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Tang R, Xie C, Zhang X. NOD1: a metabolic modulator. Front Endocrinol (Lausanne) 2025; 15:1484829. [PMID: 39906040 PMCID: PMC11790428 DOI: 10.3389/fendo.2024.1484829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 12/30/2024] [Indexed: 02/06/2025] Open
Abstract
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern recognition receptor that detects injury signals and initiates inflammatory responses and host defense. Furthermore, NOD1 serves as a metabolic mediator by influencing the metabolism of various tissues, including adipose tissue, liver, cardiovascular tissue, pancreatic β cells, adrenal glands, and bones through diverse mechanisms. It has been discovered that activated NOD1 is associated with the pathological mechanisms of certain metabolic diseases. This review presents a comprehensive summary of the impact of NOD1 on tissue-specific metabolism.
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Affiliation(s)
- Ruobing Tang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Xiyu Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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Fang H, Rodrigues e-Lacerda R, Barra NG, Kukje Zada D, Robin N, Mehra A, Schertzer JD. Postbiotic Impact on Host Metabolism and Immunity Provides Therapeutic Potential in Metabolic Disease. Endocr Rev 2025; 46:60-79. [PMID: 39235984 PMCID: PMC11720174 DOI: 10.1210/endrev/bnae025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/18/2024] [Accepted: 09/04/2024] [Indexed: 09/07/2024]
Abstract
The gut microbiota influences aspects of metabolic disease, including tissue inflammation, adiposity, blood glucose, insulin, and endocrine control of metabolism. Prebiotics or probiotics are often sought to combat metabolic disease. However, prebiotics lack specificity and can have deleterious bacterial community effects. Probiotics require live bacteria to find a colonization niche sufficient to influence host immunity or metabolism. Postbiotics encompass bacterial-derived components and molecules, which are well-positioned to alter host immunometabolism without relying on colonization efficiency or causing widespread effects on the existing microbiota. Here, we summarize the potential for beneficial and detrimental effects of specific postbiotics related to metabolic disease and the underlying mechanisms of action. Bacterial cell wall components, such as lipopolysaccharides, muropeptides, lipoteichoic acids and flagellin, have context-dependent effects on host metabolism by engaging specific immune responses. Specific types of postbiotics within broad classes of compounds, such as lipopolysaccharides and muropeptides, can have opposing effects on endocrine control of host metabolism, where certain postbiotics are insulin sensitizers and others promote insulin resistance. Bacterial metabolites, such as short-chain fatty acids, bile acids, lactate, glycerol, succinate, ethanolamine, and ethanol, can be substrates for host metabolism. Postbiotics can fuel host metabolic pathways directly or influence endocrine control of metabolism through immunomodulation or mimicking host-derived hormones. The interaction of postbiotics in the host-microbe relationship should be considered during metabolic inflammation and metabolic disease.
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Affiliation(s)
- Han Fang
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
| | - Rodrigo Rodrigues e-Lacerda
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
| | - Nicole G Barra
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
| | - Dana Kukje Zada
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
| | - Nazli Robin
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
| | - Alina Mehra
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
| | - Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, and Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada, L8N 3Z5
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Martínez-Álvaro M, Mattock J, González-Recio Ó, Saborío-Montero A, Weng Z, Lima J, Duthie CA, Dewhurst R, Cleveland MA, Watson M, Roehe R. Including microbiome information in a multi-trait genomic evaluation: a case study on longitudinal growth performance in beef cattle. Genet Sel Evol 2024; 56:19. [PMID: 38491422 PMCID: PMC10943865 DOI: 10.1186/s12711-024-00887-6] [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: 07/11/2023] [Accepted: 02/22/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Growth rate is an important component of feed conversion efficiency in cattle and varies across the different stages of the finishing period. The metabolic effect of the rumen microbiome is essential for cattle growth, and investigating the genomic and microbial factors that underlie this temporal variation can help maximize feed conversion efficiency at each growth stage. RESULTS By analysing longitudinal body weights during the finishing period and genomic and metagenomic data from 359 beef cattle, our study demonstrates that the influence of the host genome on the functional rumen microbiome contributes to the temporal variation in average daily gain (ADG) in different months (ADG1, ADG2, ADG3, ADG4). Five hundred and thirty-three additive log-ratio transformed microbial genes (alr-MG) had non-zero genomic correlations (rg) with at least one ADG-trait (ranging from |0.21| to |0.42|). Only a few alr-MG correlated with more than one ADG-trait, which suggests that a differential host-microbiome determinism underlies ADG at different stages. These alr-MG were involved in ribosomal biosynthesis, energy processes, sulphur and aminoacid metabolism and transport, or lipopolysaccharide signalling, among others. We selected two alternative subsets of 32 alr-MG that had a non-uniform or a uniform rg sign with all the ADG-traits, regardless of the rg magnitude, and used them to develop a microbiome-driven breeding strategy based on alr-MG only, or combined with ADG-traits, which was aimed at shaping the rumen microbiome towards increased ADG at all finishing stages. Combining alr-MG information with ADG records increased prediction accuracy of genomic estimated breeding values (GEBV) by 11 to 22% relative to the direct breeding strategy (using ADG-traits only), whereas using microbiome information, only, achieved lower accuracies (from 7 to 41%). Predicted selection responses varied consistently with accuracies. Restricting alr-MG based on their rg sign (uniform subset) did not yield a gain in the predicted response compared to the non-uniform subset, which is explained by the absence of alr-MG showing non-zero rg at least with more than one of the ADG-traits. CONCLUSIONS Our work sheds light on the role of the microbial metabolism in the growth trajectory of beef cattle at the genomic level and provides insights into the potential benefits of using microbiome information in future genomic breeding programs to accurately estimate GEBV and increase ADG at each finishing stage in beef cattle.
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Affiliation(s)
- Marina Martínez-Álvaro
- Institute of Animal Science and Technology, Universitat Politècnica de Valéncia, 46022, Valencia, Spain.
- Scotland's Rural College, Easter Bush, Edinburgh, EH25 9RG, UK.
| | | | | | - Alejandro Saborío-Montero
- Escuela de Zootecnia y Centro de Investigación en Nutrición Animal, Universidad de Costa Rica, San José, 11501, Costa Rica
| | | | - Joana Lima
- Scotland's Rural College, Easter Bush, Edinburgh, EH25 9RG, UK
| | | | | | | | - Mick Watson
- Scotland's Rural College, Easter Bush, Edinburgh, EH25 9RG, UK
| | - Rainer Roehe
- Scotland's Rural College, Easter Bush, Edinburgh, EH25 9RG, UK.
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Qiu J, Wu J, Chen W, Ruan Y, Mao J, Li S, Tang X, Zhao L, Li S, Li K, Liu D, Duan Y. NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow-retina crosstalk. Stem Cell Res Ther 2024; 15:38. [PMID: 38336763 PMCID: PMC10858517 DOI: 10.1186/s13287-024-03654-y] [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: 08/28/2023] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) plays a pivotal role in inducing metabolic inflammation in diabetes. Additionally, the NOD1 ligand disrupts the equilibrium of bone marrow-derived hematopoietic stem/progenitor cells, a process that has immense significance in the development of diabetic retinopathy (DR). We hypothesized that NOD1 depletion impedes the advancement of DR by resolving bone marrow dysfunction. METHODS We generated NOD1-/--Akita double-mutant mice and chimeric mice with hematopoietic-specific NOD1 depletion to study the role of NOD1 in the bone marrow-retina axis. RESULTS Elevated circulating NOD1 activators were observed in Akita mice after 6 months of diabetes. NOD1 depletion partially restored diabetes-induced structural changes and retinal electrical responses in NOD1-/--Akita mice. Loss of NOD1 significantly ameliorated the progression of diabetic retinal vascular degeneration, as determined by acellular capillary quantification. The preventive effect of NOD1 depletion on DR is linked to bone marrow phenotype alterations, including a restored HSC pool and a shift in hematopoiesis toward myelopoiesis. We also generated chimeric mice with hematopoietic-specific NOD1 ablation, and the results further indicated that NOD1 had a protective effect against DR. Mechanistically, loss of hematopoietic NOD1 resulted in reduced bone marrow-derived macrophage infiltration and decreased CXCL1 and CXCL2 secretion within the retina, subsequently leading to diminished neutrophil chemoattraction and NETosis. CONCLUSIONS The results of our study unveil, for the first time, the critical role of NOD1 as a trigger for a hematopoietic imbalance toward myelopoiesis and local retinal inflammation, culminating in DR progression. Targeting NOD1 in bone marrow may be a potential strategy for the prevention and treatment of DR.
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Affiliation(s)
- Jingwen Qiu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Wu
- Department of Hematology/Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Wenwen Chen
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Ruan
- Division of Growth, Development and Mental Health of Children and Adolescence, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Jingning Mao
- Health Medical Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shue Li
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuan Tang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lei Zhao
- Center for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shengbing Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Li
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dongfang Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yaqian Duan
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Orsini Delgado ML, Gamelas Magalhaes J, Morra R, Cultrone A. Muropeptides and muropeptide transporters impact on host immune response. Gut Microbes 2024; 16:2418412. [PMID: 39439228 PMCID: PMC11509177 DOI: 10.1080/19490976.2024.2418412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/25/2024] Open
Abstract
In bacteria, the cell envelope is the key element surrounding and protecting the bacterial content from mechanical or osmotic damages. It allows the selective interchanges of solutes, ions, cellular debris, and drugs between the cellular compartments and the external environment, thanks to the presence of transmembrane proteins called transporters. The major component of the cell envelope is the peptidoglycan, consisting of long linear glycan strands cross-linked by short peptide stems. During cell growth or under stress conditions, peptidoglycan fragments, the muropeptides, are released by bacteria and recognized by the host Pattern Recognition Receptor, promoting the activation of their innate defense mechanisms. The review sums up the salient aspects of microbiota-host interaction with a focus on the NOD-dependent immune response to bacterial peptidoglycan and on the accountability of muropeptide transporters in the crosstalk with the host and in antibiotic resistance. Furthermore, it retraces the discoveries and applications of microorganisms-derived components such as vaccines or vaccine adjuvants.
