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Li Z, Zhang C, Huang G, Zhang Z, Wang Q, Liu X, Qin Y, Zhou H, Hou A, He J, Li L, Hu X, Ding X. Deletion of Tfap2a in hepatocytes and macrophages promotes the progression of hepatocellular carcinoma by regulating SREBP1/FASN/ACC pathway and anti-inflammatory effect of IL10. Cell Death Dis 2025; 16:245. [PMID: 40180937 PMCID: PMC11968862 DOI: 10.1038/s41419-025-07500-8] [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: 11/12/2024] [Revised: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 04/05/2025]
Abstract
The transcription factor AP-2α plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2α in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2α regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN/CCl4-induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2aΔHep and Tfap2aΔMΦ mice, but not in Tfap2aΔHSC mice fed with normal chow. Tfap2aΔHep and Tfap2aΔMΦ mice treated with DEN/CCl4 for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2α binds to the promoter regions of SREBP1/ACC/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2α in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2α expression and decreases lipid accumulation in HCC cells. Clinically, AP-2α expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These results suggest that AP-2α has been identified as a novel therapeutic target in fibrosis and inflammation-related HCC, exerting anti-lipogenesis, anti-inflammatory, and anti-tumor multi-roles.
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Affiliation(s)
- Zhiwei Li
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Chun Zhang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Guixiang Huang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Zixin Zhang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Qinghao Wang
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Xiran Liu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Yanling Qin
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Hao Zhou
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Anyi Hou
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
| | - Jun He
- Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, 410007, China
| | - Limin Li
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- College of Engineering and Design, Hunan Normal University, Changsha, 410081, China
| | - Xiang Hu
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China
- Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, 410081, China
| | - Xiaofeng Ding
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, 410081, China.
- Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
- Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, 410081, China.
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Du L, Zhu J, Liu S, Yang W, Hu X, Zhang W, Cui W, Yang Y, Wang C, Yang Y, Gao T, Zhang C, Zhang R, Lou M, Zhou H, Rao J, Maoying Q, Chu Y, Wang Y, Mi W. Transient receptor potential melastatin 8 contributes to the interleukin-33-mediated cold allodynia in a mouse model of neuropathic pain. Pain 2025; 166:347-359. [PMID: 39132923 DOI: 10.1097/j.pain.0000000000003346] [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: 01/06/2024] [Accepted: 06/17/2024] [Indexed: 08/13/2024]
Abstract
ABSTRACT Cold allodynia is a common complaint of patients suffering from neuropathic pain initiated by peripheral nerve injury. However, the mechanisms that drive neuropathic cold pain remain elusive. In this study, we show that the interleukin (IL)-33/ST2 signaling in the dorsal root ganglion (DRG) is a critical contributor to neuropathic cold pain by interacting with the cold sensor transient receptor potential melastatin 8 (TRPM8). By using the St2-/- mice, we demonstrate that ST2 is required for the generation of nociceptor hyperexcitability and cold allodynia in a mouse model of spared nerve injury (SNI). Moreover, the selective elimination of ST2 function from the Nav1.8-expressing nociceptor markedly suppresses SNI-induced cold allodynia. Consistent with the loss-of-function studies, intraplantar injection of recombinant IL-33 (rIL-33) is sufficient to induce cold allodynia. Mechanistically, ST2 is co-expressed with TRPM8 in both mouse and human DRG neurons and rIL-33-induced Ca 2+ influx in mouse DRG neurons through TRPM8. Co-immunoprecipitation assays further reveal that ST2 interacts with TRPM8 in DRG neurons. Importantly, rIL-33-induced cold allodynia is abolished by pharmacological inhibition of TRPM8 and genetic ablation of the TRPM8-expressing neurons. Thus, our findings suggest that the IL-33/ST2 signaling mediates neuropathic cold pain through downstream cold-sensitive TRPM8 channels, thereby identifying a potential analgesic target for the treatment of neuropathic cold pain.
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Affiliation(s)
- Lixia Du
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Biochemistry, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianyu Zhu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shenbin Liu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wei Yang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xueming Hu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenwen Zhang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenqiang Cui
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yayue Yang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chenghao Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yachen Yang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tianchi Gao
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chen Zhang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruofan Zhang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mengping Lou
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hong Zhou
- Department of Immunology, Anhui Medical University, Hefei, Anhui, China
| | - Jia Rao
- Department of Immunology, Anhui Medical University, Hefei, Anhui, China
| | - Qiliang Maoying
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - Yuxia Chu
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - Yanqing Wang
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
| | - Wenli Mi
- Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai, China
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Ertel A, Anderegg U, Franz S, Saalbach A. Dermal White Adipose Tissue-Derived Il-33 Regulates Il-4/13 Expression in Myeloid Cells during Inflammation. J Invest Dermatol 2025; 145:370-382. [PMID: 38909842 DOI: 10.1016/j.jid.2024.05.026] [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: 02/13/2024] [Revised: 04/25/2024] [Accepted: 05/24/2024] [Indexed: 06/25/2024]
Abstract
Effective tissue response to infection and injury essentially relies on the fine-tuned induction and subsequent resolution of inflammation. Recent research highlighted multiple functions of dermal white adipose tissue (dWAT) beyond its traditional role as an energy reservoir. However, in contrast to other fat depots, there are only limited data about putative immune-regulatory functions of dWAT. Therefore, we investigated the impact of dWAT in the control of an acute skin inflammation. Skin inflammation triggers the activation of dWAT. In turn, soluble mediators of activated dWAT stimulate the expression of numerous genes controlling skin inflammation, including the T helper 2 cell cytokines Il4 and Il13, in myeloid cells in vitro. Consistently, myeloid cells isolated from inflamed skin showed a significant upregulation of Il-4/13 expression compared with those isolated from healthy skin. Mechanistically, we demonstrate that IL-33 released from activated dWAT is responsible for IL-4/13 stimulation in myeloid cells. Interestingly, obesity attenuates IL-33 secretion in dWAT during inflammation, resulting in decreased Il-4 and Il-13 expressions in myeloid cells. Our data reveal an IL-33-IL-4/13 signaling cascade initiated from dWAT in a T helper 2-independent context of inflammation that may contribute to limitation of inflammation. This cascade seems to be disturbed in individuals with obesity with prolonged inflammation.
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Affiliation(s)
- Anastasia Ertel
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Leipzig, Germany
| | - Ulf Anderegg
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Leipzig, Germany
| | - Sandra Franz
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Leipzig, Germany
| | - Anja Saalbach
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, Leipzig, Germany.
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Zhang P, Watari K, Karin M. Innate immune cells link dietary cues to normal and abnormal metabolic regulation. Nat Immunol 2025; 26:29-41. [PMID: 39747429 DOI: 10.1038/s41590-024-02037-y] [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: 01/12/2024] [Accepted: 10/24/2024] [Indexed: 01/04/2025]
Abstract
A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.
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Affiliation(s)
- Peng Zhang
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Kosuke Watari
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
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Chen Q, Xiang D, Liang Y, Meng H, Zhang X, Lu J. Interleukin-33: Expression, regulation and function in adipose tissues. Int Immunopharmacol 2024; 143:113285. [PMID: 39362016 DOI: 10.1016/j.intimp.2024.113285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024]
Abstract
Interleukin-33 (IL-33) is a pleiotropic cytokine of the IL-1 family that plays a key role in innate and adaptive immune responses and contributes to tissue homeostasis. Its role in adipose tissue function has been extensively studied, as adipose tissue serves as an important mediator of metabolic dysfunction. In adipose tissue, IL-33 is primarily produced by stromal cells. Its production is regulated by factors, such as androgens, aging, sympathetic innervation, and various inflammatory stimuli that affect the proliferation and differentiation of IL-33-producing stromal cells. Many studies have elucidated the mechanisms by which IL-33 interacts with the immune system components, local nerve fibers, and adipocytes to influence energy balance, with important consequences in obesity, cold-induced thermogenesis, and aging-related metabolic dysfunction. Here, we detail our current understanding of the molecular events that regulate the production of IL-33 within adipose tissue and discuss its role in regulating adipose function.
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Affiliation(s)
- Qianjiang Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Daochun Xiang
- The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan Liang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Haiyang Meng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xiaofen Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jingli Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China.
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Vo N, Zhang Q, Sung HK. From fasting to fat reshaping: exploring the molecular pathways of intermittent fasting-induced adipose tissue remodeling. JOURNAL OF PHARMACY & PHARMACEUTICAL SCIENCES : A PUBLICATION OF THE CANADIAN SOCIETY FOR PHARMACEUTICAL SCIENCES, SOCIETE CANADIENNE DES SCIENCES PHARMACEUTIQUES 2024; 27:13062. [PMID: 39104461 PMCID: PMC11298356 DOI: 10.3389/jpps.2024.13062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 07/05/2024] [Indexed: 08/07/2024]
Abstract
Obesity, characterised by excessive fat accumulation, is a complex chronic condition that results from dysfunctional adipose tissue expansion due to prolonged calorie surplus. This leads to rapid adipocyte enlargement that exceeds the support capacity of the surrounding neurovascular network, resulting in increased hypoxia, inflammation, and insulin resistance. Intermittent fasting (IF), a dietary regimen that cycles between periods of fasting and eating, has emerged as an effective strategy to combat obesity and improve metabolic homeostasis by promoting healthy adipose tissue remodeling. However, the precise molecular and cellular mechanisms behind the metabolic improvements and remodeling of white adipose tissue (WAT) driven by IF remain elusive. This review aims to summarise and discuss the relationship between IF and adipose tissue remodeling and explore the potential mechanisms through which IF induces alterations in WAT. This includes several key structural changes, including angiogenesis and sympathetic innervation of WAT. We will also discuss the involvement of key signalling pathways, such as PI3K, SIRT, mTOR, and AMPK, which potentially play a crucial role in IF-mediated metabolic adaptations.
