emphasized on how the adipocytes conversely motivate the polarization of macrophage. Exploring the interactions between adipocytes and macrophages may provide new therapeutic strategies for the management of obesity-related metabolic diseases.
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Affiliation(s)
- Yudie Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Bin Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glyeolipid Metabolism Disorder Disease, State Administration of Traditional Chinese Medicine, Beijing, China
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Mallardo M, Daniele A, Musumeci G, Nigro E. A Narrative Review on Adipose Tissue and Overtraining: Shedding Light on the Interplay among Adipokines, Exercise and Overtraining. Int J Mol Sci 2024; 25:4089. [PMID: 38612899 PMCID: PMC11012884 DOI: 10.3390/ijms25074089] [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: 03/18/2024] [Revised: 03/30/2024] [Accepted: 04/01/2024] [Indexed: 04/14/2024] Open
Abstract
Lifestyle factors, particularly physical inactivity, are closely linked to the onset of numerous metabolic diseases. Adipose tissue (AT) has been extensively studied for various metabolic diseases such as obesity, type 2 diabetes, and immune system dysregulation due to its role in energy metabolism and regulation of inflammation. Physical activity is increasingly recognized as a powerful non-pharmacological tool for the treatment of various disorders, as it helps to improve metabolic, immune, and inflammatory functions. However, chronic excessive training has been associated with increased inflammatory markers and oxidative stress, so much so that excessive training overload, combined with inadequate recovery, can lead to the development of overtraining syndrome (OTS). OTS negatively impacts an athlete's performance capabilities and significantly affects both physical health and mental well-being. However, diagnosing OTS remains challenging as the contributing factors, signs/symptoms, and underlying maladaptive mechanisms are individualized, sport-specific, and unclear. Therefore, identifying potential biomarkers that could assist in preventing and/or diagnosing OTS is an important objective. In this review, we focus on the possibility that the endocrine functions of AT may have significant implications in the etiopathogenesis of OTS. During physical exercise, AT responds dynamically, undergoing remodeling of endocrine functions that influence the production of adipokines involved in regulating major energy and inflammatory processes. In this scenario, we will discuss exercise about its effects on AT activity and metabolism and its relevance to the prevention and/or development of OTS. Furthermore, we will highlight adipokines as potential markers for diagnosing OTS.
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Affiliation(s)
- Marta Mallardo
- Department of Molecular and Biotechnological Medicine, University of Naples “Federico II”, 80131 Naples, Italy;
- CEINGE-Biotechnologies Advances S.c.a r.l., Via G. Salvatore 486, 80145 Naples, Italy;
| | - Aurora Daniele
- Department of Molecular and Biotechnological Medicine, University of Naples “Federico II”, 80131 Naples, Italy;
- CEINGE-Biotechnologies Advances S.c.a r.l., Via G. Salvatore 486, 80145 Naples, Italy;
| | - Giuseppe Musumeci
- Department of Biomedical and Biotechnological Sciences, Anatomy, Histology and Movement Sciences Section, School of Medicine, University of Catania, Via S. Sofia 87, 95123 Catania, Italy
- Research Center on Motor Activities (CRAM), University of Catania, 95123 Catania, Italy
| | - Ersilia Nigro
- CEINGE-Biotechnologies Advances S.c.a r.l., Via G. Salvatore 486, 80145 Naples, Italy;
- Department of Pharmaceutical, Biological, Environmental Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Via G. Vivaldi 42, 81100 Caserta, Italy
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Zhang J, Kibret BG, Vatner DE, Vatner SF. The role of brown adipose tissue in mediating healthful longevity. THE JOURNAL OF CARDIOVASCULAR AGING 2024; 4:17. [PMID: 39119146 PMCID: PMC11309368 DOI: 10.20517/jca.2024.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
There are two major subtypes of adipose tissue, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT). It has been known for a long time that WAT mediates obesity and impairs healthful longevity. More recently, interest has focused on BAT, which, unlike WAT, actually augments healthful aging. The goal of this review is to examine the role of BAT in mediating healthful longevity. A major role for BAT and its related beige adipose tissue is thermogenesis, as a mechanism to maintain body temperature by producing heat through uncoupling protein 1 (UCP1) or through UCP1-independent thermogenic pathways. Our hypothesis is that healthful longevity is, in part, mediated by BAT. BAT protects against the major causes of impaired healthful longevity, i.e., obesity, diabetes, cardiovascular disorders, cancer, Alzheimer's disease, reduced exercise tolerance, and impaired blood flow. Several genetically engineered mouse models have shown that BAT enhances healthful aging and that their BAT is more potent than wild-type (WT) BAT. For example, when BAT, which increases longevity and exercise performance in mice with disruption of the regulator of G protein signaling 14 (RGS14), is transplanted to WT mice, their exercise capacity is enhanced at 3 days after BAT transplantation, whereas BAT transplantation from WT to WT mice also resulted in increased exercise performance, but only at 8 weeks after transplantation. In view of the ability of BAT to mediate healthful longevity, it is likely that a pharmaceutical analog of BAT will become a novel therapeutic modality.
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Affiliation(s)
- Jie Zhang
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ 07103, USA
| | - Berhanu Geresu Kibret
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ 07103, USA
| | - Dorothy E. Vatner
- Department of Medicine, Rutgers, New Jersey Medical School, Newark, NJ 07103, USA
| | - Stephen F. Vatner
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, NJ 07103, USA
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24
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Zhao JY, Zhou LJ, Ma KL, Hao R, Li M. MHO or MUO? White adipose tissue remodeling. Obes Rev 2024; 25:e13691. [PMID: 38186200 DOI: 10.1111/obr.13691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 11/14/2023] [Accepted: 11/19/2023] [Indexed: 01/09/2024]
Abstract
In this review, we delve into the intricate relationship between white adipose tissue (WAT) remodeling and metabolic aspects in obesity, with a specific focus on individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). WAT is a highly heterogeneous, plastic, and dynamically secreting endocrine and immune organ. WAT remodeling plays a crucial role in metabolic health, involving expansion mode, microenvironment, phenotype, and distribution. In individuals with MHO, WAT remodeling is beneficial, reducing ectopic fat deposition and insulin resistance (IR) through mechanisms like increased adipocyte hyperplasia, anti-inflammatory microenvironment, appropriate extracellular matrix (ECM) remodeling, appropriate vascularization, enhanced WAT browning, and subcutaneous adipose tissue (SWAT) deposition. Conversely, for those with MUO, WAT remodeling leads to ectopic fat deposition and IR, causing metabolic dysregulation. This process involves adipocyte hypertrophy, disrupted vascularization, heightened pro-inflammatory microenvironment, enhanced brown adipose tissue (BAT) whitening, and accumulation of visceral adipose tissue (VWAT) deposition. The review underscores the pivotal importance of intervening in WAT remodeling to hinder the transition from MHO to MUO. This insight is valuable for tailoring personalized and effective management strategies for patients with obesity in clinical practice.