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Al-Busaidi A, Alabri O, Alomairi J, ElSharaawy A, Al Lawati A, Al Lawati H, Das S. Gut Microbiota and Insulin Resistance: Understanding the Mechanism of Better Treatment of Type 2 Diabetes Mellitus. Curr Diabetes Rev 2024; 21:e170124225723. [PMID: 38243954 DOI: 10.2174/0115733998281910231231051814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/13/2023] [Accepted: 12/20/2023] [Indexed: 01/22/2024]
Abstract
Gut microbiota refers to the population of trillions of microorganisms present in the human intestine. The gut microbiota in the gastrointestinal system is important for an individual's good health and well-being. The possibility of an intrauterine colonization of the placenta further suggests that the fetal environment before birth may also affect early microbiome development. Various factors influence the gut microbiota. Dysbiosis of microbiota may be associated with various diseases. Insulin regulates blood glucose levels, and disruption of the insulin signaling pathway results in insulin resistance. Insulin resistance or hyperinsulinemia is a pathological state in which the insulin-responsive cells have a diminished response to the hormone compared to normal physiological responses, resulting in reduced glucose uptake by the tissue cells. Insulin resistance is an important cause of type 2 diabetes mellitus. While there are various factors responsible for the etiology of insulin resistance, dysbiosis of gut microbiota may be an important contributing cause for metabolic disturbances. We discuss the mechanisms in skeletal muscles, adipose tissue, liver, and intestine by which insulin resistance can occur due to gut microbiota's metabolites. A better understanding of gut microbiota may help in the effective treatment of type 2 diabetes mellitus and metabolic syndrome.
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Affiliation(s)
- Alsalt Al-Busaidi
- Department of Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland
| | - Omer Alabri
- Department of Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland
| | - Jaifar Alomairi
- Department of Medicine, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland
| | | | | | - Hanan Al Lawati
- Pharmacy Program, Department of Pharmaceutics, Oman College of Health Sciences, Muscat 113, Oman
| | - Srijit Das
- Department of Human & Clinical Anatomy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman
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Kitajima N, Nakajo T, Katayoshi T, Tsuji-Naito K. Nucleotide-binding oligomerization domain protein-1 is expressed and involved in the inflammatory response in human sebocytes. Biochem Biophys Rep 2023; 36:101561. [PMID: 37942338 PMCID: PMC10630598 DOI: 10.1016/j.bbrep.2023.101561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 10/02/2023] [Accepted: 10/16/2023] [Indexed: 11/10/2023] Open
Abstract
Sebocytes express Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), which participate in the innate immune response of the skin. Although the roles of TLRs and NLR family pyrin domain-containing 3 (NLRP3) in inflammatory responses in sebocytes have been reported, the expression and functions of other NLR members, such as NOD protein-1 and -2 (NOD1 and NOD2, respectively), remain unclear. In this study, we showed that, in sebocytes, the expression of NOD1 is higher than that of NOD2, and that NOD1 is involved in inflammatory responses, such as the secretion of proinflammatory cytokines. A NOD1 agonist, L-alanyl-γ-D-glutamyl-meso-diaminopimelic acid (Tri-DAP) induced the expression and secretion of interleukin-8 (IL-8) and activated the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways. On the other hand, a NOD2 agonist, muramyl dipeptide, did not. Either inhibition with a NOD1 inhibitor, ML130, or knockdown of NOD1 expression abolished Tri-DAP-induced inflammatory responses, suggesting that NOD1 is involved in the immunogenic signaling system of sebocytes. Furthermore, Tri-DAP and an agonist of TLR2 or TLR4 additively increased IL-8 expression compared with each agonist alone. Our results reveal the role of NOD1 in the inflammatory responses of sebocytes and may provide a novel therapeutic target for sebaceous gland inflammatory diseases, such as acne vulgaris.
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Affiliation(s)
- Natsuko Kitajima
- DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba, 261-0025, Japan
| | - Takahisa Nakajo
- DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba, 261-0025, Japan
| | - Takeshi Katayoshi
- DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba, 261-0025, Japan
| | - Kentaro Tsuji-Naito
- DHC Corporation Laboratories, Division 2, 2-42 Hamada, Mihama-ku, Chiba, 261-0025, Japan
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Tsounis EP, Aggeletopoulou I, Mouzaki A, Triantos C. Creeping Fat in the Pathogenesis of Crohn's Disease: An Orchestrator or a Silent Bystander? Inflamm Bowel Dis 2023; 29:1826-1836. [PMID: 37260352 DOI: 10.1093/ibd/izad095] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Indexed: 06/02/2023]
Abstract
Although the phenomenon of hypertrophied adipose tissue surrounding inflamed bowel segments in Crohn's disease has been described since 1932, the mechanisms mediating the creeping fat formation and its role in the pathogenesis of the disease have not been fully unraveled. Recent advances demonstrating the multiple actions of adipose tissue beyond energy storage have brought creeping fat to the forefront of scientific research. In Crohn's disease, dysbiosis and transmural injury compromise the integrity of the intestinal barrier, resulting in an excessive influx of intraluminal microbiota and xenobiotics. The gut and peri-intestinal fat are in close anatomic relationship, implying a direct reciprocal immunologic relationship, whereas adipocytes are equipped with an arsenal of innate immunity sensors that respond to invading stimuli. As a result, adipocytes and their progenitor cells undergo profound immunophenotypic changes, leading to adipose tissue remodeling and eventual formation of creeping fat. Indeed, creeping fat is an immunologically active organ that synthesizes various pro- and anti-inflammatory cytokines, profibrotic mediators, and adipokines that serve as paracrine/autocrine signals and regulate immune responses. Therefore, creeping fat appears to be involved in inflammatory signaling, which explains why it has been associated with a higher severity or complicated phenotype of Crohn's disease. Interestingly, there is growing evidence for an alternative immunomodulatory function of creeping fat as a second barrier that prevents an abnormal systemic inflammatory response at the expense of an increasingly proliferating profibrotic environment. Further studies are needed to clarify how this modified adipose tissue exerts its antithetic effect during the course of Crohn's disease.
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Affiliation(s)
- Efthymios P Tsounis
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
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Dixon CL, Wu A, Fairn GD. Multifaceted roles and regulation of nucleotide-binding oligomerization domain containing proteins. Front Immunol 2023; 14:1242659. [PMID: 37869013 PMCID: PMC10585062 DOI: 10.3389/fimmu.2023.1242659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/19/2023] [Indexed: 10/24/2023] Open
Abstract
Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis.
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Affiliation(s)
| | - Amy Wu
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Gregory D. Fairn
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada
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Bauer S, Hezinger L, Rexhepi F, Ramanathan S, Kufer TA. NOD-like Receptors-Emerging Links to Obesity and Associated Morbidities. Int J Mol Sci 2023; 24:ijms24108595. [PMID: 37239938 DOI: 10.3390/ijms24108595] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/06/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Obesity and its associated metabolic morbidities have been and still are on the rise, posing a major challenge to health care systems worldwide. It has become evident over the last decades that a low-grade inflammatory response, primarily proceeding from the adipose tissue (AT), essentially contributes to adiposity-associated comorbidities, most prominently insulin resistance (IR), atherosclerosis and liver diseases. In mouse models, the release of pro-inflammatory cytokines such as TNF-alpha (TNF-α) and interleukin (IL)-1β and the imprinting of immune cells to a pro-inflammatory phenotype in AT play an important role. However, the underlying genetic and molecular determinants are not yet understood in detail. Recent evidence demonstrates that nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family proteins, a group of cytosolic pattern recognition receptors (PRR), contribute to the development and control of obesity and obesity-associated inflammatory responses. In this article, we review the current state of research on the role of NLR proteins in obesity and discuss the possible mechanisms leading to and the outcomes of NLR activation in the obesity-associated morbidities IR, type 2 diabetes mellitus (T2DM), atherosclerosis and non-alcoholic fatty liver disease (NAFLD) and discuss emerging ideas about possibilities for NLR-based therapeutic interventions of metabolic diseases.
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Affiliation(s)
- Sarah Bauer
- Institute of Nutritional Medicine, Department of Immunology, University of Hohenheim, 70593 Stuttgart, Germany
| | - Lucy Hezinger
- Institute of Nutritional Medicine, Department of Immunology, University of Hohenheim, 70593 Stuttgart, Germany
| | - Fjolla Rexhepi
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada
| | - Thomas A Kufer
- Institute of Nutritional Medicine, Department of Immunology, University of Hohenheim, 70593 Stuttgart, Germany
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Wolf AJ. Peptidoglycan-induced modulation of metabolic and inflammatory responses. IMMUNOMETABOLISM (COBHAM, SURREY) 2023; 5:e00024. [PMID: 37128291 PMCID: PMC10144284 DOI: 10.1097/in9.0000000000000024] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 04/06/2023] [Indexed: 05/03/2023]
Abstract
Bacterial cell wall peptidoglycan is composed of innate immune ligands and, due to its important structural role, also regulates access to many other innate immune ligands contained within the bacteria. There is a growing body of literature demonstrating how innate immune recognition impacts the metabolic functions of immune cells and how metabolic changes are not only important to inflammatory responses but are often essential. Peptidoglycan is primarily sensed in the context of the whole bacteria during lysosomal degradation; consequently, the innate immune receptors for peptidoglycan are primarily intracellular cytosolic innate immune sensors. However, during bacterial growth, peptidoglycan fragments are shed and can be found in the bloodstream of humans and mice, not only during infection but also derived from the abundant bacterial component of the gut microbiota. These peptidoglycan fragments influence cells throughout the body and are important for regulating inflammation and whole-body metabolic function. Therefore, it is important to understand how peptidoglycan-induced signals in innate immune cells and cells throughout the body interact to regulate how the body responds to both pathogenic and nonpathogenic bacteria. This mini-review will highlight key research regarding how cellular metabolism shifts in response to peptidoglycan and how systemic peptidoglycan sensing impacts whole-body metabolic function.