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Affiliation(s)
- Nathaniel Vo
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Qiwei Zhang
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Hoon-Ki Sung
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Xu D, Zhuang S, Chen H, Jiang M, Jiang P, Wang Q, Wang X, Chen R, Tang H, Tang L. IL-33 regulates adipogenesis via Wnt/β-catenin/PPAR-γ signaling pathway in preadipocytes. J Transl Med 2024; 22:363. [PMID: 38632591 PMCID: PMC11022325 DOI: 10.1186/s12967-024-05180-0] [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: 12/18/2023] [Accepted: 04/05/2024] [Indexed: 04/19/2024] Open
Abstract
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders.
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Affiliation(s)
- Danning Xu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Siqi Zhuang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hongzhi Chen
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, and Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mengjie Jiang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ping Jiang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xuemei Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ruohong Chen
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Haoneng Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Lingli Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Dai Z, Gong Z, Wang C, Long W, Liu D, Zhang H, Lei A. The role of hormones in ILC2-driven allergic airway inflammation. Scand J Immunol 2024; 99:e13357. [PMID: 39008023 DOI: 10.1111/sji.13357] [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: 08/22/2023] [Revised: 11/23/2023] [Accepted: 01/05/2024] [Indexed: 07/16/2024]
Abstract
Group 2 innate lymphoid cells (ILC2s) are a type of innate immune cells that produce a large amount of IL-5 and IL-13 and two cytokines that are crucial for various processes such as allergic airway inflammation, tissue repair and tissue homeostasis. It is known that damaged epithelial-derived alarmins, such as IL-33, IL-25 and thymic stromal lymphopoietin (TSLP), are the predominant ILC2 activators that mediate the production of type 2 cytokines. In recent years, abundant studies have found that many factors can regulate ILC2 development and function. Hormones synthesized by the body's endocrine glands or cells play an important role in immune response. Notably, ILC2s express hormone receptors and their proliferation and function can be modulated by multiple hormones during allergic airway inflammation. Here, we summarize the effects of multiple hormones on ILC2-driven allergic airway inflammation and discuss the underlying mechanisms and potential therapeutic significance.
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Affiliation(s)
- Zhongling Dai
- Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
| | - Zhande Gong
- Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
| | - Cui Wang
- Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
| | - WeiXiang Long
- Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
| | - Duo Liu
- Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
| | - Haijun Zhang
- Department of Cardiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Aihua Lei
- Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China
- Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang, China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China
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9
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Ngo TB, Josyula A, DeStefano S, Fertil D, Faust M, Lokwani R, Sadtler K. Intersection of Immunity, Metabolism, and Muscle Regeneration in an Autoimmune-Prone MRL Mouse Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306961. [PMID: 38192168 PMCID: PMC10953568 DOI: 10.1002/advs.202306961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/07/2023] [Indexed: 01/10/2024]
Abstract
Due to the limited capacity of mammals to regenerate complex tissues, researchers have worked to understand the mechanisms of tissue regeneration in organisms that maintain that capacity. One example is the MRL/MpJ mouse strain with unique regenerative capacity in ear pinnae that is absent from other strains, such as the common C57BL/6 strain. The MRL/MpJ mouse has also been associated with an autoimmune phenotype even in the absence of the mutant Fas gene described in its parent strain MRL/lpr. Due to these findings, the differences between the responses of MRL/MpJ versus C57BL/6 strain are evaluated in volumetric muscle injury and subsequent material implantation. One salient feature of the MRL/MpJ response to injury is robust adipogenesis within the muscle. This is associated with a decrease in M2-like polarization in response to biologically derived extracellular matrix scaffolds. In pro-fibrotic materials, such as polyethylene, there are fewer foreign body giant cells in the MRL/MpJ mice. As there are reports of both positive and negative influences of adipose tissue and adipogenesis on wound healing, this model can provide an important lens to investigate the interplay between stem cells, adipose tissue, and immune responses in trauma and material implantation.
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Affiliation(s)
- Tran B. Ngo
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
| | - Aditya Josyula
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
| | - Sabrina DeStefano
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
| | - Daphna Fertil
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
| | - Mondreakest Faust
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
| | - Ravi Lokwani
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
| | - Kaitlyn Sadtler
- Section on ImmunoengineeringCenter for Biomedical Engineering and Technology AccelerationNational Institute of Biomedical Imaging and BioengineeringNational Institutes of HealthBethesdaMD20814USA
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10
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Zhu W, Bai D, Ji W, Gao J. TRP channels associated with macrophages as targets for the treatment of obese asthma. Lipids Health Dis 2024; 23:49. [PMID: 38365763 PMCID: PMC10874053 DOI: 10.1186/s12944-024-02016-0] [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: 09/17/2023] [Accepted: 01/10/2024] [Indexed: 02/18/2024] Open
Abstract
Globally, obesity and asthma pose significant health challenges, with obesity being a key factor influencing asthma. Despite this, effective treatments for obese asthma, a distinct phenotype, remain elusive. Since the discovery of transient receptor potential (TRP) channels in 1969, their value as therapeutic targets for various diseases has been acknowledged. TRP channels, present in adipose tissue cells, influence fat cell heat production and the secretion of adipokines and cytokines, which are closely associated with asthma and obesity. This paper aims to investigate the mechanisms by which obesity exacerbates asthma-related inflammation and suggests that targeting TRP channels in adipose tissue could potentially suppress obese asthma and offer novel insights into its treatment.
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Affiliation(s)
- Wenzhao Zhu
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China
| | - Dinxi Bai
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China
| | - Wenting Ji
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China.
| | - Jing Gao
- Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, China.
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11
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Bradley D, Deng T, Shantaram D, Hsueh WA. Orchestration of the Adipose Tissue Immune Landscape by Adipocytes. Annu Rev Physiol 2024; 86:199-223. [PMID: 38345903 DOI: 10.1146/annurev-physiol-042222-024353] [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] [Indexed: 02/15/2024]
Abstract
Obesity is epidemic and of great concern because of its comorbid and costly inflammatory-driven complications. Extensive investigations in mice have elucidated highly coordinated, well-balanced interactions between adipocytes and immune cells in adipose tissue that maintain normal systemic metabolism in the lean state, while in obesity, proinflammatory changes occur in nearly all adipose tissue immune cells. Many of these changes are instigated by adipocytes. However, less is known about obesity-induced adipose-tissue immune cell alterations in humans. Upon high-fat diet feeding, the adipocyte changes its well-known function as a metabolic cell to assume the role of an immune cell, orchestrating proinflammatory changes that escalate inflammation and progress during obesity. This transformation is particularly prominent in humans. In this review, we (a) highlight a leading and early role for adipocytes in promulgating inflammation, (b) discuss immune cell changes and the time course of these changes (comparing humans and mice when possible), and (c) note how reversing proinflammatory changes in most types of immune cells, including adipocytes, rescues adipose tissue from inflammation and obese mice from insulin resistance.
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Affiliation(s)
- David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Pennsylvania State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA;
| | - Tuo Deng
- Second Xiangya Hospital, Central South University, Changsha, China
| | - Dharti Shantaram
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
| | - Willa A Hsueh
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA;
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12
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Ren W, Hua M, Cao F, Zeng W. The Sympathetic-Immune Milieu in Metabolic Health and Diseases: Insights from Pancreas, Liver, Intestine, and Adipose Tissues. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306128. [PMID: 38039489 PMCID: PMC10885671 DOI: 10.1002/advs.202306128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 10/28/2023] [Indexed: 12/03/2023]
Abstract
Sympathetic innervation plays a crucial role in maintaining energy balance and contributes to metabolic pathophysiology. Recent evidence has begun to uncover the innervation landscape of sympathetic projections and sheds light on their important functions in metabolic activities. Additionally, the immune system has long been studied for its essential roles in metabolic health and diseases. In this review, the aim is to provide an overview of the current research progress on the sympathetic regulation of key metabolic organs, including the pancreas, liver, intestine, and adipose tissues. In particular, efforts are made to highlight the critical roles of the peripheral nervous system and its potential interplay with immune components. Overall, it is hoped to underscore the importance of studying metabolic organs from a comprehensive and interconnected perspective, which will provide valuable insights into the complex mechanisms underlying metabolic regulation and may lead to novel therapeutic strategies for metabolic diseases.
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Affiliation(s)
- Wenran Ren
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
| | - Meng Hua
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
| | - Fang Cao
- Department of NeurosurgeryAffiliated Hospital of Zunyi Medical UniversityZunyiGuizhou563000China
| | - Wenwen Zeng
- Institute for Immunology and School of MedicineTsinghua Universityand Tsinghua‐Peking Center for Life SciencesBeijing100084China
- SXMU‐Tsinghua Collaborative Innovation Center for Frontier MedicineTaiyuan030001China
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijing100084China
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13
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Amer OE, Sabico S, Khattak MNK, Alnaami AM, Saadawy GM, Al-Daghri NM. Circulating Interleukins-33 and -37 and Their Associations with Metabolic Syndrome in Arab Adults. Int J Mol Sci 2024; 25:699. [PMID: 38255771 PMCID: PMC10815042 DOI: 10.3390/ijms25020699] [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: 12/06/2023] [Revised: 12/27/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Interleukins (ILs) are a group of cytokines known to have immunomodulatory effects; they include ILs-33 and -37 whose emerging roles in the pathogenesis of metabolic syndrome (MetS) remain under investigated. In this study, we compared circulating IL-33 and IL-37 in Arab adults with and without MetS to determine its associations with MetS components. A total of 417 Saudi participants (151 males, 266 females; mean age ± SD 41.3 ± 9.0 years; mean body mass index ± SD 30.7 ± 6.3 kg/m2) were enrolled and screened for MetS using the ATP III criteria. Anthropometrics and fasting blood samples were taken for the assessment of fasting glucose and lipids. Circulating levels of IL-33 and IL-37 were measured using commercially available assays. The results showed higher levels of serum IL-33 and IL-37 in participants with MetS than those without (IL-33, 3.34 3.42 (2.3-3.9) vs. (1-3.9), p = 0.057; IL-37, 5.1 (2.2-8.3) vs. 2.9 (2.1-6.1), p = 0.01). Additionally, having elevated levels of IL-33 was a risk factor for hypertension, low HDL-c, and hypertriglyceridemia. A stratification of the participants according to sex showed that males had higher IL-33 levels than females [3.7 (3.0-4.1) vs. 3.15 (1.4-3.8), p < 0.001], while females had higher levels of IL-37 than males [3.01 (2.2-7.0) vs. 2.9 (2.1-5.6), p = 0.06]. In conclusion, the presence of MetS substantially alters the expression of ILs-33 and -37. IL-33 in particular can be potentially used as a therapeutic target to prevent MetS progression. Longitudinal and interventional studies are warranted to confirm present findings.