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Affiliation(s)
- Jing Yi Zhao
- Research Laboratory of Molecular Biology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Juan Zhou
- Research Laboratory of Molecular Biology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Kai Le Ma
- Research Laboratory of Molecular Biology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Rui Hao
- Research Laboratory of Molecular Biology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Li
- Research Laboratory of Molecular Biology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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25
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Negroiu CE, Tudorașcu I, Bezna CM, Godeanu S, Diaconu M, Danoiu R, Danoiu S. Beyond the Cold: Activating Brown Adipose Tissue as an Approach to Combat Obesity. J Clin Med 2024; 13:1973. [PMID: 38610736 PMCID: PMC11012454 DOI: 10.3390/jcm13071973] [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: 02/24/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
With a dramatic increase in the number of obese and overweight people, there is a great need for new anti-obesity therapies. With the discovery of the functionality of brown adipose tissue in adults and the observation of beige fat cells among white fat cells, scientists are looking for substances and methods to increase the activity of these cells. We aimed to describe how scientists have concluded that brown adipose tissue is also present and active in adults, to describe where in the human body these deposits of brown adipose tissue are, to summarize the origin of both brown fat cells and beige fat cells, and, last but not least, to list some of the substances and methods classified as BAT promotion agents with their benefits and side effects. We summarized these findings based on the original literature and reviews in the field, emphasizing the discovery, function, and origins of brown adipose tissue, BAT promotion agents, and batokines. Only studies written in English and with a satisfying rating were identified from electronic searches of PubMed.
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Affiliation(s)
- Cristina Elena Negroiu
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.M.B.); (S.D.)
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Iulia Tudorașcu
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.M.B.); (S.D.)
| | - Cristina Maria Bezna
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.M.B.); (S.D.)
| | - Sanziana Godeanu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marina Diaconu
- Department of Radiology, County Clinical Emergency Hospital of Craiova, 200642 Craiova, Romania;
| | - Raluca Danoiu
- Department of Social Sciences and Humanities, University of Craiova, 200585 Craiova, Romania;
| | - Suzana Danoiu
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (C.M.B.); (S.D.)
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26
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Iida T, Ueda Y, Tsukada H, Fukumoto D, Hamaoka T. Brown adipose tissue evaluation using water and triglyceride as indices by diffuse reflectance spectroscopy. JOURNAL OF BIOPHOTONICS 2024; 17:e202300183. [PMID: 37885352 DOI: 10.1002/jbio.202300183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 10/06/2023] [Accepted: 10/24/2023] [Indexed: 10/28/2023]
Abstract
Brown adipose tissue (BAT) is related to lipid and glucose metabolism, and BAT evaluation is expected to contribute to disease prevention and treatment. We aimed to establish a BAT evaluation method using simple and non-invasive diffuse reflectance spectroscopy (DRS). We acquired diffuse reflectance spectra of BAT using DRS from rats with cold stimulation and analyzed the second-derivative spectra. To predict the amount of triglyceride in BAT from the second-derivative spectra, partial least-squares regression analysis was performed, and we examined whether BAT weight can be predicted from the amount of triglyceride by single regression analysis. By focusing on changes in the amount of triglyceride in BAT with cold stimulation, it was suggested that this amount could be predicted spectroscopically, and the predicted amount of triglyceride could be used to estimate the BAT weight with cold stimulation. If these results can be translated into humans, they may contribute to preventing metabolic disorders.
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Affiliation(s)
- Tomomi Iida
- Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan
| | - Yukio Ueda
- Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan
| | - Hideo Tsukada
- Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan
| | - Dai Fukumoto
- Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Shizuoka, Japan
| | - Takafumi Hamaoka
- Department of Sports Medicine for Health Promotion, Tokyo Medical University, Tokyo, Japan
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27
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Ziqubu K, Dludla PV, Mabhida SE, Jack BU, Keipert S, Jastroch M, Mazibuko-Mbeje SE. Brown adipose tissue-derived metabolites and their role in regulating metabolism. Metabolism 2024; 150:155709. [PMID: 37866810 DOI: 10.1016/j.metabol.2023.155709] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 09/28/2023] [Accepted: 10/14/2023] [Indexed: 10/24/2023]
Abstract
The discovery and rejuvenation of metabolically active brown adipose tissue (BAT) in adult humans have offered a new approach to treat obesity and metabolic diseases. Beyond its accomplished role in adaptive thermogenesis, BAT secretes signaling molecules known as "batokines", which are instrumental in regulating whole-body metabolism via autocrine, paracrine, and endocrine action. In addition to the intrinsic BAT metabolite-oxidizing activity, the endocrine functions of these molecules may help to explain the association between BAT activity and a healthy systemic metabolic profile. Herein, we review the evidence that underscores the significance of BAT-derived metabolites, especially highlighting their role in controlling physiological and metabolic processes involving thermogenesis, substrate metabolism, and other essential biological processes. The conversation extends to their capacity to enhance energy expenditure and mitigate features of obesity and its related metabolic complications. Thus, metabolites derived from BAT may provide new avenues for the discovery of metabolic health-promoting drugs with far-reaching impacts. This review aims to dissect the complexities of the secretory role of BAT in modulating local and systemic metabolism in metabolic health and disease.
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Affiliation(s)
- Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Phiwayinkosi V Dludla
- Cochrane South Africa, South African Medical Research Council, Tygerberg 7505, South Africa; Department of Biochemistry and Microbiology, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa 3886, South Africa
| | - Sihle E Mabhida
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Babalwa U Jack
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa
| | - Susanne Keipert
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
| | - Martin Jastroch
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden
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He L, Li H, Zhang L, Zhang J, Zhang G, Tong X, Zhang T, Wu Y, Li M, Jin L. Transcriptome analysis of norepinephrine-induced lipolysis in differentiated adipocytes of Bama pig. Gene 2023; 888:147753. [PMID: 37659599 DOI: 10.1016/j.gene.2023.147753] [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: 06/06/2023] [Revised: 08/24/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
Sympathetic innervation of white adipose tissue (WAT) plays a key role in the regulation of lipid metabolism. Sympathetic activation promotes release of norepinephrine (NE), which binds to adrenergic receptors on adipocytes, promoting adipocyte lipolysis and enhanced oxidative metabolism. However, the mechanism by which sympathetic nerves regulate lipid metabolism in pig adipose tissue remains unclear. We used NE to simulate the process of sympathetic driving in pig adipocytes. RNA sequencing (RNA-seq) was used to determine the gene expression profile of pig adipocytes responding to NE stimulation. Our data suggests that the lipolytic signaling pathway is activated in pig adipocytes upon acute stimulation of NE, resulting in enhanced lipid metabolism and lipolysis, consistent with the phenomena found in humans and mice. Specifically, differentially expressed protein coding genes (PCGs) (SIRT4, SLC27A1) are mainly associated with functions that inhibit fatty acid oxidation and promote lipid synthesis. Similarly, we investigated the changes in regulatory transcripts such as long non-coding RNAs (lncRNAs) and transcripts of uncertain coding potential (TUCP) in response to NE and found that differentially expressed lncRNAs (lncG47338, lncG30660, lncG29516, lncG3790) and TUCP (TUCP_G38001) were co-expressed with target genes related to the promotion of fatty acid β-oxidation, lipolysis and oxidative metabolism, thus acting as regulators. These results indicate a broad suite of gene expression alterations in response to NE stimulation and promote the understanding of the molecular mechanisms by which NE regulates lipid metabolism in pigs.