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Affiliation(s)
- Andrea J. Wolf
- The Karsh Division of Gastroenterology and Hepatology, F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Gulzar F, Ahmad S, Singh S, Kumar P, Sharma A, Tamrakar AK. NOD1 activation in 3T3-L1 adipocytes confers lipid accumulation in HepG2 cells. Life Sci 2023; 316:121400. [PMID: 36657640 DOI: 10.1016/j.lfs.2023.121400] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/04/2023] [Accepted: 01/12/2023] [Indexed: 01/17/2023]
Abstract
AIMS Activation of specific innate immune receptors has been characterized to modulate nutrient metabolism in individual metabolic tissue directly or indirectly via secretory molecules. Activation of the nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in adipocytes has been reported to induce lipolysis linked with insulin resistance and inflammatory response. These cues are positioned to modulate metabolic action in distal organs through paracrine/endocrine signaling. Here, we assessed the role of NOD1-mediated lipolysis and inflammatory response in adipocytes to affect lipid metabolism in hepatocytes. MAIN METHODS Human hepatoma cells (HepG2) were exposed to conditioned medium obtained from 3 T3-L1 adipocytes pretreated with NOD1 ligand (iE-DAP) and the effects on lipid accumulation, inflammation and insulin response were assessed. Activation of mechanisms leading to hepatic lipid accumulation was investigated by gene expression analysis. KEY FINDINGS The conditioned medium from NOD1-activated 3 T3-L1 adipocytes (CM-DAP) induced lipid accumulation in HepG2 cells, driven by both lipolysis and inflammatory responses. The CM-DAP-induced lipid accumulation was independent to de novo lipogenesis and resulted from the enhanced transport of fatty acids inside and consequent increase in rate of triglycerides synthesis in hepatocytes. Moreover, CM-DAP-induced lipid accumulation instigated the expression of the markers of fatty acid oxidation and VLDL assembly for the export of triglycerides from hepatocyte. Furthermore, CM-DAP-induced lipid accumulation was associated with induction of inflammatory response and impairment of insulin signaling in HepG2 cells. SIGNIFICANCE Beyond showing liver-specific mechanisms to adipocytes-derived factors, our findings support the involvement of adipose tissue as a mediator in NOD1-mediated biological responses to modulate hepatic metabolism.
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Affiliation(s)
- Farah Gulzar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shadab Ahmad
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Sushmita Singh
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Pawan Kumar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India
| | - Aditya Sharma
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Akhilesh K Tamrakar
- Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, U.P., India.
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13
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Bae J, Yang Y, Xu X, Flaherty J, Overby H, Hildreth K, Chen J, Wang S, Zhao L. Naringenin, a citrus flavanone, enhances browning and brown adipogenesis: Role of peroxisome proliferator-activated receptor gamma. Front Nutr 2022; 9:1036655. [PMID: 36438760 PMCID: PMC9686290 DOI: 10.3389/fnut.2022.1036655] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022] Open
Abstract
Identifying functional brown adipose tissue (BAT) has provided new hope for obesity treatment and prevention. Functional BAT includes classical BAT and brown-like adipose tissue converted from white adipose tissue. By promoting thermogenesis (i.e., heat production) via uncoupling protein 1 (UCP1), functional BAT can increase energy expenditure and aid obesity treatment and prevention. Naringenin (NAR) is a flavanone primarily found in citrus fruits. NAR has been reported to decrease body weight, increase energy expenditure in treated mice, and promote browning in human adipocytes. Here, we examined the effects of NAR on 3T3-L1 adipocytes' browning and β-adrenergic agonist isoproterenol (ISO)-stimulated thermogenic activation and classical murine brown adipogenesis. In addition, we demonstrated the signaling pathways and involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in the process. We found that NAR did not increase Ucp1 mRNA expression at the basal (i.e., non-ISO stimulated) condition. Instead, it enhanced Ucp1 and Pgc-1α up-regulation and thermogenesis under ISO-stimulated conditions in 3T3-L1 adipocytes. NAR promoted protein kinase A (PKA) activation and phosphorylation of p38 MAPK downstream of ISO stimulation and activated PPARγ. Pharmacological inhibition of either PKA or p38 and PPARγ knockdown attenuated Ucp1 up-regulation by NAR. Moreover, NAR promoted brown adipogenesis by increasing lipid accumulation, brown marker expression, and thermogenesis in murine brown adipocytes, which was also attenuated by PPARγ knockdown. Together, our results suggest that NAR may promote the development of functional BAT in part through PPARγ activation. NAR's role in combating human obesity warrants further investigation.
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Affiliation(s)
- Jiyoung Bae
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Yang Yang
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Xinyun Xu
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Jamie Flaherty
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Haley Overby
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Kelsey Hildreth
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Jiangang Chen
- Department of Public Health, The University of Tennessee, Knoxville, Knoxville, TN, United States
| | - Shu Wang
- College of Health Solutions, Arizona State University, Phoenix, AZ, United States
| | - Ling Zhao
- Department of Nutrition, The University of Tennessee, Knoxville, Knoxville, TN, United States,*Correspondence: Ling Zhao,
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14
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Li C, Liang Y, Qiao Y. Messengers From the Gut: Gut Microbiota-Derived Metabolites on Host Regulation. Front Microbiol 2022; 13:863407. [PMID: 35531300 PMCID: PMC9073088 DOI: 10.3389/fmicb.2022.863407] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
The human gut is the natural habitat for trillions of microorganisms, known as the gut microbiota, which play indispensable roles in maintaining host health. Defining the underlying mechanistic basis of the gut microbiota-host interactions has important implications for treating microbiota-associated diseases. At the fundamental level, the gut microbiota encodes a myriad of microbial enzymes that can modify various dietary precursors and host metabolites and synthesize, de novo, unique microbiota-derived metabolites that traverse from the host gut into the blood circulation. These gut microbiota-derived metabolites serve as key effector molecules to elicit host responses. In this review, we summarize recent studies in the understanding of the major classes of gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs), bile acids (BAs) and peptidoglycan fragments (PGNs) on their regulatory effects on host functions. Elucidation of the structures and biological activities of such gut microbiota-derived metabolites in the host represents an exciting and critical area of research.
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15
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Suau R, Pardina E, Domènech E, Lorén V, Manyé J. The Complex Relationship Between Microbiota, Immune Response and Creeping Fat in Crohn's Disease. J Crohns Colitis 2022; 16:472-489. [PMID: 34528668 DOI: 10.1093/ecco-jcc/jjab159] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In the last decade, there has been growing interest in the pathological involvement of hypertrophic mesenteric fat attached to the serosa of the inflamed intestinal segments involved in Crohn's disease [CD], known as creeping fat. In spite of its protective nature, creeping fat harbours an aberrant inflammatory activity which, in an already inflamed intestine, may explain why creeping fat is associated with a greater severity of CD. The transmural inflammation of CD facilitates the interaction of mesenteric fat with translocated intestinal microorganisms, contributing to activation of the immune response. This may be not the only way in which microorganisms alter the homeostasis of this fatty tissue: intestinal dysbiosis may also impair xenobiotic metabolism. All these CD-related alterations have a functional impact on nuclear receptors such as the farnesoid X receptor or the peroxisome proliferator-activated receptor γ, which are implicated in regulation of the immune response, adipogenesis and the maintenance of barrier function, as well as on creeping fat production of inflammatory-associated cells such as adipokines. The dysfunction of creeping fat worsens the inflammatory course of CD and may favour intestinal fibrosis and fistulizing complications. However, our current knowledge of the pathophysiology and pathogenic role of creeping fat is controversial and a better understanding might provide new therapeutic targets for CD. Here we aim to review and update the key cellular and molecular alterations involved in this inflammatory process that link the pathological components of CD with the development of creeping fat.
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Affiliation(s)
- Roger Suau
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Eva Pardina
- Biochemistry and Molecular Biomedicine Department, University of Barcelona, Barcelona (Catalonia), Spain
| | - Eugeni Domènech
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain.,Gastroenterology Department, 'Germans Trias i Pujol' University Hospital, Badalona (Catalonia), Spain
| | - Violeta Lorén
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
| | - Josep Manyé
- IBD Research Group, 'Germans Trias i Pujol' Research Institute (IGTP), Badalona (Catalonia), Spain.,Centro de Investigación Biomédica en Red (CIBER), Madrid, Spain
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16
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Takayanagi S, Watanabe K, Maruyama T, Ogawa M, Morishita K, Soga M, Hatta T, Natsume T, Hirano T, Kagechika H, Hattori K, Naguro I, Ichijo H. ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes. Sci Rep 2021; 11:22009. [PMID: 34759307 PMCID: PMC8581049 DOI: 10.1038/s41598-021-01123-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Recent studies have shown that adipose tissue is an immunological organ. While inflammation in energy-storing white adipose tissues has been the focus of intense research, the regulatory mechanisms of inflammation in heat-producing brown adipose tissues remain largely unknown. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical regulator of brown adipocyte maturation; the PKA-ASK1-p38 axis facilitates uncoupling protein 1 (UCP1) induction cell-autonomously. Here, we show that ASK1 suppresses an innate immune pathway and contributes to maintenance of brown adipocytes. We report a novel chemical pull-down method for endogenous kinases using analog sensitive kinase allele (ASKA) technology and identify an ASK1 interactor in brown adipocytes, receptor-interacting serine/threonine-protein kinase 2 (RIPK2). ASK1 disrupts the RIPK2 signaling complex and inhibits the NOD-RIPK2 pathway to downregulate the production of inflammatory cytokines. As a potential biological significance, an in vitro model for intercellular regulation suggests that ASK1 facilitates the expression of UCP1 through the suppression of inflammatory cytokine production. In parallel to our previous report on the PKA-ASK1-p38 axis, our work raises the possibility of an auxiliary role of ASK1 in brown adipocyte maintenance through neutralizing the thermogenesis-suppressive effect of the NOD-RIPK2 pathway.