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Affiliation(s)
| | | | | | | | | | - Nasser M. Al-Daghri
- Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
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14
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Hu Y, Chakarov S. Eosinophils in obesity and obesity-associated disorders. DISCOVERY IMMUNOLOGY 2023; 2:kyad022. [PMID: 38567054 PMCID: PMC10917198 DOI: 10.1093/discim/kyad022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 10/18/2023] [Accepted: 11/10/2023] [Indexed: 04/04/2024]
Abstract
Despite the rising prevalence and costs for the society, obesity etiology, and its precise cellular and molecular mechanisms are still insufficiently understood. The excessive accumulation of fat by adipocytes plays a key role in obesity progression and has many repercussions on total body physiology. In recent years the immune system as a gatekeeper of adipose tissue homeostasis has been evidenced and has become a focal point of research. Herein we focus on eosinophils, an important component of type 2 immunity, assuming fundamental, yet ill-defined, roles in the genesis, and progression of obesity and related metabolic disorders. We summarize eosinophilopoiesis and eosinophils recruitment into adipose tissue and discuss how the adipose tissue environments shape their function and vice versa. Finally, we also detail how obesity transforms the local eosinophil niche. Understanding eosinophil crosstalk with the diverse cell types within the adipose tissue environment will allow us to framework the therapeutic potential of eosinophils in obesity.
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Affiliation(s)
- Yanan Hu
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai, China
| | - Svetoslav Chakarov
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai, China
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15
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Ngo TB, Josyula A, DeStefano S, Fertil D, Faust M, Lokwani R, Sadtler K. Ectopic adipogenesis in response to injury and material implantation in an autoimmune mouse model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.05.561105. [PMID: 37986843 PMCID: PMC10659416 DOI: 10.1101/2023.10.05.561105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Due to the limited capacity of mammals to regenerate complex tissues, researchers have worked to understand the mechanisms of tissue regeneration in organisms that maintain that capacity. One example is the MRL/MpJ mouse strain with unique regenerative capacity in ear pinnae that is absent from other strains, such as the common C57BL/6 strain. The MRL/MpJ mouse has also been associated with an autoimmune phenotype even in the absence of the mutant Fas gene described in its parent strain MRL/lpr. Due to these findings, we evaluated the differences between the responses of MRL/MpJ versus C57BL/6 strain in traumatic muscle injury and subsequent material implantation. One salient feature of the MRL/MpJ response to injury was a robust adipogenesis within the muscle. This was associated with a decrease in M2-like polarization in response to biologically derived extracellular matrix scaffolds. In pro-fibrotic materials, such as polyethylene, there were fewer foreign body giant cells in the MRL/MpJ mice. As there are reports of both positive and negative influences of adipose tissue and adipogenesis on wound healing, this model could provide an important lens to investigate the interplay between stem cells, adipose tissue, and immune responses in trauma and materials implantation.
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Affiliation(s)
- Tran B. Ngo
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
| | - Aditya Josyula
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
| | - Sabrina DeStefano
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
| | - Daphna Fertil
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
| | - Mondreakest Faust
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
| | - Ravi Lokwani
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
| | - Kaitlyn Sadtler
- Section on Immunoengineering, Center for Biomedical Engineering and Technology Acceleration, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda MD 20814
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16
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Roy R, Das T, Biswas N. Orchestration of immune response by innate lymphoid cell subtype 2 at various tumor microenvironment, a suitable target for cancer immunotherapy. Int Rev Immunol 2023; 43:74-82. [PMID: 37599626 DOI: 10.1080/08830185.2023.2247021] [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: 06/27/2022] [Revised: 06/16/2023] [Accepted: 06/26/2023] [Indexed: 08/22/2023]
Abstract
Innate lymphoid cells are a mixed population of cells and critical regulators of our innate immune system. According to recent scientific literature, tissue resident innate lymphoid cell subtype 2 has been recognized as an important player of type 2 inflammatory responses, involved in different human malignancies like pancreatic, lung, acute myeloid leukemia, gastrointestinal tract cancer, etc. The current reports have revealed that, among the three main ILC sub types, subtype 2 (ILC 2), as the key regulator of initiating the type 2 inflammatory responses at the tumor microenvironment (TME). This activation of ILC-2 is a very important step for the specific downstream functioning of ILC-2. Priming of ILC-2 with different chemokines involves different cytokine secretion from the activated ILC-2 like IL-4, IL-5, IL-13, IL-9 which induce type 2 inflammatory responses involved in the complex interaction with other immune cells like NK cell, Cytotoxic T cell, MDSC and Treg cell. At the initial stage, ILC-2 activation through IL-33 may induce the anti-tumorigenic effect mediated by ILC-2/eosinophil axis. However, it is also evident that PDG2 (Prostaglandin D2)-mediated activation of ILC-2 induces the ILC-2/MDSC immune suppressive pro-tumorigenic niche at the TME. Here, in this review, we have summarized the function of ILC-2 on cancer immunity based on recent scientific work which indicates ILC-2 plays a dual role and orchestrates the immune responses toward type 2 immunity in different cancer settings.
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Affiliation(s)
- Rajdeep Roy
- Department of Life Sciences, Presidency University, Kolkata, India
| | - Tanmoy Das
- Department of Zoology, Visva-Bharati University, Shantiniketan, West Bengal, India
| | - Nabendu Biswas
- Department of Life Sciences, Presidency University, Kolkata, India
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17
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Li JH, Hepworth MR, O'Sullivan TE. Regulation of systemic metabolism by tissue-resident immune cell circuits. Immunity 2023; 56:1168-1186. [PMID: 37315533 PMCID: PMC10321269 DOI: 10.1016/j.immuni.2023.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/11/2023] [Accepted: 05/02/2023] [Indexed: 06/16/2023]
Abstract
Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
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Affiliation(s)
- Joey H Li
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA; Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Matthew R Hepworth
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA.
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18
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Feng X, Wang L, Zhou R, Zhou R, Chen L, Peng H, Huang Y, Guo Q, Luo X, Zhou H. Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging. Nat Commun 2023; 14:3208. [PMID: 37268694 DOI: 10.1038/s41467-023-38842-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 05/18/2023] [Indexed: 06/04/2023] Open
Abstract
Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8+ immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8+ immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.
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Affiliation(s)
- Xu Feng
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Liwen Wang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Ruoyu Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Rui Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Linyun Chen
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Hui Peng
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Yan Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Qi Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
| | - Xianghang Luo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 410008, Changsha, Hunan, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, 410008, Changsha, Hunan, China
| | - Haiyan Zhou
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008, Changsha, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 410008, Changsha, Hunan, China.
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19
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Matsuyama T, Machida K, Mizuno K, Matsuyama H, Dotake Y, Shinmura M, Takagi K, Inoue H. The Functional Role of Group 2 Innate Lymphoid Cells in Asthma. Biomolecules 2023; 13:893. [PMID: 37371472 DOI: 10.3390/biom13060893] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/24/2023] [Accepted: 05/24/2023] [Indexed: 06/29/2023] Open
Abstract
Asthma is a heterogeneous disease characterized by chronic airway inflammation. Group 2 innate lymphoid cells (ILC2) play an important role in the pathogenesis of asthma. ILC2s lack antigen-specific receptors and respond to epithelial-derived cytokines, leading to the induction of airway eosinophilic inflammation in an antigen-independent manner. Additionally, ILC2s might be involved in the mechanism of steroid resistance. Numerous studies in both mice and humans have shown that ILC2s induce airway inflammation through inflammatory signals, including cytokines and other mediators derived from immune or non-immune cells. ILC2s and T helper type 2 (Th2) cells collaborate through direct and indirect interactions to organize type 2 immune responses. Interestingly, the frequencies or numbers of ILC2 are increased in the blood and bronchoalveolar lavage fluid of asthma patients, and the numbers of ILC2s in the blood and sputum of severe asthmatics are significantly larger than those of mild asthmatics. These findings may contribute to the regulation of the immune response in asthma. This review article highlights our current understanding of the functional role of ILC2s in asthma.