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Affiliation(s)
- Li He
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Hong Li
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Linzhen Zhang
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Jiaman Zhang
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Geng Zhang
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Xingyan Tong
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Tingting Zhang
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Yifan Wu
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China
| | - Mingzhou Li
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China.
| | - Long Jin
- Sichuan Provincial Key Laboratory of Animal Breeding and Genetics, Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, China.
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Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol 2023; 24:816-834. [PMID: 37491579 DOI: 10.1038/s41580-023-00631-w] [Citation(s) in RCA: 149] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2023] [Indexed: 07/27/2023]
Abstract
The formation of new blood vessels, called angiogenesis, is an essential pathophysiological process in which several families of regulators have been implicated. Among these, vascular endothelial growth factor A (VEGFA; also known as VEGF) and its two tyrosine kinase receptors, VEGFR1 and VEGFR2, represent a key signalling pathway mediating physiological angiogenesis and are also major therapeutic targets. VEGFA is a member of the gene family that includes VEGFB, VEGFC, VEGFD and placental growth factor (PLGF). Three decades after its initial isolation and cloning, VEGFA is arguably the most extensively investigated signalling system in angiogenesis. Although many mediators of angiogenesis have been identified, including members of the FGF family, angiopoietins, TGFβ and sphingosine 1-phosphate, all current FDA-approved anti-angiogenic drugs target the VEGF pathway. Anti-VEGF agents are widely used in oncology and, in combination with chemotherapy or immunotherapy, are now the standard of care in multiple malignancies. Anti-VEGF drugs have also revolutionized the treatment of neovascular eye disorders such as age-related macular degeneration and ischaemic retinal disorders. In this Review, we emphasize the molecular, structural and cellular basis of VEGFA action as well as recent findings illustrating unexpected interactions with other pathways and provocative reports on the role of VEGFA in regenerative medicine. We also discuss clinical and translational aspects of VEGFA. Given the crucial role that VEGFA plays in regulating angiogenesis in health and disease, this molecule is largely the focus of this Review.
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Affiliation(s)
- Lorena Pérez-Gutiérrez
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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Gao H, Li Y, Jin Y, Zhang L, Xia X, Liu J, Wang H, Xie Y, Ding W. Electroacupuncture activates angiogenesis by regulating the PI3K/Pten/Thbs1 signaling pathway to promote the browning of adipose tissue in HFD-induced obese mice. Biomed Pharmacother 2023; 166:115386. [PMID: 37651803 DOI: 10.1016/j.biopha.2023.115386] [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: 06/25/2023] [Revised: 08/23/2023] [Accepted: 08/23/2023] [Indexed: 09/02/2023] Open
Abstract
This study investigated the effect of electroacupuncture (EA) on the browning of white adipose tissue (WAT) via angiogenesis and its potential mechanism in obese mice. Four-week-old male C56BL/6 mice were randomly divided into a high-fat diet (HFD) and a normal chow diet (ND) group. After 12 weeks, HFD mice were randomly divided into two groups to receive or not receive EA for 3 weeks. After EA treatment, body weight, adipocyte size, serum glucose (GLU), triacylglycerol (TG), cholesterol (CHO), leptin (Lep), monocyte chemoattractant protein-1 (MCP-1), WAT browning-related genes, angiogenesis-related genes, and the PI3K/Pten/Thbs1 signaling pathway were evaluated. The results indicated that EA significantly reduced body weight, adipocyte size, and serum concentrations of GLU, TG, CHO, Lep and MCP-1 and promoted WAT browning. Angiogenesis and the PI3K/Pten/Thbs1 signaling pathway were all activated by EA intervention. The expression levels were consistent with the results of RNA-seq and confirmed via qRTPCR and WB. Our study showed that EA may activate angiogenesis via the PI3K/Pten/Thbs1 signaling pathway in WAT, thereby promoting the browning and thermogenesis of adipose tissue.
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Affiliation(s)
- Hongyan Gao
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanhui Li
- Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Yue Jin
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Li Zhang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xiuwen Xia
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jinkun Liu
- Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Huaifu Wang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ya Xie
- Sichuan Provincial People's Hospital Jinniu Hospital, Chengdu 610007, China
| | - Weijun Ding
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Aboouf MA, Gorr TA, Hamdy NM, Gassmann M, Thiersch M. Myoglobin in Brown Adipose Tissue: A Multifaceted Player in Thermogenesis. Cells 2023; 12:2240. [PMID: 37759463 PMCID: PMC10526770 DOI: 10.3390/cells12182240] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/01/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Brown adipose tissue (BAT) plays an important role in energy homeostasis by generating heat from chemical energy via uncoupled oxidative phosphorylation. Besides its high mitochondrial content and its exclusive expression of the uncoupling protein 1, another key feature of BAT is the high expression of myoglobin (MB), a heme-containing protein that typically binds oxygen, thereby facilitating the diffusion of the gas from cell membranes to mitochondria of muscle cells. In addition, MB also modulates nitric oxide (NO•) pools and can bind C16 and C18 fatty acids, which indicates a role in lipid metabolism. Recent studies in humans and mice implicated MB present in BAT in the regulation of lipid droplet morphology and fatty acid shuttling and composition, as well as mitochondrial oxidative metabolism. These functions suggest that MB plays an essential role in BAT energy metabolism and thermogenesis. In this review, we will discuss in detail the possible physiological roles played by MB in BAT thermogenesis along with the potential underlying molecular mechanisms and focus on the question of how BAT-MB expression is regulated and, in turn, how this globin regulates mitochondrial, lipid, and NO• metabolism. Finally, we present potential MB-mediated approaches to augment energy metabolism, which ultimately could help tackle different metabolic disorders.
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Affiliation(s)
- Mostafa A. Aboouf
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Thomas A. Gorr
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
| | - Nadia M. Hamdy
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Max Gassmann
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
| | - Markus Thiersch
- Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland
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Pestel J, Blangero F, Watson J, Pirola L, Eljaafari A. Adipokines in obesity and metabolic-related-diseases. Biochimie 2023; 212:48-59. [PMID: 37068579 DOI: 10.1016/j.biochi.2023.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/03/2023] [Accepted: 04/13/2023] [Indexed: 04/19/2023]
Abstract
The discovery of leptin in the 1990s led to a reconsideration of adipose tissue (AT) as not only a fatty acid storage organ, but also a proper endocrine tissue. AT is indeed capable of secreting bioactive molecules called adipokines for white AT or batokines for brown/beige AT, which allow communication with numerous organs, especially brain, heart, liver, pancreas, and/or the vascular system. Adipokines exert pro or anti-inflammatory activities. An equilibrated balance between these two sets ensures homeostasis of numerous tissues and organs. During the development of obesity, AT remodelling leads to an alteration of its endocrine activity, with increased secretion of pro-inflammatory adipokines relative to the anti-inflammatory ones, as shown in the graphical abstract. Pro-inflammatory adipokines take part in the initiation of local and systemic inflammation during obesity and contribute to comorbidities associated to obesity, as detailed in the present review.