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Affiliation(s)
- Saki Takayanagi
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Kengo Watanabe
- Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Takeshi Maruyama
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Motoyuki Ogawa
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Kazuhiro Morishita
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Mayumi Soga
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Tomohisa Hatta
- grid.208504.b0000 0001 2230 7538Molecular Profiling Research Center for Drug Discovery, The National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064 Japan
| | - Tohru Natsume
- grid.208504.b0000 0001 2230 7538Cellular and Molecular Biotechnology Research Institute, The National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064 Japan
| | - Tomoya Hirano
- grid.265073.50000 0001 1014 9130Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062 Japan ,Present Address: Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094 Japan
| | - Hiroyuki Kagechika
- grid.265073.50000 0001 1014 9130Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062 Japan
| | - Kazuki Hattori
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Isao Naguro
- grid.26999.3d0000 0001 2151 536XLaboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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17
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Martínez-Álvaro M, Zubiri-Gaitán A, Hernández P, Greenacre M, Ferrer A, Blasco A. Comprehensive functional core microbiome comparison in genetically obese and lean hosts under the same environment. Commun Biol 2021; 4:1246. [PMID: 34725460 PMCID: PMC8560826 DOI: 10.1038/s42003-021-02784-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 10/11/2021] [Indexed: 12/31/2022] Open
Abstract
Our study provides an exhaustive comparison of the microbiome core functionalities (captured by 3,936 microbial gene abundances) between hosts with divergent genotypes for intramuscular lipid deposition. After 10 generations of divergent selection for intramuscular fat in rabbits and 4.14 phenotypic standard deviations (SD) of selection response, we applied a combination of compositional and multivariate statistical techniques to identify 122 cecum microbial genes with differential abundances between the lines (ranging from -0.75 to +0.73 SD). This work elucidates that microbial biosynthesis lipopolysaccharides, peptidoglycans, lipoproteins, mucin components, and NADH reductases, amongst others, are influenced by the host genetic determination for lipid accretion in muscle. We also differentiated between host-genetically influenced microbial mechanisms regulating lipid deposition in body or intramuscular reservoirs, with only 28 out of 122 MGs commonly contributing to both. Importantly, the results of this study are of relevant interest for the efficient development of strategies fighting obesity.
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18
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Schmid A, Schäffler A, Karrasch T. CTRP-3 Regulates NOD1-mediated Inflammation and NOD1 Expression in Adipocytes and Adipose Tissue. Inflammation 2021; 44:2260-2269. [PMID: 34165676 PMCID: PMC8616866 DOI: 10.1007/s10753-021-01497-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 11/29/2022]
Abstract
The anti-inflammatory adipokine CTRP-3 might affect innate immune reactions such as NOD1. The impact of CTRP-3 on NOD1-mediated inflammation in adipocytes and monocytic cells as well as on NOD1 expression was investigated. Murine 3T3-L1 pre-adipocytes and adipocytes as well as human THP-1 monocyte-like cells were co-stimulated with the synthetic NOD1 agonist Tri-DAP and recombinant CTRP-3. Gonadal adipose tissue and primary adipocytes were obtained from a murine model carrying a knockout (KO) of CTRP-3 in adipocytes but not in stroma-vascular cells. Wildtype mice with lipopolysaccharide (LPS)-induced elevated NOD1 expression were treated with CTRP-3. Secreted inflammatory cytokines in cell supernatants were measured by ELISA and mRNA levels were quantified by RT-PCR. Pro-inflammatory chemokine and cytokine secretion (MCP-1, RANTES, TNFα) was induced by NOD1 activation in adipocytes and monocyte-like cells, and MCP-1 and RANTES release was effectively inhibited by pre-incubation of cells with CTRP-3. CTRP-3 also antagonized LPS-triggered induction of NOD1 gene expression in murine adipose tissue, whereas adipocyte CTRP-3 deficiency upregulated NOD1 expression in adipose tissue. CTRP-3 is an effective antagonist of peptidoglycan-induced, NOD1-mediated inflammation and of LPS-induced NOD1 expression. Since basal NOD1 expression is increased by adipocyte CTRP-3 deficiency, there have to be also inflammation-independent mechanisms of NOD1 expression regulation by CTRP-3.
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Affiliation(s)
- Andreas Schmid
- Department of Internal Medicine III, University Hospital of Giessen, Giessen, Germany.
| | - Andreas Schäffler
- Department of Internal Medicine III, University Hospital of Giessen, Giessen, Germany
| | - Thomas Karrasch
- Department of Internal Medicine III, University Hospital of Giessen, Giessen, Germany
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19
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Fernández-García V, González-Ramos S, Martín-Sanz P, Laparra JM, Boscá L. NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health. Biomedicines 2021; 9:519. [PMID: 34066406 PMCID: PMC8148154 DOI: 10.3390/biomedicines9050519] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 02/07/2023] Open
Abstract
Immunonutrition appears as a field with great potential in modern medicine. Since the immune system can trigger serious pathophysiological disorders, it is essential to study and implement a type of nutrition aimed at improving immune system functioning and reinforcing it individually for each patient. In this sense, the nucleotide-binding oligomerization domain-1 (NOD1), one of the members of the pattern recognition receptors (PRRs) family of innate immunity, has been related to numerous pathologies, such as cancer, diabetes, or cardiovascular diseases. NOD1, which is activated by bacterial-derived peptidoglycans, is known to be present in immune cells and to contribute to inflammation and other important pathways, such as fibrosis, upon recognition of its ligands. Since immunonutrition is a significant developing research area with much to discover, we propose NOD1 as a possible target to consider in this field. It is relevant to understand the cellular and molecular mechanisms that modulate the immune system and involve the activation of NOD1 in the context of immunonutrition and associated pathological conditions. Surgical or pharmacological treatments could clearly benefit from the synergy with specific and personalized nutrition that even considers the health status of each subject.
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Affiliation(s)
- Victoria Fernández-García
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.F.-G.); (P.M.-S.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Melchor Fernández Almagro 6, 28029 Madrid, Spain
| | - Silvia González-Ramos
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.F.-G.); (P.M.-S.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Melchor Fernández Almagro 6, 28029 Madrid, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.F.-G.); (P.M.-S.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas (CIBERehd), 28029 Madrid, Spain
| | - José M. Laparra
- Madrid Institute for Advanced studies in Food (IMDEA Food), Ctra. Cantoblanco 8, 28049 Madrid, Spain;
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain; (V.F.-G.); (P.M.-S.)
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Melchor Fernández Almagro 6, 28029 Madrid, Spain
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20
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Zangara MT, Johnston I, Johnson EE, McDonald C. Mediators of Metabolism: An Unconventional Role for NOD1 and NOD2. Int J Mol Sci 2021; 22:ijms22031156. [PMID: 33503814 PMCID: PMC7866072 DOI: 10.3390/ijms22031156] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/16/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023] Open
Abstract
In addition to their classical roles as bacterial sensors, NOD1 and NOD2 have been implicated as mediators of metabolic disease. Increased expression of NOD1 and/or NOD2 has been reported in a range of human metabolic diseases, including obesity, diabetes, non-alcoholic fatty liver disease, and metabolic syndrome. Although NOD1 and NOD2 share intracellular signaling pathway components, they are differentially upregulated on a cellular level and have opposing impacts on metabolic disease development in mouse models. These NOD-like receptors may directly mediate signaling downstream of cell stressors, such as endoplasmic reticulum stress and calcium influx, or in response to metabolic signals, such as fatty acids and glucose. Other studies suggest that stimulation of NOD1 or NOD2 by their bacterial ligands can result in inflammation, altered insulin responses, increased reactive oxygen signaling, and mitochondrial dysfunction. The activating stimuli for NOD1 and NOD2 in the context of metabolic disease are controversial and may be a combination of both metabolic and circulating bacterial ligands. In this review, we will summarize the current knowledge of how NOD1 and NOD2 may mediate metabolism in health and disease, as well as highlight areas of future investigation.
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Affiliation(s)
- Megan T. Zangara
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Isabel Johnston
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
| | - Erin E. Johnson
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
- Department of Biology, John Carroll University, University Heights, OH 44118, USA
| | - Christine McDonald
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; (M.T.Z.); (I.J.); (E.E.J.)
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Correspondence: ; Tel.: +1-216-445-7058
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21
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Sharma A, Singh S, Ahmad S, Gulzar F, Schertzer JD, Tamrakar AK. NOD1 activation induces oxidative stress via NOX1/4 in adipocytes. Free Radic Biol Med 2021; 162:118-128. [PMID: 33279617 DOI: 10.1016/j.freeradbiomed.2020.11.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 11/11/2020] [Accepted: 11/26/2020] [Indexed: 12/20/2022]
Abstract
Activation of innate immune components promotes cell autonomous inflammation in adipocytes. Oxidative stress links pattern recognition receptor-mediated detection of inflammatory ligands and the immune response. Reactive oxygen species (ROS) may mediate the effect of nucleotide-binding oligomerization domain protein-1 (NOD1) activation on inflammation in adipocytes. Here, we define the potential role of NADPH oxidase (NOX)-derived ROS in NOD1-mediated inflammatory response in adipocytes. Differentiated 3T3-L1 adipocytes were treated with NOD1 activating ligand D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) to evaluate the oxidative stress and contribution of NOX as source of intracellular ROS. NOD1 activation potently induced ROS generation in 3T3-L1 adipocytes. Of the NOX family members, expression of NOX1 and NOX4 was increased upon NOD1 activation, in a PKCδ-dependent manner. siRNA-mediated down-regulation of NOX1 or NOX4 inhibited NOD1-mediated ROS production and increased the expression of antioxidant defense enzyme catalase and superoxide dismutase (SOD). siRNA-mediated lowering of NOX1 or NOX4 also suppressed NOD1-mediated activation of JNK1/2 and NF-κB, and consequent activation of inflammatory response in 3T3-L1 adipocytes. In summary, our findings demonstrate that NOD1 activation provokes oxidative stress in adipocytes via NOX1/4 and that oxidative stress, at least in part, contributes to induction of inflammatory response. Defining the source of ROS after immune response engagement may lead to new therapeutic strategies for adipose tissue inflammation.