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Affiliation(s)
- Takahiro Matsuyama
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Kentaro Machida
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Keiko Mizuno
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Hiromi Matsuyama
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Yoichi Dotake
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Masahiro Shinmura
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Koichi Takagi
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
| | - Hiromasa Inoue
- Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan
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20
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Jin Z, Meng W, Xiao T, Deng J, Wang J, Wen J, Chen K, Wang L, Liu J, Li Q, He J, Wang Z, Liu W, Liu F. Vertical sleeve gastrectomy-derived gut metabolite licoricidin activates beige fat thermogenesis to combat obesity. Theranostics 2023; 13:3103-3116. [PMID: 37284437 PMCID: PMC10240825 DOI: 10.7150/thno.81893] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 04/17/2023] [Indexed: 06/08/2023] Open
Abstract
Obesity is a chronic metabolic disease, affecting individuals throughout the world. Bariatric surgery such as vertical sleeve gastrectomy (VSG) provides sustained weight loss and improves glucose homeostasis in obese mice and humans. However, the precise underlying mechanisms remain elusive. In this study, we investigated the potential roles and the mechanisms of action of gut metabolites in VSG-induced anti-obesity effect and metabolic improvement. Methods: High-fat diet (HFD)-fed C57BL/6J mice were subjected to VSG. Energy dissipation in mice was monitored using metabolic cage experiments. The effects of VSG on gut microbiota and metabolites were determined by 16S rRNA sequencing and metabolomics, respectively. The metabolic beneficial effects of the identified gut metabolites were examined in mice by both oral administration and fat pad injection of the metabolites. Results: VSG in mice greatly increased thermogenic gene expression in beige fat, which was correlated with increased energy expenditure. VSG reshaped gut microbiota composition, resulting in elevated levels of gut metabolites including licoricidin. Licoricidin treatment promoted thermogenic gene expression in beige fat by activating the Adrb3-cAMP-PKA signaling pathway, leading to reduced body weight gain in HFD-fed mice. Conclusions: We identify licoricidin, which mediates the crosstalk between gut and adipose tissue in mice, as a VSG-provoked anti-obesity metabolite. Identification of anti-obesity small molecules should provide new insights into treatment options for obesity and its associated metabolic diseases.
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Affiliation(s)
- Zhangliu Jin
- Department of General Surgery, Division of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Wen Meng
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Ting Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
- Department of Hepatology, Hunan Children's Hospital, Changsha 410000, Hunan, China
| | - Jiangming Deng
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jing Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jie Wen
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Kai Chen
- Department of General Surgery, Division of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Liwen Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Juanhong Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Qingxin Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jieyu He
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Zheng Wang
- College of Bioscience & Biotechnology of Hunan Agricultural University, Changsha 410128, Hunan, China
| | - Wei Liu
- Department of General Surgery, Division of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, and Metabolic Syndrome Research Center, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
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21
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Liu Y, Liu Z, Liang J, Sun C. ILC2s control obesity by regulating energy homeostasis and browning of white fat. Int Immunopharmacol 2023; 120:110272. [PMID: 37210911 DOI: 10.1016/j.intimp.2023.110272] [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: 01/28/2023] [Revised: 04/27/2023] [Accepted: 04/29/2023] [Indexed: 05/23/2023]
Abstract
Innate lymphoid cells (ILCs) have been a hot topic in recent research, they are widely distributed in vivo and play an important role in different tissues. The important role of group 2 innate lymphoid cells (ILC2s) in the conversion of white fat into beige fat has attracted widespread attention. Studies have shown that ILC2s regulate adipocyte differentiation and lipid metabolism. This article reviews the types and functions of ILCs, focusing on the relationship between differentiation, development and function of ILC2s, and elaborates on the relationship between peripheral ILC2s and browning of white fat and body energy homeostasis. This has important implications for the future treatment of obesity and related metabolic diseases.
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Affiliation(s)
- Yuexia Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Zunhai Liu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Juntong Liang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Chao Sun
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
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22
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Wang HW, Tang J, Sun L, Li Z, Deng M, Dai Z. Mechanism of immune attack in the progression of obesity-related type 2 diabetes. World J Diabetes 2023; 14:494-511. [PMID: 37273249 PMCID: PMC10236992 DOI: 10.4239/wjd.v14.i5.494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
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Affiliation(s)
- Hua-Wei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ming Deng
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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23
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Kabat AM, Pearce EL, Pearce EJ. Metabolism in type 2 immune responses. Immunity 2023; 56:723-741. [PMID: 37044062 PMCID: PMC10938369 DOI: 10.1016/j.immuni.2023.03.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 04/14/2023]
Abstract
The immune response is tailored to the environment in which it takes place. Immune cells sense and adapt to changes in their surroundings, and it is now appreciated that in addition to cytokines made by stromal and epithelial cells, metabolic cues provide key adaptation signals. Changes in immune cell activation states are linked to changes in cellular metabolism that support function. Furthermore, metabolites themselves can signal between as well as within cells. Here, we discuss recent progress in our understanding of how metabolic regulation relates to type 2 immunity firstly by considering specifics of metabolism within type 2 immune cells and secondly by stressing how type 2 immune cells are integrated more broadly into the metabolism of the organism as a whole.
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Affiliation(s)
- Agnieszka M Kabat
- Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Erika L Pearce
- Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA
| | - Edward J Pearce
- Bloomberg Kimmel Institute, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21287, USA.
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24
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Cheong LY, Wang B, Wang Q, Jin L, Kwok KHM, Wu X, Shu L, Lin H, Chung SK, Cheng KKY, Hoo RLC, Xu A. Fibroblastic reticular cells in lymph node potentiate white adipose tissue beiging through neuro-immune crosstalk in male mice. Nat Commun 2023; 14:1213. [PMID: 36869026 PMCID: PMC9984541 DOI: 10.1038/s41467-023-36737-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 02/15/2023] [Indexed: 03/05/2023] Open
Abstract
Lymph nodes (LNs) are always embedded in the metabolically-active white adipose tissue (WAT), whereas their functional relationship remains obscure. Here, we identify fibroblastic reticular cells (FRCs) in inguinal LNs (iLNs) as a major source of IL-33 in mediating cold-induced beiging and thermogenesis of subcutaneous WAT (scWAT). Depletion of iLNs in male mice results in defective cold-induced beiging of scWAT. Mechanistically, cold-enhanced sympathetic outflow to iLNs activates β1- and β2-adrenergic receptor (AR) signaling in FRCs to facilitate IL-33 release into iLN-surrounding scWAT, where IL-33 activates type 2 immune response to potentiate biogenesis of beige adipocytes. Cold-induced beiging of scWAT is abrogated by selective ablation of IL-33 or β1- and β2-AR in FRCs, or sympathetic denervation of iLNs, whereas replenishment of IL-33 reverses the impaired cold-induced beiging in iLN-deficient mice. Taken together, our study uncovers an unexpected role of FRCs in iLNs in mediating neuro-immune interaction to maintain energy homeostasis.
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Affiliation(s)
- Lai Yee Cheong
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Baile Wang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China. .,Department of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Qin Wang
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Leigang Jin
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kelvin H M Kwok
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiaoping Wu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Lingling Shu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Huige Lin
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China
| | - Sookja Kim Chung
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China.,Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Kenneth K Y Cheng
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China
| | - Ruby L C Hoo
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China. .,Department of Medicine, The University of Hong Kong, Hong Kong, China. .,Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong, China.
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25
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Puttur F, Lloyd CM. Breathing easy: Dopamine quenches the ILC2 flame. Immunity 2023; 56:229-231. [PMID: 36792567 DOI: 10.1016/j.immuni.2023.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Communication between nerves and group 2 innate lymphoid cells (ILC2s) is thought to regulate allergic airway inflammation, but the molecular mechanisms are unclear. In this issue of Immunity, Cao et al. uncover an essential role for dopamine in inhibiting ILC2 function via metabolic restriction, thereby ameliorating key features of asthma pathogenesis.
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Affiliation(s)
- Franz Puttur
- National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK
| | - Clare M Lloyd
- National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
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26
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Qian X, Meng X, Zhang S, Zeng W. Neuroimmune regulation of white adipose tissues. FEBS J 2022; 289:7830-7853. [PMID: 34564950 DOI: 10.1111/febs.16213] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 08/21/2021] [Accepted: 09/24/2021] [Indexed: 01/14/2023]
Abstract
The white adipose tissues (WAT) are located in distinct depots throughout the body. They serve as an energy reserve, providing fatty acids for other tissues via lipolysis when needed, and function as an endocrine organ to regulate systemic metabolism. Their activities are coordinated through intercellular communications among adipocytes and other cell types such as residential and infiltrating immune cells, which are collectively under neuronal control. The adipocytes and immune subtypes including macrophages/monocytes, eosinophils, neutrophils, group 2 innate lymphoid cells (ILC2s), T and B cells, dendritic cells (DCs), and natural killer (NK) cells display cellular and functional diversity in response to the energy states and contribute to metabolic homeostasis and pathological conditions. Accumulating evidence reveals that neuronal innervations control lipid deposition and mobilization via regulating lipolysis, adipocyte size, and cellularity. Vice versa, the neuronal innervations and activity are influenced by cellular factors in the WAT. Though the literature describing adipose tissue cells is too extensive to cover in detail, we strive to highlight a selected list of neuronal and immune components in this review. The cell-to-cell communications and the perspective of neuroimmune regulation are emphasized to enlighten the potential therapeutic opportunities for treating metabolic disorders.