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Affiliation(s)
- Julien Pestel
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Ferdinand Blangero
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Julia Watson
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Luciano Pirola
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France
| | - Assia Eljaafari
- INSERM U1060-CarMeN /Université Claude Bernard Lyon 1/INRAE/ Université Claude Bernard Lyon 1: Laboratoire CarMeN, 165 chemin du Grand Revoyet, CHLS, 69310 Pierre Bénite, France; Hospices Civils de Lyon: 2 quai des Célestins, 69001 Lyon, France.
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Nie T, Lu J, Zhang H, Mao L. Latest advances in the regulatory genes of adipocyte thermogenesis. Front Endocrinol (Lausanne) 2023; 14:1250487. [PMID: 37680891 PMCID: PMC10482227 DOI: 10.3389/fendo.2023.1250487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023] Open
Abstract
An energy imbalance cause obesity: more energy intake or less energy expenditure, or both. Obesity could be the origin of many metabolic disorders, such as type 2 diabetes and cardiovascular disease. UCP1 (uncoupling protein1), which is highly and exclusively expressed in the thermogenic adipocytes, including beige and brown adipocytes, can dissipate proton motive force into heat without producing ATP to increase energy expenditure. It is an attractive strategy to combat obesity and its related metabolic disorders by increasing non-shivering adipocyte thermogenesis. Adipocyte thermogenesis has recently been reported to be regulated by several new genes. This work provided novel and potential targets to activate adipocyte thermogenesis and resist obesity, such as secreted proteins ADISSP and EMC10, enzyme SSU72, etc. In this review, we have summarized the latest research on adipocyte thermogenesis regulation to shed more light on this topic.
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Affiliation(s)
- Tao Nie
- School of Basic Medicine, Hubei University of Arts and Science, Xiangyang, China
| | - Jinli Lu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Hua Zhang
- Department of Medical Iconography, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Liufeng Mao
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
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Dai Z, Zhang Y, Meng Y, Li S, Suonan Z, Sun Y, Ji J, Shen Q, Zheng H, Xue Y. Targeted delivery of nutraceuticals derived from food for the treatment of obesity and its related complications. Food Chem 2023; 418:135980. [PMID: 36989644 DOI: 10.1016/j.foodchem.2023.135980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 03/29/2023]
Abstract
Nutraceuticals which are abundant in foods have attracted much attention due to their bioactive activities of anti-obesity, anti-hyperlipidemia and anti-atherosclerosis. Unfortunately, the poor bioavailability severely undermines their envisioned benefits. Therefore, there is an urgent need to develop suitable delivery systems to promote the benefits of their biological activity. Targeted drug delivery system (TDDS) is a novel drug delivery system that can selectively concentrate drugs on targets in the body, improve the bioavailability of agents and reduce side effects. This emerging drug delivery system provides a new strategy for the treatment of obesity with nutraceuticals and would be a promising alternative to be widely used in the food field. This review summarizes the recent studies on the application in the targeted delivery of nutraceuticals for treating obesity and its related complications, especially the available receptors and their corresponding ligands for TDDS and the evaluation methods of the targeting ability.
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35
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Zhong Y, Wang Y, Li X, Qin H, Yan S, Rao C, Fan D, Liu D, Deng F, Miao Y, Yang L, Huang K. PRMT4 Facilitates White Adipose Tissue Browning and Thermogenesis by Methylating PPARγ. Diabetes 2023; 72:1095-1111. [PMID: 37216643 PMCID: PMC10382653 DOI: 10.2337/db22-1016] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 05/10/2023] [Indexed: 05/24/2023]
Abstract
Obesity is a global health threat, and the induction of white adipose tissue (WAT) browning presents a promising therapeutic method for it. Recent publications revealed the essential role of protein arginine methyltransferase 4 (PRMT4) in lipid metabolism and adipogenesis, but its involvement in WAT browning has not been investigated. Our initial studies found that the expression of PRMT4 in adipocytes was upregulated in cold-induced WAT browning but downregulated in obesity. Besides, PRMT4 overexpression in inguinal adipose tissue accelerated WAT browning and thermogenesis to protect against high-fat diet-induced obesity and metabolic disruptions. Mechanistically, our work demonstrated that PRMT4 methylated peroxisome proliferator-activated receptor-γ (PPARγ) on Arg240 to enhance its interaction with the coactivator PR domain-containing protein 16 (PRDM16), leading to the increased expression of thermogenic genes. Taken together, our results uncover the essential role of the PRMT4/PPARγ/PRDM16 axis in the pathogenesis of WAT browning. ARTICLE HIGHLIGHTS Protein arginine methyltransferase 4 (PRMT4) expression was upregulated during cold exposure and negatively correlated with body mass of mice and humans. PRMT4 overexpression in inguinal white adipose tissue of mice improved high-fat diet-induced obesity and associated metabolic impairment due to enhanced heat production. PRMT4 methylated peroxisome proliferator-activated receptor-γ on Arg240 and facilitated the binding of the coactivator PR domain-containing protein 16 to initiate adipose tissue browning and thermogenesis. PRMT4-dependent methylation of peroxisome proliferator-activated receptor-γ on Arg240 is important in the process of inguinal white adipose tissue browning.