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Affiliation(s)
- Aditya Sharma
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Sushmita Singh
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shadab Ahmad
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Farah Gulzar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences and Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, 1200 Main St. W., Hamilton, ON, L8N 3Z5, Canada
| | - Akhilesh K Tamrakar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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22
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Transcriptomic Analysis Reveals the Protection of Astragaloside IV against Diabetic Nephropathy by Modulating Inflammation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9542165. [PMID: 32855769 PMCID: PMC7443226 DOI: 10.1155/2020/9542165] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/23/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
Background Diabetic nephropathy (DN) is one of the leading causes of end-stage kidney disease. Recently, there is no specific drug available to block the kidney damage. Astragaloside IV (AS-IV) is a major active component of Astragalus membranaceus (Fisch) Bge and has been demonstrated to benefit the kidney functions. This study explores the potential pharmacological action of AS-IV in DN of rats. Methods Male Sprague-Dawley rats were fed with high-fat diet and injected with streptozotocin to induce diabetes. The diabetic rats were randomized and treated with vehicle or AS-IV (80 mg/kg) daily by gavage for 12 weeks as the DN or AS-IV group, respectively. The normal control rats were fed with normal chow and injected with vehicles (n = 8 per group). These rats were monitored for diabetes- and kidney function-related measures. The expression profiles of gene mRNA transcripts in the kidney tissues were analyzed by RNA-seq and quantitative RT-PCR. The levels of advanced glycation end products (AGEs), IL-1β, and IL-18 in the serum samples and kidney tissues were quantified by ELISA. The levels of collagen IV (COL-4) and fibronectin (FN) expression in kidney tissues were examined by immunohistochemistry and Western blot. Results In comparison with the DN group, AS-IV treatment significantly reduced blood glucose levels, food and water consumption, 24 h urine, renal index values, 24 h urine total proteins, blood urea nitrogen (BUN) levels, and creatinine clearance rates (CCR), accompanied by minimizing the DN-induced early kidney damages, fibrosis, and microstructural changes. Furthermore, AS-IV treatment significantly modulated the DN-altered gene transcription profiles in the kidney of rats, particularly for inflammation-related genes, including the nucleotide-binding oligomerization domain-like receptor signaling, which was validated by quantitative RT-PCR. AS-IV treatment significantly decreased the levels of serum and kidney AGEs, IL-1β, and IL-18 expression and fibrosis indexes in the kidney of rats. Conclusion AS-IV treatment ameliorated the severity of DN by inhibiting inflammation-related gene expression in the kidney of rats.
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Cavallari JF, Barra NG, Foley KP, Lee A, Duggan BM, Henriksbo BD, Anhê FF, Ashkar AA, Schertzer JD. Postbiotics for NOD2 require nonhematopoietic RIPK2 to improve blood glucose and metabolic inflammation in mice. Am J Physiol Endocrinol Metab 2020; 318:E579-E585. [PMID: 32101030 DOI: 10.1152/ajpendo.00033.2020] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose-lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in nonhematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that were evident during a glucose tolerance test (GTT) in high-fat diet (HFD)-fed wild-type (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in nonhematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance but NOD2 activation in nonhematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.
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Affiliation(s)
- Joseph F Cavallari
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Nicole G Barra
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Kevin P Foley
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Amanda Lee
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Brittany M Duggan
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Brandyn D Henriksbo
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Fernando Forato Anhê
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
| | - Ali A Ashkar
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada
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24
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Marangon D, Boda E, Parolisi R, Negri C, Giorgi C, Montarolo F, Perga S, Bertolotto A, Buffo A, Abbracchio MP, Lecca D. In vivo silencing of miR-125a-3p promotes myelin repair in models of white matter demyelination. Glia 2020; 68:2001-2014. [PMID: 32163190 DOI: 10.1002/glia.23819] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 02/13/2020] [Accepted: 03/02/2020] [Indexed: 12/18/2022]
Abstract
In the last decade, microRNAs have been increasingly recognized as key modulators of glial development. Recently, we identified miR-125a-3p as a new player in oligodendrocyte physiology, regulating in vitro differentiation of oligodendrocyte precursor cells (OPCs). Here, we show that miR-125a-3p is upregulated in active lesions of multiple sclerosis (MS) patients and in OPCs isolated from the spinal cord of chronic experimental autoimmune encephalomyelitis (EAE) mice, but not in those isolated from the spontaneously remyelinating corpus callosum of lysolecithin-treated mice. To test whether a sustained expression of miR-125a-3p in OPCs contribute to defective remyelination, we modulated miR-125a-3p expression in vivo and ex vivo after lysolecithin-induced demyelination. We found that lentiviral over-expression of miR-125a-3p impaired OPC maturation, whereas its downregulation accelerated remyelination. Transcriptome analysis and luciferase reporter assay revealed that these effects are partly mediated by the direct interaction of miR-125a-3p with Slc8a3, a sodium-calcium membrane transporter, and identified novel candidate targets, such as Gas7, that we demonstrated necessary to correctly address oligodendrocytes to terminal maturation. These findings show that miR-125a-3p upregulation negatively affects OPC maturation in vivo, suggest its role in the pathogenesis of demyelinating diseases and unveil new targets for future promyelinating protective interventions.
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Affiliation(s)
- Davide Marangon
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Enrica Boda
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
| | - Roberta Parolisi
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
| | - Camilla Negri
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Corinna Giorgi
- European Brain Research Institute Rita Levi-Montalcini, Rome, Italy
| | - Francesca Montarolo
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology-CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Italy
| | - Simona Perga
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology-CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Italy
| | - Antonio Bertolotto
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology-CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Italy
| | - Annalisa Buffo
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
| | - Maria P Abbracchio
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Davide Lecca
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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Rivers SL, Klip A, Giacca A. NOD1: An Interface Between Innate Immunity and Insulin Resistance. Endocrinology 2019; 160:1021-1030. [PMID: 30807635 PMCID: PMC6477778 DOI: 10.1210/en.2018-01061] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/19/2019] [Indexed: 12/17/2022]
Abstract
Insulin resistance is driven, in part, by activation of the innate immune system. We have discussed the evidence linking nucleotide-binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor, to the onset and progression of obesity-induced insulin resistance. On a molecular level, crosstalk between downstream NOD1 effectors and the insulin receptor pathway inhibits insulin signaling, potentially through reduced insulin receptor substrate action. In vivo studies have demonstrated that NOD1 activation induces peripheral, hepatic, and whole-body insulin resistance. Also, NOD1-deficient models are protected from high-fat diet (HFD)-induced insulin resistance. Moreover, hematopoietic NOD1 deficiency prevented HFD-induced changes in proinflammatory macrophage polarization status, thus protecting against the development of metabolic inflammation and insulin resistance. Serum from HFD-fed mice activated NOD1 signaling ex vivo; however, the molecular identity of the activating factors remains unclear. Many have proposed that an HFD changes the gut permeability, resulting in increased translocation of bacterial fragments and increased circulating NOD1 ligands. In contrast, others have suggested that NOD1 ligands are endogenous and potentially lipid-derived metabolites produced during states of nutrient overload. Nevertheless, that NOD1 contributes to the development of insulin resistance, and that NOD1-based therapy might provide benefit, is an exciting advancement in metabolic research.
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Affiliation(s)
- Sydney L Rivers
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Amira Klip
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Adria Giacca
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Correspondence: Adria Giacca, MD, Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, No. 3336, Toronto, Ontario M5S 1A8, Canada. E-mail:
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26
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Fang YX, Zou Y, Wang GT, Huang SH, Zhou YJ, Zhou YJ. lnc TINCR induced by NOD1 mediates inflammatory response in 3T3-L1 adipocytes. Gene 2019; 698:150-156. [PMID: 30851423 DOI: 10.1016/j.gene.2019.02.047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2018] [Revised: 01/06/2019] [Accepted: 02/11/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Investigating the expression of the lnc RNAs screened above between normal and insulin resistant 3T3-L1 adipocytes. Addressing the mechanism underlying the regulation of inflammation response by lnc TINCR. METHODS 3T3-L1 preadipocytes were induced to differentiate into mature adipocytes. Oil red O staining was used to find the fat droplets in mature adipocytes. Mature adipocytes were randomized to normal control group and Tri-DAP (NOD1 ligand) group. After the establishment of insulin resistance model, we used deep RNA sequencing(RNA-Seq) to identify lncRNAs that are regulated during NODI activation in mouse adipocytes. Real-time PCR was used to analyze the expression of lnc TINCR, proinflammatory IL-6, TNF-α, Cxcl1 and RIPK2 in the presence or absence of Tri-DAP(10 μg/ml). We employed siRNA against lnc TINCR to confirm its effects in inflammatory response. RESULTS Deep RNA sequencing identified 81 lncRNAs and 167 coding genes that were significantly up-related while 78 lncRNAs and 82 coding genes that were significantly down-related greater than twofold during NOD1 activation in adipocytes. We discovered that lnc TINCR, termed lnc TINCR(Tri-DAP-inducible non-protein coding RNA) is greatly upregulated in Tri-DAP activated adipocytes. Moreover knockdown of lnc TINCR dampens the proinflammatory response (P < 0.05; in adipocytes). CONCLUSIONS lnc TINCR is a positive regulator of inflammation-induced insulin resistance presumably via activation of NOD1 signaling pathways.
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Affiliation(s)
- Ying-Xin Fang
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yun Zou
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Guang-Ting Wang
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Shao-Hua Huang
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yan-Jun Zhou
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yi-Jun Zhou
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China.
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27
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Sharma A, Maurya CK, Arha D, Rai AK, Singh S, Varshney S, Schertzer JD, Tamrakar AK. Nod1-mediated lipolysis promotes diacylglycerol accumulation and successive inflammation via PKCδ-IRAK axis in adipocytes. Biochim Biophys Acta Mol Basis Dis 2019; 1865:136-146. [DOI: 10.1016/j.bbadis.2018.10.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/10/2018] [Accepted: 10/30/2018] [Indexed: 02/08/2023]
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28
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Wallet SM, Puri V, Gibson FC. Linkage of Infection to Adverse Systemic Complications: Periodontal Disease, Toll-Like Receptors, and Other Pattern Recognition Systems. Vaccines (Basel) 2018; 6:E21. [PMID: 29621153 PMCID: PMC6027258 DOI: 10.3390/vaccines6020021] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 03/25/2018] [Accepted: 03/30/2018] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that provide innate immune sensing of conserved pathogen-associated molecular patterns (PAMPs) to engage early immune recognition of bacteria, viruses, and protozoa. Furthermore, TLRs provide a conduit for initiation of non-infectious inflammation following the sensing of danger-associated molecular patterns (DAMPs) generated as a consequence of cellular injury. Due to their essential role as DAMP and PAMP sensors, TLR signaling also contributes importantly to several systemic diseases including cardiovascular disease, diabetes, and others. The overlapping participation of TLRs in the control of infection, and pathogenesis of systemic diseases, has served as a starting point for research delving into the poorly defined area of infection leading to increased risk of various systemic diseases. Although conflicting studies exist, cardiovascular disease, diabetes, cancer, rheumatoid arthritis, and obesity/metabolic dysfunction have been associated with differing degrees of strength to infectious diseases. Here we will discuss elements of these connections focusing on the contributions of TLR signaling as a consequence of bacterial exposure in the context of the oral infections leading to periodontal disease, and associations with metabolic diseases including atherosclerosis and type 2 diabetes.