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Affiliation(s)
- Xinmin Qian
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Xia Meng
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Shan Zhang
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Wenwen Zeng
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Beijing, China.,Beijing Key Laboratory for Immunological Research on Chronic Diseases, Beijing, China
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27
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Cardoso F. The brain-fat connection. Science 2022; 378:485. [DOI: 10.1126/science.ade2132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Type 2 innate lymphoid cells shape metabolism through a brain-body circuit
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Affiliation(s)
- Filipa Cardoso
- Champalimaud Research, Champalimaud Foundation, Lisboa, Portugal
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28
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Xiong L, Nutt SL, Seillet C. Innate lymphoid cells: More than just immune cells. Front Immunol 2022; 13:1033904. [PMID: 36389661 PMCID: PMC9643152 DOI: 10.3389/fimmu.2022.1033904] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022] Open
Abstract
Since their discovery, innate lymphoid cells (ILCs) have been described as the innate counterpart of the T cells. Indeed, ILCs and T cells share many features including their common progenitors, transcriptional regulation, and effector cytokine secretion. Several studies have shown complementary and redundant roles for ILCs and T cells, leaving open questions regarding why these cells would have been evolutionarily conserved. It has become apparent in the last decade that ILCs, and rare immune cells more generally, that reside in non-lymphoid tissue have non-canonical functions for immune cells that contribute to tissue homeostasis and function. Viewed through this lens, ILCs would not be just the innate counterpart of T cells, but instead act as a link between sensory cells that monitor any changes in the environment that are not necessarily pathogenic and instruct effector cells that act to maintain body homeostasis. As these non-canonical functions of immune cells are operating in absence of pathogenic signals, it opens great avenues of research for immunologists that they now need to identify the physiological cues that regulate these cells and how the process confers a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions. In the review, we highlight how ILCs participate in the physiologic function of the tissue in which they reside and how physiological cues, in particular neural inputs control their homeostatic activity.
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Affiliation(s)
- Le Xiong
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Stephen L. Nutt
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Cyril Seillet
- Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
- *Correspondence: Cyril Seillet,
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29
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Wang G, Song A, Bae M, Wang QA. Adipose Tissue Plasticity in Aging. Compr Physiol 2022; 12:4119-4132. [PMID: 36214190 DOI: 10.1002/cphy.c220005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
As a dynamic endocrine organ, white adipose tissue (WAT) stores lipids and plays a critical role in maintaining whole-body energy homeostasis and insulin sensitivity. A large group of the population over 65 years old suffer from increased WAT mass, especially in the visceral location. Visceral adiposity accelerates aging through promoting age-associated chronic conditions, significantly shortening life expectancy. Unlike WAT, brown adipose tissue (BAT) functions as an effective energy sink that burns and disposes of excess lipids and glucose upon activation of thermogenesis. Unfortunately, the thermogenic activity of BAT declines during aging. New appreciation of cellular and functional remodeling of WAT and BAT during aging has emerged in recent years. Efforts are underway to explore the potential underlying mechanisms behind these age-associated alterations in WAT and BAT and the impact of these alterations on whole-body metabolism. Lastly, it is intriguing to translate our knowledge obtained from animal models to the clinic to prevent and treat age-associated metabolic disorders. © 2022 American Physiological Society. Compr Physiol 12: 4119-4132, 2022.
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Affiliation(s)
- Guan Wang
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA
| | - Anying Song
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA
| | - Marie Bae
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA
| | - Qiong A Wang
- Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, California, USA.,Comprehensive Cancer Center, Beckman Research Institute, City of Hope Medical Center, Duarte, California, USA
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30
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Puente-Ruiz SC, Jais A. Reciprocal signaling between adipose tissue depots and the central nervous system. Front Cell Dev Biol 2022; 10:979251. [PMID: 36200038 PMCID: PMC9529070 DOI: 10.3389/fcell.2022.979251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/24/2022] [Indexed: 11/13/2022] Open
Abstract
In humans, various dietary and social factors led to the development of increased brain sizes alongside large adipose tissue stores. Complex reciprocal signaling mechanisms allow for a fine-tuned interaction between the two organs to regulate energy homeostasis of the organism. As an endocrine organ, adipose tissue secretes various hormones, cytokines, and metabolites that signal energy availability to the central nervous system (CNS). Vice versa, the CNS is a critical regulator of adipose tissue function through neural networks that integrate information from the periphery and regulate sympathetic nerve outflow. This review discusses the various reciprocal signaling mechanisms in the CNS and adipose tissue to maintain organismal energy homeostasis. We are focusing on the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are discussing central mechanisms that fine-tune the immune system in adipose tissue depots and contribute to organ homeostasis. Elucidating this complex signaling network that integrates peripheral signals to generate physiological outputs to maintain the optimal energy balance of the organism is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes.
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31
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Lin J, Liu J, Ma R, Hao J, Liang Y, Zhao J, Zhang A, Meng H, Lu J. Interleukin-33: Metabolic checkpoints, metabolic processes, and epigenetic regulation in immune cells. Front Immunol 2022; 13:900826. [PMID: 35979357 PMCID: PMC9376228 DOI: 10.3389/fimmu.2022.900826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Interleukin-33 (IL-33) is a pleiotropic cytokine linked to various immune cells in the innate and adaptive immune systems. Recent studies of the effects of IL-33 on immune cells are beginning to reveal its regulatory mechanisms at the levels of cellular metabolism and epigenetic modifications. In response to IL-33 stimulation, these programs are intertwined with transcriptional programs, ultimately determining the fate of immune cells. Understanding these specific molecular events will help to explain the complex role of IL-33 in immune cells, thereby guiding the development of new strategies for immune intervention. Here, we highlight recent findings that reveal how IL-33, acting as an intracellular nuclear factor or an extracellular cytokine, alters metabolic checkpoints and cellular metabolism, which coordinately contribute to cell growth and function. We also discuss recent studies supporting the role of IL-33 in epigenetic alterations and speculate about the mechanisms underlying this relationship.
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Affiliation(s)
- Jian Lin
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiyun Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Rui Ma
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jie Hao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Liang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junjie Zhao
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ailing Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Haiyang Meng
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingli Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Engineering Research Center of Clinical Mass Spectrometry for Precision Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Zhengzhou Key Laboratory of Clinical Mass Spectrometry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Jingli Lu,
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32
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Luo L, Liu M. Adiponectin: friend or foe in obesity and inflammation. MEDICAL REVIEW (2021) 2022; 2:349-362. [PMID: 37724325 PMCID: PMC10388816 DOI: 10.1515/mr-2022-0002] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/27/2022] [Indexed: 09/20/2023]
Abstract
Adiponectin is an adipokine predominantly produced by fat cells, circulates and exerts insulin-sensitizing, cardioprotective and anti-inflammatory effects. Dysregulation of adiponectin and/or adiponectin signaling is implicated in a number of metabolic diseases such as obesity, insulin resistance, diabetes, and cardiovascular diseases. However, while the insulin-sensitizing and cardioprotective effects of adiponectin have been widely appreciated in the field, the obesogenic and anti-inflammatory effects of adiponectin are still of much debate. Understanding the physiological function of adiponectin is critical for adiponectin-based therapeutics for the treatment of metabolic diseases.
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Affiliation(s)
- Liping Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
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33
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Misawa T, Wagner M, Koyasu S. ILC2s and Adipose Tissue Homeostasis: Progress to Date and the Road Ahead. Front Immunol 2022; 13:876029. [PMID: 35784368 PMCID: PMC9243262 DOI: 10.3389/fimmu.2022.876029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/04/2022] [Indexed: 11/14/2022] Open
Abstract
Group 2 innate lymphoid cells (ILC2s) were initially identified as a new type of lymphocytes that produce vigorous amounts of type 2 cytokines in adipose tissue. Subsequent studies revealed that ILC2s are present not only in adipose tissue but also in various other tissues such as lung and skin. ILC2s are generally recognized as tissue-resident immune cells that regulate tissue homeostasis. ILC2s express receptors for various humoral factors and thus can change their functions or distribution depending on the environment and circumstances. In this review, we will outline our recent understanding of ILC2 biology and discuss future directions for ILC2 research, particularly in adipose tissue and metabolic homeostasis.
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Affiliation(s)
- Takuma Misawa
- Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Marek Wagner
- Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Shigeo Koyasu
- Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- *Correspondence: Shigeo Koyasu,
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Lee JH, Ealey KN, Patel Y, Verma N, Thakkar N, Park SY, Kim JR, Sung HK. Characterization of adipose depot-specific stromal cell populations by single-cell mass cytometry. iScience 2022; 25:104166. [PMID: 35434565 PMCID: PMC9010757 DOI: 10.1016/j.isci.2022.104166] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/18/2022] [Accepted: 03/24/2022] [Indexed: 11/17/2022] Open
Abstract
The increased prevalence of obesity and metabolic diseases has heightened interest in adipose tissue biology and its potential as a therapeutic target. To better understand cellular heterogeneity and complexity of white adipose tissue (WAT), we employed cytometry by time-of-flight (CyTOF) to characterize immune and stromal cells in visceral and subcutaneous WAT depots under normal and high-fat diet feeding, by quantifying the expression levels of 32 surface marker proteins. We observed comparable proportions of immune cells in two WAT depots under steady state, but depot-distinct subtypes of adipose precursor cells (APC), suggesting differences in their adipogenic and fibrogenic potential. Furthermore, in addition to pro-inflammatory immune cell shifts, significant pro-fibrotic changes were observed in APCs under high-fat diet, suggesting that APCs are early responders to dietary challenges. We propose CyTOF as a complementary and alternative tool to current high-throughput single-cell transcriptomic analyses to better understand the function and plasticity of adipose tissue.