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Affiliation(s)
- Yi Zhong
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yilong Wang
- Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoguang Li
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haojie Qin
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shu Yan
- Heart Center and Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Caijun Rao
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Fan
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Duqiu Liu
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Liyuan Cardiovascular Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fei Deng
- Department of Urology, The Second Xiangya Hospital, Central South University, Hunan, China
| | - Yanli Miao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ling Yang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Huang
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Research Center of Metabolic and Cardiovascular Disease, Huazhong University of Science and Technology,Wuhan, China
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Liu J, Wei L, Chen T, Wang H, Luo J, Chen X, Jiang Q, Xi Q, Sun J, Zhang L, Zhang Y. MiR-143 Targets SYK to Regulate NEFA Uptake and Contribute to Thermogenesis in Male Mice. Endocrinology 2023; 164:bqad114. [PMID: 37486737 DOI: 10.1210/endocr/bqad114] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 07/25/2023]
Abstract
Excessive energy intake is the main cause of obesity, and stimulation of brown adipose tissue (BAT) and white adipose tissue (WAT) thermogenesis has emerged as an attractive tool for antiobesity. Although miR-143 has been reported to be associated with BAT thermogenesis, its role remains unclear. Here, we found that miR-143 had highest expression in adipose tissue, especially in BAT. During short-term cold exposure or CL316,243 was injected, miR-143 was markedly downregulated in BAT and subcutaneous WAT (scWAT). Moreover, knockout (KO) of miR-143 increases the body temperature of mice upon cold exposure, which may be due to the increased thermogenesis of BAT and scWAT. More importantly, supplementation of miR-143 in BAT of KO mice can inhibit the increase in body temperature in KO mice. Mechanistically, spleen tyrosine kinase was revealed for the first time as a new target of miR-143, and deletion of miR-143 facilitates fatty acid uptake in BAT. In addition, we found that brown adipocytes can promote fat mobilization of white adipocytes, and miR-143 may participate in this process. Meanwhile, we demonstrate that inactivation of adenylate cyclase 9 (AC9) in BAT inhibits thermogenesis through AC9-PKA-AMPK-CREB-UCP1 signaling pathway. Overall, our results reveal a novel function of miR-143 on thermogenesis, and a new functional link of the BAT and WAT.
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Affiliation(s)
- Jie Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
- Sanya Institute, Hainan Academy of Agricultural Sciences (Hainan Experi-mental Animal Research Center), Sanya, Hainan 572000, China
- Institute of Animal Husbandry and Veterinary Medicine, Hainan Academy of Agricultural Sciences, Hainan Key Laboratory for Tropical Animal Breeding and Disease Research, Haikou, Hainan 571100, China
| | - Limin Wei
- Sanya Institute, Hainan Academy of Agricultural Sciences (Hainan Experi-mental Animal Research Center), Sanya, Hainan 572000, China
- Institute of Animal Husbandry and Veterinary Medicine, Hainan Academy of Agricultural Sciences, Hainan Key Laboratory for Tropical Animal Breeding and Disease Research, Haikou, Hainan 571100, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Huan Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Xingping Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
- Jiangxi Province Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Lin Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, Guang-dong 510642, China
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Shamsi F, Zheng R, Ho LL, Chen K, Tseng YH. Comprehensive analysis of intercellular communication in the thermogenic adipose niche. Commun Biol 2023; 6:761. [PMID: 37479789 PMCID: PMC10361964 DOI: 10.1038/s42003-023-05140-2] [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: 11/21/2022] [Accepted: 07/12/2023] [Indexed: 07/23/2023] Open
Abstract
Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a strategy against obesity. BAT undergoes major remodeling in a cold environment. This remodeling results from changes in the number and function of brown adipocytes, expanding the network of blood vessels and sympathetic nerves, and changes in the composition and function of immune cells. Such synergistic adaptation requires extensive crosstalk between individual cells in the tissue to coordinate their responses. To understand the mechanisms of intercellular communication in BAT, we apply the CellChat algorithm to single-cell transcriptomic data of mouse BAT. We construct an integrative network of the ligand-receptor interactome in BAT and identify the major signaling inputs and outputs of each cell type. By comparing the ligand-receptor interactions in BAT of mice housed at different environmental temperatures, we show that cold exposure enhances the intercellular interactions among the major cell types in BAT, including adipocytes, adipocyte progenitors, lymphatic and vascular endothelial cells, myelinated and non-myelinated Schwann cells, and immune cells. These interactions are predicted to regulate the remodeling of the extracellular matrix, the inflammatory response, angiogenesis, and neurite growth. Together, our integrative analysis of intercellular communications in BAT and their dynamic regulation in response to housing temperatures provides a new understanding of the mechanisms underlying BAT thermogenesis. The resources presented in this study offer a valuable platform for future investigations of BAT development and thermogenesis.
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Affiliation(s)
- Farnaz Shamsi
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02115, USA.
- Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, 10010, USA.
- Department of Cell Biology, Grossman School of Medicine, New York University, New York, NY, 10016, USA.
| | - Rongbin Zheng
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Li-Lun Ho
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Kaifu Chen
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, 02115, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
| | - Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02115, USA.
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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Wang B, Du M. Increasing adipocyte number and reducing adipocyte size: the role of retinoids in adipose tissue development and metabolism. Crit Rev Food Sci Nutr 2023; 64:10608-10625. [PMID: 37427553 PMCID: PMC10776826 DOI: 10.1080/10408398.2023.2227258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2023]
Abstract
The rising prevalence of obesity is a grave public health threat. In response to excessive energy intake, adipocyte hypertrophy impairs cellular function and leads to metabolic dysfunctions while de novo adipogenesis leads to healthy adipose tissue expansion. Through burning fatty acids and glucose, the thermogenic activity of brown/beige adipocytes can effectively reduce the size of adipocytes. Recent studies show that retinoids, especially retinoic acid (RA), promote adipose vascular development which in turn increases the number of adipose progenitors surrounding the vascular vessels. RA also promotes preadipocyte commitment. In addition, RA promotes white adipocyte browning and stimulates the thermogenic activity of brown/beige adipocytes. Thus, vitamin A is a promising anti-obesity micronutrient.
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Affiliation(s)
- Bo Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, 100193, PR China
| | - Min Du
- Laboratory of Nutrigenomics and Growth Biology, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
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40
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Neri D, Ramos-Lobo AM, Lee S, Lafond A, Zeltser LM. Rearing mice at 22°C programs increased capacity to respond to chronic exposure to cold but not high fat diet. Mol Metab 2023; 73:101740. [PMID: 37211277 PMCID: PMC10248272 DOI: 10.1016/j.molmet.2023.101740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023] Open
Abstract
OBJECTIVE Rodent models raised at environmental temperatures of 21-22 °C are increasingly switched to thermoneutral housing conditions in adulthood to better capture human physiology. We quantified the developmental effects of rearing mice at an ambient temperature of 22 °C vs. 30 °C on metabolic responses to cold and high fat diet (HFD) in adulthood. METHODS Mice were reared from birth to 8 weeks of age at 22 °C or 30 °C, when they were acclimated to single housing at the same temperature for 2-3 weeks in indirect calorimetry cages. Energy expenditure attributable to basal metabolic rate, physical activity, thermic effect of food, and adaptive cold- or diet-induced thermogenesis was calculated. Responses to cooling were evaluated by decreasing the ambient temperature from 22 °C to 14 °C, while responses to HFD feeding were assessed at 30 °C. Influences of rearing temperature on thermogenic responses that emerge over hours, days and weeks were assessed by maintaining mice in the indirect calorimetry cages throughout the study. RESULTS At an ambient temperature of 22 °C, total energy expenditure (TEE) was 12-16% higher in mice reared at 22 °C as compared to 30 °C. Rearing temperature had no effect on responses in the first hours or week of the 14 °C challenge. Differences emerged in the third week, when TEE increased an additional 10% in mice reared at 22 °C, but mice reared at 30 °C could not sustain this level of cold-induced thermogenesis. Rearing temperature only affected responses to HFD during the first week, due to differences in the timing but not the strength of metabolic adaptations. CONCLUSION Rearing at 22 °C does not have a lasting effect on metabolic adaptations to HFD at thermoneutrality, but it programs an enhanced capacity to respond to chronic cold challenges in adulthood. These findings highlight the need to consider rearing temperature when using mice to model cold-induced thermogenesis.