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Affiliation(s)
- Shannon M Wallet
- Department of Oral Biology, College of Dental Medicine, University of Florida, Gainesville, FL 32610, USA.
| | - Vishwajeet Puri
- Department of Biomedical Sciences and Diabetes Institute, Ohio University, Athens, OH 45701, USA.
| | - Frank C Gibson
- Department of Oral Biology, College of Dental Medicine, University of Florida, Gainesville, FL 32610, USA.
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29
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NOD1 and NOD2: Molecular targets in prevention and treatment of infectious diseases. Int Immunopharmacol 2017; 54:385-400. [PMID: 29207344 DOI: 10.1016/j.intimp.2017.11.036] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 11/23/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023]
Abstract
Nucleotide-binding oligomerization domain (NOD) 1 and NOD2 are pattern-recognition receptors responsible for sensing fragments of bacterial peptidoglycan known as muropeptides. Stimulation of innate immunity by systemic or local administration of NOD1 and NOD2 agonists is an attractive means to prevent and treat infectious diseases. In this review, we discuss novel data concerning structural features of selective and non-selective (dual) NOD1 and NOD2 agonists, main signaling pathways and biological effects induced by NOD1 and NOD2 stimulation, including induction of pro-inflammatory cytokines, type I interferons and antimicrobial peptides, induction of autophagy, alterations of metabolism. We also discuss interactions between NOD1/NOD2 and Toll-like receptor agonists in terms of synergy and cross-tolerance. Finally, we review available animal data on the role of NOD1 and NOD2 in protection against infections, and discuss how these data could be applied in human infectious diseases.
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30
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Ren Y, Wan T, Zuo Z, Cui H, Peng X, Fang J, Deng J, Hu Y, Yu S, Shen L, Ma X, Wang Y, Ren Z. Resistin increases the expression of NOD2 in mouse monocytes. Exp Ther Med 2017; 13:2523-2528. [PMID: 28565874 DOI: 10.3892/etm.2017.4288] [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: 01/14/2016] [Accepted: 01/20/2017] [Indexed: 11/05/2022] Open
Abstract
Previous studies have indicated that resistin, a type of adipokine, contributes to the development of insulin resistance and type 2 diabetes mellitus, and mediates inflammatory reactions. However, a specific receptor for resistin has not yet been identified. In this study, the relationship between resistin and nucleotide-binding oligomerization domain-like receptors, as well as resistin signal transduction, was examined through transfection, quantitative polymerase chain reaction, western blot analysis and ELISA. The mRNA expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a key immune receptor related to insulin resistance, was significantly increased by resistin treatment at concentrations of 100, 150 and 200 ng/ml (P<0.05, P<0.01 and P<0.01, respectively). The mRNA expression of downstream signaling molecules in the NOD2 signaling pathway, receptor-interacting serine/threonine-protein kinase 2 (RIP2; P<0.01 at 6, 12 and 24 h) and inhibitor of NF-κB kinase subunit beta (P<0.01 at 3, 6, 12 and 24 h) were significantly increased by resistin treatment compared with the control. The mRNA expression of key proinflammatory cytokines, tumor necrosis factor α, IL (interleukin)-6 and IL-1β, were also significantly increased by resistin treatment compared with the control (P<0.01). NOD2 knockdown by small interfering RNA (siRNA) significantly decreased the expression of NOD2 and RIP2 (P<0.01), and there was no significant increase in the levels of cytokines, as compared with treatment with control siRNA. These findings indicate that the inflammatory reaction induced by resistin involves the NOD2-nuclear factor (NF)-κB signaling pathway. The inhibition of NF-κB significantly decreased the secretion of key inflammatory cytokines (P<0.01), suggesting that NF-κB signaling mechanisms are essential to the resistin-induced inflammatory response.
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Affiliation(s)
- Yi Ren
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Taomei Wan
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Zhicai Zuo
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Hengmin Cui
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Xi Peng
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Jing Fang
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Junliang Deng
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Yanchun Hu
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Shuming Yu
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Liuhong Shen
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Xiaoping Ma
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Ya Wang
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
| | - Zhihua Ren
- Sichuan Province Key Laboratory of Animal Disease and Human Health, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan 611130, P.R. China
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Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia. Sci Rep 2017; 7:1578. [PMID: 28484277 PMCID: PMC5431485 DOI: 10.1038/s41598-017-01822-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 03/31/2017] [Indexed: 01/01/2023] Open
Abstract
Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin resistance via Nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Receptor-interacting serine/threonine-protein kinase 2 (Ripk2) mediates Nod1-induced immunity, but the role of Ripk2 in metabolism is ill-defined. We hypothesized that Ripk2 was required for Nod1-mediated inflammation, lipolysis and dysglycemia. This is relevant because certain tyrosine kinase inhibitors (TKIs) inhibit Ripk2 and there is clinical evidence of TKIs lowering inflammation and blood glucose. Here, we showed that only a subset of TKIs known to inhibit Ripk2 attenuated Nod1 ligand-mediated adipocyte lipolysis. TKIs that inhibit Ripk2 decreased cytokine responses induced by Nod1-activating peptidoglycan, but not endotoxin in both metabolic and immune cells. Pre-treatment of adipocytes or macrophages with the TKI gefitinib inhibited Nod1-induced Cxcl1 and Il-6 secretion. Furthermore, treatment of mice with gefitinib prevented Nod1-induced glucose intolerance in vivo. Ripk2 was required for these effects on inflammation and metabolism, since Nod1-mediated cytokine and blood glucose changes were absent in Ripk2−/− mice. Our data show that specific TKIs used in cancer also inhibit Nod1-Ripk2 immunometabolism responses indicative of metabolic disease.
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Chakraborty S, Bhattacharyya R, Banerjee D. Infections: A Possible Risk Factor for Type 2 Diabetes. Adv Clin Chem 2017; 80:227-251. [PMID: 28431641 DOI: 10.1016/bs.acc.2016.11.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Diabetes mellitus is one of the biggest challenges to human health globally, with an estimated 95% of the global diabetic population having type 2 diabetes. Classical causes for type 2 diabetes, such as genetics and obesity, do not account for the high incidence of the disease. Recent data suggest that infections may precipitate insulin resistance via multiple mechanisms, such as the proinflammatory cytokine response, the acute-phase response, and the alteration of the nutrient status. Even pathogen products, such as lipopolysaccharide and peptidoglycans, can be diabetogenic. Therefore, we argue that infections that are known to contribute to insulin resistance should be considered as risk factors for type 2 diabetes.
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Affiliation(s)
- Surajit Chakraborty
- Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Dibyajyoti Banerjee
- Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
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Troxerutin Attenuates Enhancement of Hepatic Gluconeogenesis by Inhibiting NOD Activation-Mediated Inflammation in High-Fat Diet-Treated Mice. Int J Mol Sci 2016; 18:ijms18010031. [PMID: 28029143 PMCID: PMC5297666 DOI: 10.3390/ijms18010031] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/13/2016] [Accepted: 12/21/2016] [Indexed: 12/20/2022] Open
Abstract
Recent evidence suggests that troxerutin, a trihydroxyethylated derivative of natural bioflavonoid rutin, exhibits beneficial effects on diabetes-related symptoms. Here we investigated the effects of troxerutin on the enhancement of hepatic gluconeogenesis in high-fat diet (HFD)-treated mice and the mechanisms underlying these effects. Mice were divided into four groups: Control group, HFD group, HFD + Troxerutin group, and Troxerutin group. Troxerutin was treated by daily oral administration at doses of 150 mg/kg/day for 20 weeks. Tauroursodeoxycholic acid (TUDCA) was used to inhibit endoplasmic reticulum stress (ER stress). Our results showed that troxerutin effectively improved obesity and related metabolic parameters, and liver injuries in HFD-treated mouse. Furthermore, troxerutin significantly attenuated enhancement of hepatic gluconeogenesis in HFD-fed mouse. Moreover, troxerutin notably suppressed nuclear factor-κB (NF-κB) p65 transcriptional activation and release of inflammatory cytokines in HFD-treated mouse livers. Mechanismly, troxerutin dramatically decreased Nucleotide oligomerization domain (NOD) expression, as well as interaction between NOD1/2 with interacting protein-2 (RIP2), by abating oxidative stress-induced ER stress in HFD-treated mouse livers, which was confirmed by TUDCA treatment. These improvement effects of troxerutin on hepatic glucose disorders might be mediated by its anti-obesity effect. In conclusion, troxerutin markedly diminished HFD-induced enhancement of hepatic gluconeogenesis via its inhibitory effects on ER stress-mediated NOD activation and consequent inflammation, which might be mediated by its anti-obesity effect.
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Feerick CL, McKernan DP. Understanding the regulation of pattern recognition receptors in inflammatory diseases - a 'Nod' in the right direction. Immunology 2016; 150:237-247. [PMID: 27706808 DOI: 10.1111/imm.12677] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 09/15/2016] [Accepted: 09/28/2016] [Indexed: 12/11/2022] Open
Abstract
Nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs) are a family of 23 receptors known as pattern recognition receptors; they are expressed in many cell types and play a key role in the innate immune response. The NLRs are activated by pathogen-associated molecular patterns, which include structurally conserved molecules present on the surfaces of bacteria. The activation of these NLRs by pathogens results in the downstream activation of signalling kinases and transcription factors, culminating in the transcription of genes coding for pro-inflammatory factors. Expression of NLR is altered in many cellular, physiological and disease states. There is a lack of understanding of the mechanisms by which NLR expression is regulated, particularly in chronic inflammatory states. Genetic polymorphisms and protein interactions are included in such mechanisms. This review seeks to examine the current knowledge regarding the regulation of this family of receptors and their signalling pathways as well as how their expression changes in disease states with particular focus on NOD1 and NOD2 in inflammatory bowel diseases among others.
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Affiliation(s)
- Claire L Feerick
- Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland
| | - Declan P McKernan
- Pharmacology & Therapeutics, National University of Ireland, Galway, Ireland
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Keček Plešec K, Urbančič D, Gobec M, Pekošak A, Tomašič T, Anderluh M, Mlinarič-Raščan I, Jakopin Ž. Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2. Bioorg Med Chem 2016; 24:5221-5234. [PMID: 27601373 DOI: 10.1016/j.bmc.2016.08.044] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 08/22/2016] [Accepted: 08/23/2016] [Indexed: 01/01/2023]
Abstract
NOD1 and NOD2 are important members of the pattern recognition receptor family and play a crucial role within the context of innate immunity. However, overactivation of NODs, especially of NOD1, has also been implicated in a number of diseases. Surprisingly, NOD1 remains a virtually unexploited target in this respect. To gain additional insight into the structure-activity relationships of NOD1 inhibitors, a series of novel analogs has been designed and synthesized and then screened for their NOD1-inhibitory activity. Selected compounds were also investigated for their NOD2-inhibitory activity. Two compounds 4 and 15, were identified as potent mixed inhibitors of NOD1 and NOD2, displaying a balanced inhibitory activity on both targets in the low micromolar range. The results obtained have enabled a deeper understanding of the structural requirements for NOD1 and NOD2 inhibition.