Application of CyTOF for cellular characterization in two adipose depots Adipose depot-distinct APC subpopulations APCs are early responders under obesogenic conditions to regulate WAT fibrosis
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Affiliation(s)
- Ju Hee Lee
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Kafi N. Ealey
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Yash Patel
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
| | - Navkiran Verma
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Nikita Thakkar
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - So Young Park
- Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Jae-Ryong Kim
- Department of Physiology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
- Corresponding author
| | - Hoon-Ki Sung
- Translational Medicine Program, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Corresponding author
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35
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Wang C, Zhang X, Luo L, Luo Y, Yang X, Ding X, Wang L, Le H, Feldman LER, Men X, Yan C, Huang W, Feng Y, Liu F, Yang XO, Liu M. Adipocyte-derived PGE2 is required for intermittent fasting-induced Treg proliferation and improvement of insulin sensitivity. JCI Insight 2022; 7:153755. [PMID: 35260536 PMCID: PMC8983131 DOI: 10.1172/jci.insight.153755] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
The intermittent fasting (IF) diet has profound benefits for diabetes prevention. However, the precise mechanisms underlying IF's beneficial effects remain poorly defined. Here, we show that the expression levels of cyclooxygenase-2 (COX-2), an enzyme that produces prostaglandins, are suppressed in white adipose tissue (WAT) of obese humans. In addition, the expression of COX-2 in WAT is markedly upregulated by IF in obese mice. Adipocyte-specific depletion of COX-2 led to reduced fractions of CD4+Foxp3+ Tregs and a substantial decrease in the frequency of CD206+ macrophages, an increase in the abundance of γδT cells in WAT under normal chow diet conditions, and attenuation of IF-induced antiinflammatory and insulin-sensitizing effects, despite a similar antiobesity effect in obese mice. Mechanistically, adipocyte-derived prostaglandin E2 (PGE2) promoted Treg proliferation through the CaMKII pathway in vitro and rescued Treg populations in adipose tissue in COX-2-deficient mice. Ultimately, inactivation of Tregs by neutralizing anti-CD25 diminished IF-elicited antiinflammatory and insulin-sensitizing effects, and PGE2 restored the beneficial effects of IF in COX-2-KO mice. Collectively, our study reveals that adipocyte COX-2 is a key regulator of Treg proliferation and that adipocyte-derived PGE2 is essential for IF-elicited type 2 immune response and metabolic benefits.
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Affiliation(s)
- Chunqing Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xing Zhang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Liping Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Yan Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xin Yang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xiaofeng Ding
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Lu Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Huyen Le
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Lily Elizabeth R. Feldman
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Xuebo Men
- Baodi Clinical College of Tian Jin Medical University, Tianjin, China
| | - Cen Yan
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Wendong Huang
- Department of Diabetes Complications & Metabolism Research, City of Hope, Duarte, California, USA
| | - Yingmei Feng
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Feng Liu
- Metabolic Syndrome Research Center, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xuexian O. Yang
- Department of Molecular Genetics and Microbiology and,Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.,Autophagy Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
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Antuna-Puente B, Fellahi S, McAvoy C, Fève B, Bastard JP. Interleukins in adipose tissue: Keeping the balance. Mol Cell Endocrinol 2022; 542:111531. [PMID: 34910978 DOI: 10.1016/j.mce.2021.111531] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023]
Abstract
The role of the immune system is to defend the host and preserve the functionality in response to stress. This function is not limited to infection or injury as it also plays a role in the response to overnutrition. Indeed, low-grade chronic activation of the immune system associated with overnutrition may be deleterious, contributing importantly to diabetes and long-term complications, such as cardiovascular disorders. Increasing evidence shows that adipose tissue participates in the obesity-related inflammatory response and that interleukins are one of the key players, either as a pro-inflammatory response to the metabolic dysregulation or to restore homeostasis. The crosstalk between adipocytes and immune cells through some important interleukins and their role in metabolic disruption is the topic of this review.
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Affiliation(s)
- Barbara Antuna-Puente
- Infection Disease Division, Department of Medicine, Queen's University, Kingston, ON, Canada.
| | - Soraya Fellahi
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Département de Biochimie-pharmacologie-biologie Moléculaire-génétique Médicale, Créteil, France; Sorbonne Université-Inserm, Centre de Recherche Saint-Antoine UMR S_938, 75012, Paris Institut Hospitalo-Universitaire de Cardio-Métabolisme et Nutrition (ICAN), Paris, France
| | - Chloé McAvoy
- Unité de Recherche Clinique de L'Est Parisien (URC-Est), Hôpital Saint Antoine, Paris, France
| | - Bruno Fève
- Sorbonne Université-Inserm, Centre de Recherche Saint-Antoine UMR S_938, 75012, Paris Institut Hospitalo-Universitaire de Cardio-Métabolisme et Nutrition (ICAN), Paris, France; Assistance Publique- Hôpitaux de Paris -Hôpital Saint-Antoine, Service D'Endocrinologie-Diabétologie, Centre de Référence des Maladies Rares de L'Insulino-Sécrétion et de L'Insulino-Sensibilité (PRISIS), 75012, Paris, France
| | - Jean-Philippe Bastard
- Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, Département de Biochimie-pharmacologie-biologie Moléculaire-génétique Médicale, Créteil, France; FHU-SENEC, INSERM U955 and Université Paris Est (UPEC), UMR U955, Faculté de Santé, Créteil, France
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37
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Role of Distinct Fat Depots in Metabolic Regulation and Pathological Implications. Rev Physiol Biochem Pharmacol 2022; 186:135-176. [PMID: 35915363 DOI: 10.1007/112_2022_73] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
People suffering from obesity and associated metabolic disorders including diabetes are increasing exponentially around the world. Adipose tissue (AT) distribution and alteration in their biochemical properties play a major role in the pathogenesis of these diseases. Emerging evidence suggests that AT heterogeneity and depot-specific physiological changes are vital in the development of insulin resistance in peripheral tissues like muscle and liver. Classically, AT depots are classified into white adipose tissue (WAT) and brown adipose tissue (BAT); WAT is the site of fatty acid storage, while BAT is a dedicated organ of metabolic heat production. The discovery of beige adipocyte clusters in WAT depots indicates AT heterogeneity has a more central role than hither to ascribed. Therefore, we have discussed in detail the current state of understanding on cellular and molecular origin of different AT depots and their relevance toward physiological metabolic homeostasis. A major focus is to highlight the correlation between altered WAT distribution in the body and metabolic pathogenesis in animal models and humans. We have also underscored the disparity in the molecular (including signaling) changes in various WAT tissues during diabetic pathogenesis. Exercise-mediated beneficial alteration in WAT physiology/distribution that protects against metabolic disorders is evolving. Here we have discussed the depot-specific biochemical adjustments induced by different forms of exercise. A detailed understanding of the molecular details of inter-organ crosstalk via substrate utilization/storage and signaling through chemokines provide strategies to target selected WAT depots to pharmacologically mimic the benefits of exercise countering metabolic diseases including diabetes.
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Chen H, Sun L, Feng L, Yin Y, Zhang W. Role of Innate lymphoid Cells in Obesity and Insulin Resistance. Front Endocrinol (Lausanne) 2022; 13:855197. [PMID: 35574038 PMCID: PMC9091334 DOI: 10.3389/fendo.2022.855197] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Obesity, a growing chronic metabolic disease, greatly increases the risk of metabolic syndrome which includes type 2 diabetes, fatty liver and cardiovascular diseases. Obesity-associated metabolic diseases significantly contribute to mortality and reduce life expectancy. Recently, innate lymphoid cells (ILCs) have emerged as crucial regulators of metabolic homeostasis and tissue inflammation. This review focuses on the roles of ILCs in different metabolic tissues, including adipose tissue, liver, pancreas, and intestine. We briefly outline the relationship between obesity, inflammation, and insulin resistance. We then discuss how ILCs in distinct metabolic organs may function to maintain metabolic homeostasis and contribute to obesity and its associated metabolic diseases. The potential of ILCs as the therapeutic target for obesity and insulin resistance is also addressed.
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Affiliation(s)
- Hong Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Lijun Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Lu Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Yue Yin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- *Correspondence: Weizhen Zhang, ; Yue Yin,
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
- *Correspondence: Weizhen Zhang, ; Yue Yin,
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39
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Marcelin G, Clément K. The multifaceted progenitor fates in healthy or unhealthy adipose tissue during obesity. Rev Endocr Metab Disord 2021; 22:1111-1119. [PMID: 34105090 DOI: 10.1007/s11154-021-09662-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/01/2021] [Indexed: 10/21/2022]
Abstract
While obesity is defined as an excessive fat accumulation conferring a risk to metabolic health, increased adipose mass by itself does not fully explain obesity's propensity to promote metabolic alterations. Adipose tissue regulates multiple processes critical for energy homeostasis and its dysfunction favors the development and perpetuation of metabolic diseases. Obesity drives inflammatory leucocyte infiltration in adipose tissue and fibrotic transformation of the fat depots. Both features associate with metabolic alterations such as impaired glucose control and resistance to fat mass loss. In this context, adipose progenitors, an heterogenous resident population of mesenchymal stromal cells, display functions important to shape healthy or unhealthy adipose tissue expansion. We, here, outline the current understanding of adipose progenitor biology in the context of obesity-induced adipose tissue remodeling.
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Affiliation(s)
- Geneviève Marcelin
- Nutrition and Obesities : Systemic Approaches (NutriOmics, UMRS U1269), Sorbonne Universités, INSERM, Paris, France
| | - Karine Clément
- Nutrition and Obesities : Systemic Approaches (NutriOmics, UMRS U1269), Sorbonne Universités, INSERM, Paris, France.
- Nutrition Department, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, CRNH Ile de France, 75013, Paris, France.