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Affiliation(s)
- Daniele Neri
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Angela M Ramos-Lobo
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Seoeun Lee
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Alexandre Lafond
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Lori M Zeltser
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
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Castellá M, Blasco-Roset A, Peyrou M, Gavaldà-Navarro A, Villarroya J, Quesada-López T, Lorente-Poch L, Sancho J, Szymczak F, Piron A, Rodríguez-Fernández S, Carobbio S, Goday A, Domingo P, Vidal-Puig A, Giralt M, Eizirik DL, Villarroya F, Cereijo R. Adipose tissue plasticity in pheochromocytoma patients suggests a role of the splicing machinery in human adipose browning. iScience 2023; 26:106847. [PMID: 37250773 PMCID: PMC10209542 DOI: 10.1016/j.isci.2023.106847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 03/31/2023] [Accepted: 05/04/2023] [Indexed: 05/31/2023] Open
Abstract
Adipose tissue from pheochromocytoma patients acquires brown fat features, making it a valuable model for studying the mechanisms that control thermogenic adipose plasticity in humans. Transcriptomic analyses revealed a massive downregulation of splicing machinery components and splicing regulatory factors in browned adipose tissue from patients, with upregulation of a few genes encoding RNA-binding proteins potentially involved in splicing regulation. These changes were also observed in cell culture models of human brown adipocyte differentiation, confirming a potential involvement of splicing in the cell-autonomous control of adipose browning. The coordinated changes in splicing are associated with a profound modification in the expression levels of splicing-driven transcript isoforms for genes involved in the specialized metabolism of brown adipocytes and those encoding master transcriptional regulators of adipose browning. Splicing control appears to be a relevant component of the coordinated gene expression changes that allow human adipose tissue to acquire a brown phenotype.
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Affiliation(s)
- Moisés Castellá
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Albert Blasco-Roset
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Marion Peyrou
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Aleix Gavaldà-Navarro
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Joan Villarroya
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Tania Quesada-López
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Hospital de la Santa Creu i Sant Pau, and Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
| | | | - Juan Sancho
- Endocrine Surgery Unit, Hospital del Mar, 08003 Barcelona, Spain
| | - Florian Szymczak
- ULB Center for Diabetes Research, Medical Faculty, Université Libre De Bruxelles (ULB), 1070 Brussels, Belgium
- Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Anthony Piron
- ULB Center for Diabetes Research, Medical Faculty, Université Libre De Bruxelles (ULB), 1070 Brussels, Belgium
- Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Sonia Rodríguez-Fernández
- University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge 289, UK
| | - Stefania Carobbio
- Bases Moleculares de Patologías Humanas, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
| | - Albert Goday
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
- Endocrinology Service, Hospital del Mar, IMIM, 08003 Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Pere Domingo
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Hospital de la Santa Creu i Sant Pau, and Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain
| | - Antonio Vidal-Puig
- University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge 289, UK
| | - Marta Giralt
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Décio L. Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre De Bruxelles (ULB), 1070 Brussels, Belgium
| | - Francesc Villarroya
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
| | - Rubén Cereijo
- Departament de Bioquímica i Biomedicina Molecular, Universitat de Barcelona; Institut de Biomedicina de la Universitat de Barcelona (IBUB); and Institut de Recerca de Sant Joan de Déu, 08028 Barcelona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, 28029 Madrid, Spain
- Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Hospital de la Santa Creu i Sant Pau, and Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
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Wang S, Liu Y, Chen J, He Y, Ma W, Liu X, Sun X. Effects of multi-organ crosstalk on the physiology and pathology of adipose tissue. Front Endocrinol (Lausanne) 2023; 14:1198984. [PMID: 37383400 PMCID: PMC10293893 DOI: 10.3389/fendo.2023.1198984] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 05/26/2023] [Indexed: 06/30/2023] Open
Abstract
In previous studies, adipocytes were found to play an important role in regulating whole-body nutrition and energy balance, and are also important in energy metabolism, hormone secretion, and immune regulation. Different adipocytes have different contributions to the body, with white adipocytes primarily storing energy and brown adipocytes producing heat. Recently discovered beige adipocytes, which have characteristics in between white and brown adipocytes, also have the potential to produce heat. Adipocytes interact with other cells in the microenvironment to promote blood vessel growth and immune and neural network interactions. Adipose tissue plays an important role in obesity, metabolic syndrome, and type 2 diabetes. Dysfunction in adipose tissue endocrine and immune regulation can cause and promote the occurrence and development of related diseases. Adipose tissue can also secrete multiple cytokines, which can interact with organs; however, previous studies have not comprehensively summarized the interaction between adipose tissue and other organs. This article reviews the effect of multi-organ crosstalk on the physiology and pathology of adipose tissue, including interactions between the central nervous system, heart, liver, skeletal muscle, and intestines, as well as the mechanisms of adipose tissue in the development of various diseases and its role in disease treatment. It emphasizes the importance of a deeper understanding of these mechanisms for the prevention and treatment of related diseases. Determining these mechanisms has enormous potential for identifying new targets for treating diabetes, metabolic disorders, and cardiovascular diseases.
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Affiliation(s)
- Sufen Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yifan Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Jiaqi Chen
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Yuejing He
- Clinical Laboratory, Dongguan Eighth People’s Hospital, Dongguan, China
| | - Wanrui Ma
- Department of General Medicine, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
| | - Xinguang Liu
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
| | - Xuerong Sun
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China
- Institute of Aging Research, School of Medical Technology, Guangdong Medical University, Dongguan, China
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Cao Y, Langer R, Ferrara N. Targeting angiogenesis in oncology, ophthalmology and beyond. Nat Rev Drug Discov 2023; 22:476-495. [PMID: 37041221 DOI: 10.1038/s41573-023-00671-z] [Citation(s) in RCA: 131] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2023] [Indexed: 04/13/2023]
Abstract
Angiogenesis is an essential process in normal development and in adult physiology, but can be disrupted in numerous diseases. The concept of targeting angiogenesis for treating diseases was proposed more than 50 years ago, and the first two drugs targeting vascular endothelial growth factor (VEGF), bevacizumab and pegaptanib, were approved in 2004 for the treatment of cancer and neovascular ophthalmic diseases, respectively. Since then, nearly 20 years of clinical experience with anti-angiogenic drugs (AADs) have demonstrated the importance of this therapeutic modality for these disorders. However, there is a need to improve clinical outcomes by enhancing therapeutic efficacy, overcoming drug resistance, defining surrogate markers, combining with other drugs and developing the next generation of therapeutics. In this Review, we examine emerging new targets, the development of new drugs and challenging issues such as the mode of action of AADs and elucidating mechanisms underlying clinical benefits; we also discuss possible future directions of the field.