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Affiliation(s)
- Kaja Keček Plešec
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Dunja Urbančič
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Martina Gobec
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Aleksandra Pekošak
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Tihomir Tomašič
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Marko Anderluh
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Irena Mlinarič-Raščan
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Žiga Jakopin
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
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Di Rosa M, Malaguarnera L. Chitinase 3 Like-1: An Emerging Molecule Involved in Diabetes and Diabetic Complications. Pathobiology 2016; 83:228-242. [PMID: 27189062 DOI: 10.1159/000444855] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 02/18/2016] [Indexed: 01/05/2025] Open
Abstract
Chitinase 3 like-1 (CHI3L1) is a chitinase-like protein member of family 18 chitinases, expressed in innate immune cells and involved in endothelial dysfunction and tissue remodelling. Since CHI3L1 is highly expressed in a variety of inflammatory diseases of infectious and non-infectious aetiology, it is recognised as a non-invasive prognostic biomarker for inflammation. A variety of studies revealing the increase in CHI3L1 levels in obesity, insulin resistance and in pathological conditions, such as atherosclerosis, coronary artery disease, acute ischaemic stroke, nephropathy, diabetic retinopathy and osteolytic processes, have suggested that CHI3L1 may also play a critical role in the evolution and complication of diabetes mellitus (DM). In this review we highlight the impact of CHI3L1 expression in DM and its contribution to the complication of this disease.
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Affiliation(s)
- Michelino Di Rosa
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
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Aravindhan V, Madhumitha H. Metainflammation in Diabetic Coronary Artery Disease: Emerging Role of Innate and Adaptive Immune Responses. J Diabetes Res 2016; 2016:6264149. [PMID: 27610390 PMCID: PMC5004008 DOI: 10.1155/2016/6264149] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/19/2016] [Indexed: 02/06/2023] Open
Abstract
Globally, noncommunicable chronic diseases such as Type-2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD) are posing a major threat to the world. T2DM is known to potentiate CAD which had led to the coining of a new clinical entity named diabetic CAD (DM-CAD), leading to excessive morbidity and mortality. The synergistic interaction between these two comorbidities is through sterile inflammation which is now being addressed as metabolic inflammation or metainflammation, which plays a pivotal role during both early and late stages of T2DM and also serves as a link between T2DM and CAD. This review summarises the current concepts on the role played by both innate and adaptive immune responses in setting up metainflammation in DM-CAD. More specifically, the role played by innate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), NOD1-like receptors (NLRs), Rig-1-like receptors (RLRs), and C-type lectin like receptors (CLRs) and metabolic endotoxemia in fuelling metainflammation in DM-CAD would be discussed. Further, the role played by adaptive immune cells (Th1, Th2, Th17, and Th9 cells) in fuelling metainflammation in DM-CAD will also be discussed.
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Affiliation(s)
- Vivekanandhan Aravindhan
- Department of Genetics, Dr. ALM. PG. IBMS, University of Madras, Chennai 600113, India
- *Vivekanandhan Aravindhan:
| | - Haridoss Madhumitha
- AU-KBC Research Centre, MIT Campus of Anna University, Chennai 600044, India
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Maurya CK, Arha D, Rai AK, Kumar SK, Pandey J, Avisetti DR, Kalivendi SV, Klip A, Tamrakar AK. NOD2 activation induces oxidative stress contributing to mitochondrial dysfunction and insulin resistance in skeletal muscle cells. Free Radic Biol Med 2015; 89:158-69. [PMID: 26404168 DOI: 10.1016/j.freeradbiomed.2015.07.154] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 07/20/2015] [Accepted: 07/24/2015] [Indexed: 01/11/2023]
Abstract
Nucleotide-binding oligomerization domain protein-2 (NOD2) activation in skeletal muscle cells has been associated with insulin resistance, but the underlying mechanisms are not yet clear. Here we demonstrate the implication of oxidative stress in the development of mitochondrial dysfunction and insulin resistance in response to NOD2 activation in skeletal muscle cells. Treatment with the selective NOD2 ligand muramyl dipeptide (MDP) increased mitochondrial reactive oxygen species (ROS) generation in L6 myotubes. MDP-induced ROS production was associated with increased levels of protein carbonyls and reduction in citrate synthase activity, cellular ATP level, and mitochondrial membrane potential, as well as altered expression of genes involved in mitochondrial function and metabolism. Antioxidant treatment attenuated MDP-induced ROS production and restored mitochondrial functions. In addition, the presence of antioxidant prevented NOD2-mediated activation of MAPK kinases and the inflammatory response. This was associated with reduced serine phosphorylation of insulin receptor substrate-1 (IRS-1) and improved insulin-stimulated tyrosine phosphorylation of IRS-1 and downstream activation of Akt phosphorylation. These data indicate that oxidative stress plays a role in NOD2 activation-induced inflammatory response and that MDP-induced oxidative stress correlates with impairment of mitochondrial functions and induction of insulin resistance in skeletal muscle cells.
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Affiliation(s)
- Chandan K Maurya
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Deepti Arha
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Amit K Rai
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shashi Kant Kumar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Jyotsana Pandey
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Deepa R Avisetti
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Shasi V Kalivendi
- Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
| | - Amira Klip
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Akhilesh K Tamrakar
- Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
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Qian LL, Li HT, Zhang L, Fang QC, Jia WP. Effect of the Gut Microbiota on Obesity and Its Underlying Mechanisms: an Update. BIOMEDICAL AND ENVIRONMENTAL SCIENCES : BES 2015; 28:839-847. [PMID: 26695364 DOI: 10.1016/s0895-3988(15)30116-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 10/27/2015] [Indexed: 01/05/2025]
Affiliation(s)
- Ling Ling Qian
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200025, China; Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hua Ting Li
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200025, China
| | - Lei Zhang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200025, China; Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Qi Chen Fang
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200025, China
| | - Wei Ping Jia
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai 200025, China; Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Zhang W, Tang Z, Zhu X, Xia N, Zhao Y, Wang S, Cui S, Wang C. TRAF1 knockdown alleviates palmitate-induced insulin resistance in HepG2 cells through NF-κB pathway. Biochem Biophys Res Commun 2015; 467:527-33. [PMID: 26449452 DOI: 10.1016/j.bbrc.2015.09.165] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 09/30/2015] [Indexed: 12/29/2022]
Abstract
High-fat diet (HFD) and inflammation are key contributors to insulin resistance (IR) and Type 2 diabetes mellitus (T2DM). With HFD, plasma free fatty acids (FFAs) can activate the nuclear factor-κB (NF-κB) in target tissues, then initiate negative crosstalk between FFAs and insulin signaling. However, the molecular link between IR and inflammation remains to be identified. We here reported that tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, was involved in the onset of IR in hepatocytes. TRAF1 was significantly up-regulated in insulin-resistant liver tissues and palmitate (PA)-treated HepG2 cells. In addition, we showed that depletion of TRAF1 led to inhibition of the activity of NF-κB. Given the fact that the activation of NF-κB played a facilitating role in IR, the phosphorylation of Akt and GSK3β was also analyzed. We found that depletion of TRAF1 markedly reversed PA-induced attenuation of the phosphorylation of Akt and GSK3β in the cells. The accumulation of lipid droplets in hepatocyte and expression of two key gluconeogenic enzymes, PEPCK and G6Pase, were also determined and found to display a similar tendency with the phosphorylation of Akt and GSK3β. Glucose uptake assay indicated that knocking down TRAF1 blocked the effect of PA on the suppression of glucose uptake. These data implicated that TRAF1 knockdown might alleviate PA-induced IR in HepG2 cells through NF-κB pathway.
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Affiliation(s)
- Wanlu Zhang
- Department of Pathogen Biology, Medical College, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Zhuqi Tang
- Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Xiaohui Zhu
- Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Nana Xia
- Department of Pathogen Biology, Medical College, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Yun Zhao
- Department of Pathogen Biology, Medical College, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Suxin Wang
- Department of Pathogen Biology, Medical College, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China; Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, 19 Qixiu Road, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Shiwei Cui
- Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, Jiangsu Province, People's Republic of China.
| | - Cuifang Wang
- Department of Endocrinology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong 226001, Jiangsu Province, People's Republic of China.
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Grant RW, Stephens JM. Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. Am J Physiol Endocrinol Metab 2015; 309:E205-13. [PMID: 26058863 DOI: 10.1152/ajpendo.00053.2015] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 06/03/2015] [Indexed: 12/26/2022]
Abstract
Adipose tissue has the largest capacity to store energy in the body and provides energy through the release of free fatty acids during times of energy need. Different types of immune cells are recruited to adipose tissue under various physiological conditions, indicating that these cells contribute to the regulation of adipose tissue. One major pathway influenced by a number of immune cells is the release of free fatty acids through lipolysis during both physiological (e.g., cold stress) and pathophysiological processes (e.g., obesity, type 2 diabetes). Adipose tissue expansion during obesity leads to immune cell infiltration and adipose tissue remodeling, a homeostatic process that promotes inflammation in adipose tissue. The release of proinflammatory cytokines stimulates lipolysis and causes insulin resistance, leading to adipose tissue dysfunction and systemic disruptions of metabolism. This review focuses on the interactions of cytokines and other inflammatory molecules that regulate adipose tissue lipolysis during physiological and pathophysiological states.