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40
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Olguín-Martínez E, Ruiz-Medina BE, Licona-Limón P. Tissue-Specific Molecular Markers and Heterogeneity in Type 2 Innate Lymphoid Cells. Front Immunol 2021; 12:757967. [PMID: 34759931 PMCID: PMC8573327 DOI: 10.3389/fimmu.2021.757967] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/21/2021] [Indexed: 12/25/2022] Open
Abstract
Innate lymphoid cells (ILCs) are the most recently described group of lymphoid subpopulations. These tissue-resident cells display a heterogeneity resembling that observed on different groups of T cells, hence their categorization as cytotoxic NK cells and helper ILCs type 1, 2 and 3. Each one of these groups is highly diverse and expresses different markers in a context-dependent manner. Type 2 innate lymphoid cells (ILC2s) are activated in response to helminth parasites and regulate the immune response. They are involved in the etiology of diseases associated with allergic responses as well as in the maintenance of tissue homeostasis. Markers associated with their identification differ depending on the tissue and model used, making the study and understanding of these cells a cumbersome task. This review compiles evidence for the heterogeneity of ILC2s as well as discussion and analyses of molecular markers associated with their identity, function, tissue-dependent expression, and how these markers contribute to the interaction of ILC2s with specific microenvironments to maintain homeostasis or respond to pathogenic challenges.
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Affiliation(s)
- Enrique Olguín-Martínez
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico
| | - Blanca E Ruiz-Medina
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico
| | - Paula Licona-Limón
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, Mexico
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41
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Luo L, Wang L, Luo Y, Romero E, Yang X, Liu M. Glucocorticoid/Adiponectin Axis Mediates Full Activation of Cold-Induced Beige Fat Thermogenesis. Biomolecules 2021; 11:1573. [PMID: 34827571 PMCID: PMC8615797 DOI: 10.3390/biom11111573] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023] Open
Abstract
Glucocorticoids (GCs), a class of corticosteroids produced by the adrenal cortex in response to stress, exert obesity-promoting effects. Although adaptive thermogenesis has been considered an effective approach to counteract obesity, whether GCs play a role in regulating cold stress-induced thermogenesis remains incompletely understood. Here, we show that the circulating levels of stress hormone corticosterone (GC in rodents) were significantly elevated, whereas the levels of adiponectin, an adipokine that was linked to cold-induced adaptive thermogenesis, were decreased 48 h post cold exposure. The administration of a glucocorticoid hydrocortisone downregulated adiponectin protein and mRNA levels in both WAT and white adipocytes, and upregulated thermogenic gene expression in inguinal fat. In contrast, mifepristone, a glucocorticoid receptor antagonist, enhanced adiponectin expression and suppressed energy expenditure in vivo. Mechanistically, hydrocortisone suppressed adiponectin expression by antagonizing PPARγ in differentiated 3T3-L1 adipocytes. Ultimately, adiponectin deficiency restored mifepristone-decreased oxygen consumption and suppressed the expression of thermogenic genes in inguinal fat. Taken together, our study reveals that the GCs/adiponectin axis is a key regulator of beige fat thermogenesis in response to acute cold stress.
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Affiliation(s)
- Liping Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (L.L.); (L.W.); (Y.L.); (E.R.); (X.Y.)
| | - Lu Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (L.L.); (L.W.); (Y.L.); (E.R.); (X.Y.)
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Yan Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (L.L.); (L.W.); (Y.L.); (E.R.); (X.Y.)
- Department of Endocrinology and Metabolism, Metabolic Syndrome Research Center, The Second Xiangya Hospital, Central South University, Changsha 410011, China
- Key Laboratory of Diabetes Immunology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Estevan Romero
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (L.L.); (L.W.); (Y.L.); (E.R.); (X.Y.)
| | - Xin Yang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (L.L.); (L.W.); (Y.L.); (E.R.); (X.Y.)
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; (L.L.); (L.W.); (Y.L.); (E.R.); (X.Y.)
- Autophagy, Inflammation and Metabolism Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
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O'Brien CJO, Haberman ER, Domingos AI. A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity. Annu Rev Cell Dev Biol 2021; 37:549-573. [PMID: 34613819 PMCID: PMC7614880 DOI: 10.1146/annurev-cellbio-120319-114106] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.
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Affiliation(s)
- Conan J O O'Brien
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
| | - Emma R Haberman
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
| | - Ana I Domingos
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
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43
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Painter JD, Akbari O. Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes. Front Immunol 2021; 12:727008. [PMID: 34489979 PMCID: PMC8416625 DOI: 10.3389/fimmu.2021.727008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/29/2021] [Indexed: 12/13/2022] Open
Abstract
Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.
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Affiliation(s)
- Jacob D Painter
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Omid Akbari
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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44
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Cardoso F, Klein Wolterink RGJ, Godinho-Silva C, Domingues RG, Ribeiro H, da Silva JA, Mahú I, Domingos AI, Veiga-Fernandes H. Neuro-mesenchymal units control ILC2 and obesity via a brain-adipose circuit. Nature 2021; 597:410-414. [PMID: 34408322 PMCID: PMC7614847 DOI: 10.1038/s41586-021-03830-7] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 07/16/2021] [Indexed: 12/12/2022]
Abstract
Signals from sympathetic neurons and immune cells regulate adipocytes and thereby contribute to fat tissue biology. Interactions between the nervous and immune systems have recently emerged as important regulators of host defence and inflammation1-4. Nevertheless, it is unclear whether neuronal and immune cells co-operate in brain-body axes to orchestrate metabolism and obesity. Here we describe a neuro-mesenchymal unit that controls group 2 innate lymphoid cells (ILC2s), adipose tissue physiology, metabolism and obesity via a brain-adipose circuit. We found that sympathetic nerve terminals act on neighbouring adipose mesenchymal cells via the β2-adrenergic receptor to control the expression of glial-derived neurotrophic factor (GDNF) and the activity of ILC2s in gonadal fat. Accordingly, ILC2-autonomous manipulation of the GDNF receptor machinery led to alterations in ILC2 function, energy expenditure, insulin resistance and propensity to obesity. Retrograde tracing and chemical, surgical and chemogenetic manipulations identified a sympathetic aorticorenal circuit that modulates ILC2s in gonadal fat and connects to higher-order brain areas, including the paraventricular nucleus of the hypothalamus. Our results identify a neuro-mesenchymal unit that translates cues from long-range neuronal circuitry into adipose-resident ILC2 function, thereby shaping host metabolism and obesity.
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Affiliation(s)
- Filipa Cardoso
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | | | | | - Rita G Domingues
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
- Lydia Becker Institute of Immunology and Inflammation, Manchester Collaborative Centre for Inflammation Research (MCCIR), Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Hélder Ribeiro
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal
| | | | - Inês Mahú
- Max Planck Institute for Metabolism Research, Köln, Germany
| | - Ana I Domingos
- Department of Physiology, Anatomy & Genetics, Oxford University, Oxford, UK
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Cheong LY, Xu A. Intercellular and inter-organ crosstalk in browning of white adipose tissue: molecular mechanism and therapeutic complications. J Mol Cell Biol 2021; 13:466-479. [PMID: 34185049 PMCID: PMC8530522 DOI: 10.1093/jmcb/mjab038] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/27/2021] [Accepted: 05/11/2021] [Indexed: 12/26/2022] Open
Abstract
Adipose tissue (AT) is highly plastic and heterogeneous in response to environmental and nutritional changes. The development of heat-dissipating beige adipocytes in white AT (WAT) through a process known as browning (or beiging) has garnered much attention as a promising therapeutic strategy for obesity and its related metabolic complications. This is due to its inducibility in response to thermogenic stimulation and its association with improved metabolic health. WAT consists of adipocytes, nerves, vascular endothelial cells, various types of immune cells, adipocyte progenitor cells, and fibroblasts. These cells contribute to the formation of beige adipocytes through the release of protein factors that significantly influence browning capacity. In addition, inter-organ crosstalk is also important for beige adipocyte biogenesis. Here, we summarize recent findings on fat depot-specific differences, secretory factors participating in intercellular and inter-organ communications that regulate the recruitment of thermogenic beige adipocytes, as well as challenges in targeting beige adipocytes as a potential anti-obese therapy.
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Affiliation(s)
- Lai Yee Cheong
- The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.,Department of Medicine, The University of Hong Kong, Hong Kong, China.,Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
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46
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Kurokawa A, Kondo M, Arimura K, Ashino S, Tagaya E. Less airway inflammation and goblet cell metaplasia in an IL-33-induced asthma model of leptin-deficient obese mice. Respir Res 2021; 22:166. [PMID: 34074279 PMCID: PMC8170793 DOI: 10.1186/s12931-021-01763-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 05/27/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Obesity-associated asthma is a phenotype of severe asthma. Late-onset, non-eosinophilic and female-dominant phenotype is highly symptomatic and difficult to treat. Leptin, an adipokine, exerts an immunomodulatory effect. IL-33 associated with innate immunity induces type 2 inflammation and is present in adipose tissue. The purpose of this study was to elucidate the pathogenesis of obesity-associated asthma by focusing on the interaction between leptin and IL-33. METHODS In leptin-deficient obese (ob/ob) and wild-type mice, IL-33 was instilled intranasally on three consecutive days. In part of the mice, leptin was injected intraperitoneally prior to IL-33 treatment. The mice were challenged with methacholine, and airway hyperresponsiveness (AHR) was assessed by resistance (Rrs) and elastance (Ers) of the respiratory system using the forced oscillation technique. Cell differentiation, IL-5, IL-13, eotaxin, keratinocyte-derived chemokine (KC) in bronchoalveolar lavage fluid (BALF) and histology of the lung were analyzed. For the in vitro study, NCI-H292 cells were stimulated with IL-33 in the presence or absence of leptin. Mucin-5AC (MUC5AC) levels were measured using an enzyme-linked immunosorbent assay. RESULTS Ob/ob mice showed greater Rrs and Ers than wild-type mice. IL-33 with leptin, but not IL-33 alone, enhanced Ers rather than Rrs challenged with methacholine in ob/ob mice, whereas it enhanced Rrs alone in wild-type mice. IL-33-induced eosinophil numbers, cytokine levels in BALF, eosinophilic infiltration around the bronchi, and goblet cell metaplasia were less in ob/ob mice than in wild-type mice. However, leptin pretreatment attenuated these changes in ob/ob mice. MUC5AC levels were increased by co-stimulation with IL-33 and leptin in vitro. CONCLUSIONS Ob/ob mice show innate AHR. IL-33 with leptin, but not IL-33 alone, induces airway inflammation and goblet cell metaplasia and enhances AHR involving peripheral airway closure. This is presumably accelerated by mucus in ob/ob mice. These results may explain some aspects of the pathogenesis of obesity-associated asthma.