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Affiliation(s)
- Yihai Cao
- Department of Microbiology, Tumour and Cell Biology, Karolinska Institute, Stockholm, Sweden.
| | - Robert Langer
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Napoleone Ferrara
- Department of Pathology, University of California San Diego, La Jolla, CA, USA.
- Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
- Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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Zhang S, Chen J, Li Q, Zeng W. Opioid growth factor receptor promotes adipose tissue thermogenesis via enhancing lipid oxidation. LIFE METABOLISM 2023; 2:load018. [PMID: 39872016 PMCID: PMC11749475 DOI: 10.1093/lifemeta/load018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 04/23/2023] [Accepted: 05/01/2023] [Indexed: 01/29/2025]
Abstract
The thermogenic brown and beige adipocytes consume fatty acids and generate heat to maintain core body temperature in the face of cold challenges. Since their validated presence in humans, the activation of thermogenic fat has been an attractive target for treating obesity and related metabolic diseases. Here, we reported that the opioid growth factor receptor (Ogfr) was highly expressed in adipocytes and promoted thermogenesis. The mice with genetic deletion of Ogfr in adipocytes displayed an impaired capacity to counter environmental cold challenges. Meanwhile, Ogfr ablation in adipocytes led to reduced fatty acid oxidation, enhanced lipid accumulation, impaired glucose tolerance, and exacerbated tissue inflammation under chronic high-fat diet (HFD)-fed conditions. At the cellular level, OGFr enhanced the production of mitochondrial trifunctional protein subunit α (MTPα) and also interacted with MTPα, thus promoting fatty acid oxidation. Together, our study demonstrated the important role of OGFr in fatty acid metabolism and adipose thermogenesis.
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Affiliation(s)
- Shan Zhang
- Institute for Immunology, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China
| | - Jianhui Chen
- Institute for Immunology, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China
| | - Qingqing Li
- Institute for Immunology, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China
| | - Wenwen Zeng
- Institute for Immunology, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China
- Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing 100084, China
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45
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Smad4-mediated angiogenesis facilitates the beiging of white adipose tissue in mice. iScience 2023; 26:106272. [PMID: 36915676 PMCID: PMC10005906 DOI: 10.1016/j.isci.2023.106272] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 01/12/2023] [Accepted: 02/19/2023] [Indexed: 03/12/2023] Open
Abstract
Beige adipocytes are thermogenic with high expression of uncoupling protein 1 in the white adipose tissue (WAT), accompanied by angiogenesis. Previous studies showed that Smad4 is important for angiogenesis. Here we studied whether endothelial Smad4-mediated angiogenesis is involved in WAT beiging. Inducible knockout of endothelial cell (EC) selective Smad4 (Smad4 iEC-KO) was achieved by using the Smad4 Floxp/floxp and Tie2 CreERT2 mice. Beige fat induction achieved by cold or adrenergic agonist, and angiogenesis were attenuated in WAT of Smad4 iEC-KO mice, with the less proliferation of ECs and adipogenic precursors. RNA sequencing of human ECs showed that Smad4 is involved in angiogenesis-related pathways. Knockdown of SMAD4 attenuated the upregulation of VEGFA, PDGFA, and angiogenesis in vitro. Treatment of human ECs with palmitic acid-induced Smad1/5 phosphorylation and the upregulation of core endothelial genes. Our study shows that endothelial Smad4 is involved in WAT beiging through angiogenesis and the expansion of adipose precursors into beige adipocytes.
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Merlo E, Zimerman J, Dos Santos FCF, Zanol JF, da Costa CS, Carneiro PH, Miranda-Alves L, Warner GR, Graceli JB. Subacute and low dose of tributyltin exposure leads to brown adipose abnormalities in male rats. Toxicol Lett 2023; 376:26-38. [PMID: 36638932 PMCID: PMC9928871 DOI: 10.1016/j.toxlet.2023.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 01/07/2023] [Accepted: 01/09/2023] [Indexed: 01/12/2023]
Abstract
Tributyltin (TBT) is an obesogenic endocrine disrupting chemical (EDC) linked with several metabolic complications. Brown adipose tissue (BAT) is the principal site for thermogenesis, making it a potential target for obesity management and metabolic disease. However, few studies have evaluated TBT effect on BAT function. In this investigation, we assessed whether subacute (15 days) and low dose of TBT exposure (100 ng/kg/day) results in abnormal BAT morphophysiology in adult male rats. Body temperature, BAT morphology, inflammation, oxidative stress, collagen deposition and BAT metabolic gene expression markers were assessed in room temperature (Room, ∼24 ºC) and after cold tolerance test (Cold, ∼4 ºC) conditions. A reduction in body temperature was observed in both Room and Cold conditions in TBT rats, suggesting abnormal BAT thermogenic function. Changes in BAT morphology were observed in TBT rats, with an increase in BAT lipid accumulation, an increase in BAT unilocular adipocyte number and a decrease in BAT multilocular adipocyte number in Room condition. All these parameters were opposite in Cold condition TBT rats, leading to a borderline increase in BAT UCP1 protein expression. An increase in BAT mast cell number was observed in TBT rats in Room condition. An increase in ED1 protein expression (macrophage marker) was observed in TBT rats in Cold condition. Oxidative stress and collagen deposition increased in both Room and Cold conditions in TBT rats. TBT exposure caused a borderline increase in BAT COL1A1 protein expression in Cold condition. Further, strong negative correlations were observed between body temperature and BAT lipid accumulation, and BAT lipid accumulation and multilocular adipocyte number. Thus, these data suggest that TBT exposure impaired BAT morphophysiology through impacts on lipid accumulation, inflammation, fibrosis and oxidative stress in male rats.
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Affiliation(s)
- Eduardo Merlo
- Department of Morphology, Federal University of Espírito Santo, Vitória, Brazil
| | - Jeanini Zimerman
- Department of Morphology, Federal University of Espírito Santo, Vitória, Brazil
| | | | - Jordana F Zanol
- Department of Morphology, Federal University of Espírito Santo, Vitória, Brazil
| | - Charles S da Costa
- Department of Morphology, Federal University of Espírito Santo, Vitória, Brazil
| | - Pedro H Carneiro
- Experimental Endocrinology Research, Development and Innovation Group, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Brazil; Postgraduate Program in Endocrinology, School of Medicine, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, Ilha do Governador, Cidade Universitária, UFRJ, RJ, Brazil
| | - Leandro Miranda-Alves
- Experimental Endocrinology Research, Development and Innovation Group, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Brazil; Postgraduate Program in Endocrinology, School of Medicine, Federal University of Rio de Janeiro, Av. Carlos Chagas Filho, Ilha do Governador, Cidade Universitária, UFRJ, RJ, Brazil
| | - Genoa R Warner
- Department of Chemistry and Environmental Science, New Jersey Institute of Technology, USA
| | - Jones B Graceli
- Department of Morphology, Federal University of Espírito Santo, Vitória, Brazil.
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Vliora M, Ravelli C, Grillo E, Corsini M, Flouris AD, Mitola S. The impact of adipokines on vascular networks in adipose tissue. Cytokine Growth Factor Rev 2023; 69:61-72. [PMID: 35953434 DOI: 10.1016/j.cytogfr.2022.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023]
Abstract
Adipose tissue (AT) is a highly active and plastic endocrine organ. It secretes numerous soluble molecules known as adipokines, which act locally to AT control the remodel and homeostasis or exert pleiotropic functions in different peripheral organs. Aberrant production or loss of certain adipokines contributes to AT dysfunction associated with metabolic disorders, including obesity. The AT plasticity is strictly related to tissue vascularization. Angiogenesis supports the AT expansion, while regression of blood vessels is associated with AT hypoxia, which in turn mediates tissue inflammation, fibrosis and metabolic dysfunction. Several adipokines can regulate endothelial cell functions and are endowed with either pro- or anti-angiogenic properties. Here we address the role of adipokines in the regulation of angiogenesis. A better understanding of the link between adipokines and angiogenesis will open the way for novel therapeutic approaches to treat obesity and metabolic diseases.
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Affiliation(s)
- Maria Vliora
- FAME Laboratory, Department of Exercise Science, University of Thessaly, Trikala, Greece; Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, Brescia, Italy
| | - Cosetta Ravelli
- Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, Brescia, Italy
| | - Elisabetta Grillo
- Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, Brescia, Italy
| | - Michela Corsini
- Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, Brescia, Italy
| | - Andreas D Flouris
- FAME Laboratory, Department of Exercise Science, University of Thessaly, Trikala, Greece
| | - Stefania Mitola
- Department of Molecular and Translational Medicine, University of Brescia, Via Branze 39, Brescia, Italy.
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Dang J, Yu Z, Wang T, Jiao Y, Wang K, Dou W, Yi C, Song B. Effects of Melatonin on Fat Graft Retention Through Browning of Adipose Tissue and Alternative Macrophage Polarization. Aesthetic Plast Surg 2023:10.1007/s00266-022-03242-6. [PMID: 36633654 DOI: 10.1007/s00266-022-03242-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/18/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND Melatonin is a widely used drug that can affect adipocyte inflammation, resulting in adipose tissue browning. Inducing the browning of white fat and changing the inflammatory microenvironment of early transplanted fat have positive effects on the retention rate of fat grafts. This study aimed to evaluate the effects of melatonin on fat graft retention, determine whether it is related to adipose tissue browning and the inflammatory microenvironment, and explore the underlying mechanisms. METHODS A C57BL/6 mice fat transplantation model was established. The mice were divided into a control group (ethanol), a high-dose group (40 mg/kg/day melatonin), a medium-dose group (20 mg/kg/day melatonin), and a low-dose group (10 mg/kg/day melatonin). They were also given oral gavage treatment for 2 weeks. The grafted fat was collected 2, 4, and 12 weeks after treatment. RESULTS The medium-dose and high-dose melatonin groups had significantly higher fat graft retention rates than the control group at 12 weeks. The medium-dose melatonin group had smaller multilocular adipocytes, which enhanced the expression of uncoupling protein 1 and increased neovascularization in the grafted fat. The medium-dose group also had a higher distribution of M2 macrophages. CONCLUSIONS These findings suggest that melatonin administration can improve the retention of fat grafts through polarization of macrophages toward the anti-inflammatory type and induction of adipose tissue browning. NO LEVEL ASSIGNED This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Affiliation(s)
- Juanli Dang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhou Yu
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Tong Wang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yan Jiao
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Kai Wang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Wenjie Dou
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chenggang Yi
- Department of Plastic Surgery, Medical School, The Second Affiliated Hospital, Zhejiang University, Hangzhou, China.
| | - Baoqiang Song
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
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Annese T, Tamma R, Ribatti D. IKOSA ® CAM Assay Application to Quantify Blood Vessels on Chick Chorioallantoic Membrane (CAM). Methods Mol Biol 2023; 2572:129-139. [PMID: 36161413 DOI: 10.1007/978-1-0716-2703-7_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Among in vivo angiogenesis assays, chick chorioallantoic membrane (CAM) assay has allowed meaningful progress in elucidating the mechanism of the vasoproliferative response to several pro- and antiangiogenic factors, thanks to its low costs, relatively easy management, and lower ethical concerns compared to other animal in vivo models.Here, we present a method to quantify angiogenesis and antiangiogenesis processes in the CAM based on the segmentation of microscopic images of blood vessels. Images captured from in vivo CAM samples can be analyzed for their vascularization with IKOSA CAM Assay to measure their total area, length, mean thickness, and the number of branching points. This chapter presents a detailed protocol to perform a CAM assay and analysis, and the IKOSA CAM Assay output is described.
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Affiliation(s)
- Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
- Department of Medicine and Surgery, LUM University, Casamassima, Bari, Italy
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
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Chen YJ, Liao PX, Kuo WH, Chen CY, Ding ST, Wang MH. Assessment of Brown and Beige Adipose Tissue Activation in Mice Using PET/CT Imaging. Methods Mol Biol 2023; 2662:135-145. [PMID: 37076677 DOI: 10.1007/978-1-0716-3167-6_12] [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: 04/21/2023]
Abstract
In response to cold induction, brown adipose tissues (BAT) and emerged brown-like adipocytes (beige adipocytes) in subcutaneous white adipose tissues (WAT browning/beiging) are activated. Thermogenesis is increased during glucose and fatty acid uptake and metabolism in adult humans and mice. This activation of BAT or WAT beiging to generate heat helps to counteract diet-induced obesity. This protocol applies the glucose analog radiotracer 18F-fluorodeoxyglucose (FDG), coupled with positron emission tomography and computed tomography (PET/CT) scanning to evaluate cold-induced thermogenesis in the active BAT (interscapular region) and browned/beiged WAT (subcutaneous adipose region) in mice. The PET/CT scanning technique not only can quantify cold-induced glucose uptake in well-known BAT and beige-fat depots but also helps to visualize the anatomical location of novel uncharacterized mouse BAT and beige fat where cold-induced glucose uptake is high. Histological analysis is further employed to validate signals of delineated anatomical regions in PET/CT images as bona fide mouse BAT or beiged WAT fat depots.
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Affiliation(s)
- Yu-Jen Chen
- Institute of Biotechnology and Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan.
| | - Pei-Xin Liao
- Institute of Biotechnology and Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Wen-Hung Kuo
- Department of Surgery, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ching-Yi Chen
- Institute of Biotechnology and Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Shih-Torng Ding
- Institute of Biotechnology and Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan
| | - Mei-Hui Wang
- Institute of Nuclear Energy Research, Taoyuan, Taiwan
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