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Affiliation(s)
- Atsushi Kurokawa
- Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - Mitsuko Kondo
- Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
| | - Ken Arimura
- Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - Shigeru Ashino
- Department of Microbiology and Immunology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - Etsuko Tagaya
- Department of Respiratory Medicine, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
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47
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Michailidou Z, Gomez-Salazar M, Alexaki VI. Innate Immune Cells in the Adipose Tissue in Health and Metabolic Disease. J Innate Immun 2021; 14:4-30. [PMID: 33849008 DOI: 10.1159/000515117] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 02/09/2021] [Indexed: 11/19/2022] Open
Abstract
Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, are characterized by chronic low-grade tissue and systemic inflammation. During obesity, the adipose tissue undergoes immunometabolic and functional transformation. Adipose tissue inflammation is driven by innate and adaptive immune cells and instigates insulin resistance. Here, we discuss the role of innate immune cells, that is, macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid type 2 cells, dendritic cells, and mast cells, in the adipose tissue in the healthy (lean) and diseased (obese) state and describe how their function is shaped by the obesogenic microenvironment, and humoral, paracrine, and cellular interactions. Moreover, we particularly outline the role of hypoxia as a central regulator in adipose tissue inflammation. Finally, we discuss the long-lasting effects of adipose tissue inflammation and its potential reversibility through drugs, caloric restriction, or exercise training.
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Affiliation(s)
- Zoi Michailidou
- Centre for Cardiovascular Sciences, Edinburgh University, Edinburgh, United Kingdom
| | - Mario Gomez-Salazar
- Centre for Cardiovascular Sciences, Edinburgh University, Edinburgh, United Kingdom
| | - Vasileia Ismini Alexaki
- Institute for Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
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48
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Tang H, Liu N, Feng X, Yang Y, Fang Y, Zhuang S, Dai Y, Liu M, Tang L. Circulating levels of IL-33 are elevated by obesity and positively correlated with metabolic disorders in Chinese adults. J Transl Med 2021; 19:52. [PMID: 33541367 PMCID: PMC7863234 DOI: 10.1186/s12967-021-02711-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Interleukin-33 (IL-33) plays a pivotal role in regulating innate immune response and metabolic homeostasis. However, whether its circulating level is correlated with obesity and metabolic disorders in humans remains largely unknown. We aimed to address this gap by determining IL-33 serum level and its downstream type 2 inflammatory cytokines interleukin-5 (IL-5) and interleukin-13 (IL-13) in overweight/obese population, and analyzing the specific associations between IL-33 and obesity metabolic phenotypes. METHODS 217 subjects were enrolled and divided into three groups: healthy control (HC) subjects, metabolically healthy overweight/obese (MHOO) subjects and metabolically unhealthy overweight/obese (MUOO) subjects. Circulating levels of IL-33, IL-5 and IL-13 were measured using ELISA analyses. Multivariate regression analyses were further performed to determine the independent association between IL-33 and obesity metabolic phenotypes. RESULTS Circulating levels of IL-33 were significantly elevated in subjects of MUOO group compared with HC group and MHOO group, while no significant difference was observed between the latter two groups in IL-33 levels. Consistent with this, serum levels of IL-5/13 were higher in the MUOO group compared with HC and MHOO groups. After adjusted for all confounders, MUOO phenotype was significantly associated with increased IL-33 serum levels (OR = 1.70; 95% CI 1.09-2.64; p = 0.019). With the MHOO group as the reference population, higher circulating level of IL-33 was also positively associated with MUOO phenotype after adjusting for confounders (OR = 1.50; 95% CI 1.20-1.88; p = 2.91E-4). However, there was no significant association between MHOO phenotype and IL-33 levels (p = 0.942). Trend analysis further confirmed the positive correlation between MUOO phenotype and IL-33 level (p for trend = 0.019). Additionally, IL-33 was significantly and positively correlated with diastolic blood pressure (DBP), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), neutrophil and IL-5 only in MUOO group, while inversely correlated with high density lipoprotein cholesterol (HDL-C) in MHOO subjects. CONCLUSION Circulating levels of IL-33 were significantly elevated in overweight/obese Chinese adults with metabolic disorders. Increased levels of IL-33 were positively associated with metabolically unhealthy overweight/obese phenotype and several metabolic syndrome risk factors.
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Affiliation(s)
- Haoneng Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Ning Liu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
- Medical College, Yueyang Vocational and Technical College, Yueyang, 414000, China
| | - Xiaojing Feng
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yanyi Yang
- Health Management Center, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yiyuan Fang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Siqi Zhuang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Yufeng Dai
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA
- Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Lingli Tang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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49
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Wang L, Luo Y, Luo L, Wu D, Ding X, Zheng H, Wu H, Liu B, Yang X, Silva F, Wang C, Zhang X, Zheng X, Chen J, Brigman J, Mandell M, Zhou Z, Liu F, Yang XO, Liu M. Adiponectin restrains ILC2 activation by AMPK-mediated feedback inhibition of IL-33 signaling. J Exp Med 2021; 218:e20191054. [PMID: 33104171 PMCID: PMC7590510 DOI: 10.1084/jem.20191054] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 10/20/2019] [Accepted: 09/01/2020] [Indexed: 12/11/2022] Open
Abstract
ILC2s are present in adipose tissue and play a critical role in regulating adipose thermogenesis. However, the mechanisms underlying the activation of adipose-resident ILC2s remain poorly defined. Here, we show that IL-33, a potent ILC2 activator, stimulates phosphorylation of AMPK at Thr172 via TAK1 in primary ILC2s, which provides a feedback mechanism to inhibit IL-33-induced NF-κB activation and IL-13 production. Treating ILC2s with adiponectin or an adiponectin receptor agonist (AdipoRon) activated AMPK and decreased IL-33-NF-κB signaling. AdipoRon also suppressed cold-induced thermogenic gene expression and energy expenditure in vivo. In contrast, adiponectin deficiency increased the ILC2 fraction and activation, leading to up-regulated thermogenic gene expression in adipose tissue of cold-exposed mice. ILC2 deficiency or blocking ILC2 function by neutralization of the IL-33 receptor with anti-ST2 diminished the suppressive effect of adiponectin on cold-induced adipose thermogenesis and energy expenditure. Taken together, our study reveals that adiponectin is a negative regulator of ILC2 function in adipose tissue via AMPK-mediated negative regulation of IL-33 signaling.
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Affiliation(s)
- Lu Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Central South University, Changsha, Hunan, China
| | - Liping Luo
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Dandan Wu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
- Department of Microbiology and Molecular Genetics, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Xiaofeng Ding
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Handong Zheng
- Department of Microbiology and Molecular Genetics, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Haisha Wu
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bilian Liu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Central South University, Changsha, Hunan, China
| | - Xin Yang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Floyd Silva
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Chunqing Wang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Xing Zhang
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Xianyun Zheng
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Jindong Chen
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jonathan Brigman
- Department of Neuroscience, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Michael Mandell
- Department of Microbiology and Molecular Genetics, University of New Mexico Health Sciences Center, Albuquerque, NM
- Autophagy, Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Zhiguang Zhou
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Central South University, Changsha, Hunan, China
| | - Feng Liu
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, TX
| | - Xuexian O. Yang
- Department of Microbiology and Molecular Genetics, University of New Mexico Health Sciences Center, Albuquerque, NM
- Autophagy, Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM
- Autophagy, Inflammation and Metabolism Center for Biomedical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM
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50
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Zhou H, Peng X, Hu J, Wang L, Luo H, Zhang J, Zhang Y, Li G, Ji Y, Zhang J, Bai J, Liu M, Zhou Z, Liu F. DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production. Nat Commun 2021; 12:326. [PMID: 33436607 PMCID: PMC7804451 DOI: 10.1038/s41467-020-20665-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 12/10/2020] [Indexed: 01/17/2023] Open
Abstract
Adipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.
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MESH Headings
- Adipocytes, Brown/drug effects
- Adipocytes, Brown/metabolism
- Adipose Tissue, Brown/drug effects
- Adipose Tissue, Brown/metabolism
- Adipose Tissue, White/drug effects
- Adipose Tissue, White/metabolism
- Animals
- Diet, High-Fat
- Down-Regulation/drug effects
- Energy Metabolism/drug effects
- Feeding Behavior
- Glutathione Transferase/deficiency
- Glutathione Transferase/metabolism
- Insulin Resistance
- Interferon-gamma/administration & dosage
- Interferon-gamma/biosynthesis
- Interferon-gamma/pharmacology
- Male
- Mice, Knockout
- Mitochondria/drug effects
- Mitochondria/metabolism
- Obesity/genetics
- Obesity/pathology
- T-Lymphocytes/drug effects
- T-Lymphocytes/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/metabolism
- Thermogenesis/drug effects
- Thermogenesis/genetics
- Uncoupling Protein 1/metabolism
- Mice
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Affiliation(s)
- Haiyan Zhou
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China.
| | - Xinyi Peng
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Jie Hu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Liwen Wang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Hairong Luo
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Junyan Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Yacheng Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Guobao Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Yujiao Ji
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Juli Bai
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA
| | - Meilian Liu
- Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM, 87131, USA
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, 410011, Changsha, Hunan, China.
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
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