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Affiliation(s)
- Ryan W Grant
- Department of Nutrition Science, Purdue University, West Lafayette, Indiana
| | - Jacqueline M Stephens
- Adipocyte Biology Lab, Pennington Biomedical Research Center, Baton Rouge, Louisiana; and Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana
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Zhou YJ, Liu C, Li CL, Song YL, Tang YS, Zhou H, Li A, Li Y, Weng Y, Zheng FP. Increased NOD1, but not NOD2, activity in subcutaneous adipose tissue from patients with metabolic syndrome. Obesity (Silver Spring) 2015; 23:1394-400. [PMID: 26052894 DOI: 10.1002/oby.21113] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 03/03/2015] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Nucleotide-binding oligomerization domain (NOD) protein, as cytoplasmic receptor of the innate immune response, plays an important role in adipose inflammation and insulin resistance in obesity. Our objective was to examine adipose tissue (AT) NOD in nascent metabolic syndrome (MetS) patients and to investigate its association with MetS features. METHODS Thirty-four MetS subjects and 31 controls were recruited. Fasting blood was collected, and abdominal subcutaneous AT was obtained by biopsy for NOD1/NOD2 expression and activity. RESULTS MetS subjects showed significantly increased expression for NOD1 on adipose depots as compared to controls. In addition to increased expression of downstream signaling mediators RIPK2 and NF-κB p65 nuclear translocation, there was remarkably higher release of monocyte chemotactic protein1 (MCP-1), interleukin (IL)-6, and IL-8 in MetS versus controls following priming of the isolated adipocytes with NOD1 ligand iE-DAP. With regard to NOD2, the differences between the two groups were not significant in either basal state or after activation. Increased NOD1 positively correlated with waist circumference. NOD1 was also correlated with HbA1c and HOMA-IR. NOD1 positively correlated with serum levels of IL-6, MCP-1, and NF-κB activity. CONCLUSIONS Activation of the innate immune pathway via NOD1 may be partially responsible for the increased systemic inflammation and insulin resistance in MetS.
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Affiliation(s)
- Yi-Jun Zhou
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Cong Liu
- Department of Endocrinology and Metabolism, Shengjing Hospital, China Medical University, Shenyang, Liaoning, China
| | - Chun-Li Li
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yu-Ling Song
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yin-Si Tang
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Hui Zhou
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Ai Li
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yan Li
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Yang Weng
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Fang-Ping Zheng
- Department of Endocrinology and Metabolism, Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
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Bae J, Chen J, Zhao L. Chronic activation of pattern recognition receptors suppresses brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes. Biochem Cell Biol 2015; 93:251-261. [PMID: 25741603 DOI: 10.1139/bcb-2014-0139] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Brown adipose tissue (BAT) holds promise to combat obesity through energy-spending, non-shivering thermogenesis. Understanding of regulation of BAT development can lead to novel strategies to increase BAT mass and function for obesity treatment and prevention. Here, we report the effects of chronic activation of PRR on brown adipogenesis of multipotent mesodermal stem C3H10T1/2 cells and immortalized brown pre-adipocytes from the classical interscapular BAT of mice. Activation of NOD1, TLR4, or TLR2 by their respective synthetic ligand suppressed brown marker gene expression and lipid accumulation during differentiation of brown-like adipocytes of C3H10T1/2. Activation of the PRR only during the commitment was sufficient to suppress the differentiation. PRR activation suppressed PGC-1α mRNA, but induced PRDM16 mRNA at the commitment. Consistently, PRR activation suppressed the differentiation of immortalized brown pre-adipocytes. Activation of PRR induced NF-κB activation in both cells, which correlated with their abilities to suppress PPARγ transactivation, a critical event for brown adipogenesis. Taken together, our results demonstrate that chronic PRR activation suppressed brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes, possibly through suppression of PPARγ transactivation. The results suggest that anti- inflammatory therapies targeting PRRs may be beneficial for the BAT development.
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Affiliation(s)
- Jiyoung Bae
- Department of Nutrition, The University of Tennessee, 1215 W. Cumberland Avenue, Knoxville, TN 37996-1920, USA
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Kaparakis-Liaskos M. The intracellular location, mechanisms and outcomes of NOD1 signaling. Cytokine 2015; 74:207-12. [PMID: 25801093 DOI: 10.1016/j.cyto.2015.02.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 02/16/2015] [Indexed: 01/01/2023]
Abstract
The host has developed an array of systems that enables protection against infection and response to injury, ultimately resulting in the generation of a pro-inflammatory response. The most rapid immune response is mediated via the innate immune system, which is comprised of germ line encoded pathogen recognition receptors (PRRs). This PRR mediated system functions by specifically recognizing conserved structures of microbial molecules or products, known as microbial-associated molecular patterns (MAMPs), ultimately enabling transduction of signaling cascades, gene transcription and the development of a pro-inflammatory innate immune response. The intracellular PRRs nucleotide-binding oligomerization domain protein 1 (NOD1) and NOD2 will be the focus of this review. A brief overview of NOD1 and NOD2 and recent advances in the field regarding the intracellular location and mechanisms of NOD1 signaling will be discussed. These new findings have broadened our understanding of the mechanisms whereby NOD1 signaling results in the induction of the cellular degradation pathway of autophagy and the development of pro-inflammatory responses that activate the adaptive immune system.
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Affiliation(s)
- Maria Kaparakis-Liaskos
- Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Clayton, Victoria 3168, Australia.
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Prieto P, Vallejo-Cremades MT, Benito G, González-Peramato P, Francés D, Agra N, Terrón V, Gónzalez-Ramos S, Delgado C, Ruiz-Gayo M, Pacheco I, Velasco-Martín JP, Regadera J, Martín-Sanz P, López-Collazo E, Boscá L, Fernández-Velasco M. NOD1 receptor is up-regulated in diabetic human and murine myocardium. Clin Sci (Lond) 2014; 127:665-677. [PMID: 24934088 DOI: 10.1042/cs20140180] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Type 2 diabetes has a complex pathology that involves a chronic inflammatory state. Emerging evidence suggests a link between the innate immune system receptor NOD1 (nucleotide-binding and oligomerization domain 1) and the pathogenesis of diabetes, in monocytes and hepatic and adipose tissues. The aim of the present study was to assess the role of NOD1 in the progression of diabetic cardiomyopathy. We have measured NOD1 protein in cardiac tissue from Type 2 diabetic (db) mice. Heart and isolated cardiomyocytes from db mice revealed a significant increase in NOD1, together with an up-regulation of nuclear factor κB (NF-κB) and increased apoptosis. Heart tissue also exhibited an enhanced expression of pro-inflammatory cytokines. Selective NOD1 activation with C12-γ-D-glutamyl-m-diaminopimelic acid (iEDAP) resulted in an increased NF-κB activation and apoptosis, demonstrating the involvement of NOD1 both in wild-type and db mice. Moreover, HL-1 cardiomyocytes exposed to elevated concentrations of glucose plus palmitate displayed an enhanced NF-κB activity and apoptotic profile, which was prevented by silencing of NOD1 expression. To address this issue in human pathology, NOD1 expression was evaluated in myocardium obtained from patients with Type 2 diabetes (T2DMH) and from normoglycaemic individuals without cardiovascular histories (NH). We have found that NOD1 was expressed in both NH and T2DMH; however, NOD1 expression was significantly pronounced in T2DMH. Furthermore, both the pro-inflammatory cytokine tumour necrosis factor α (TNF-α) and the apoptosis mediator caspase-3 were up-regulated in T2DMH samples. Taken together, our results define an active role for NOD1 in the heightened inflammatory environment associated with both experimental and human diabetic cardiac disease.
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Affiliation(s)
- Patricia Prieto
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
| | | | - Gemma Benito
- †Instituto de Investigación Hospital Universitario La Paz (IDIPAZ), Madrid, Spain
| | - Pilar González-Peramato
- ‡Departamento de Anatomía Patológica, Hospital Universitario La Paz, Universidad Autonoma de Madrid, Madrid, Spain
| | - Daniel Francés
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
| | - Noelia Agra
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
| | - Verónica Terrón
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
| | - Silvia Gónzalez-Ramos
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
| | - Carmen Delgado
- §Centro de Investigaciones Biológicas. Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | | | | | - Juan P Velasco-Martín
- ††Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Javier Regadera
- ††Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Paloma Martín-Sanz
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
| | | | - Lisardo Boscá
- *Instituto de Investigaciones Biomédicas Alberto Sols, Centro Mixto CSIC-UAM, Madrid, Spain
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Ha CWY, Lam YY, Holmes AJ. Mechanistic links between gut microbial community dynamics, microbial functions and metabolic health. World J Gastroenterol 2014; 20:16498-16517. [PMID: 25469018 PMCID: PMC4248193 DOI: 10.3748/wjg.v20.i44.16498] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Revised: 06/26/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
Gut microbes comprise a high density, biologically active community that lies at the interface of an animal with its nutritional environment. Consequently their activity profoundly influences many aspects of the physiology and metabolism of the host animal. A range of microbial structural components and metabolites directly interact with host intestinal cells and tissues to influence nutrient uptake and epithelial health. Endocrine, neuronal and lymphoid cells in the gut also integrate signals from these microbial factors to influence systemic responses. Dysregulation of these host-microbe interactions is now recognised as a major risk factor in the development of metabolic dysfunction. This is a two-way process and understanding the factors that tip host-microbiome homeostasis over to dysbiosis requires greater appreciation of the host feedbacks that contribute to regulation of microbial community composition. To date, numerous studies have employed taxonomic profiling approaches to explore the links between microbial composition and host outcomes (especially obesity and its comorbidities), but inconsistent host-microbe associations have been reported. Available data indicates multiple factors have contributed to discrepancies between studies. These include the high level of functional redundancy in host-microbiome interactions combined with individual variation in microbiome composition; differences in study design, diet composition and host system between studies; and inherent limitations to the resolution of rRNA-based community profiling. Accounting for these factors allows for recognition of the common microbial and host factors driving community composition and development of dysbiosis on high fat diets. New therapeutic intervention options are now emerging.
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Ricciardi CJ, Bae J, Esposito D, Komarnytsky S, Hu P, Chen J, Zhao L. 1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration. Eur J Nutr 2014; 54:1001-12. [PMID: 25296887 DOI: 10.1007/s00394-014-0778-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 09/30/2014] [Indexed: 01/12/2023]
Abstract
PURPOSE The vitamin D system plays a role in metabolism regulation. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) suppressed 3T3-L1 white adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure, whereas mice with adipose-specific VDR over-expression showed decreased energy expenditure. Brown adipose tissue (BAT), now known to be present in adult humans, functions in non-shivering thermogenesis by uncoupling ATP synthesis from respiration and plays an important role in energy expenditure. However, the effects of 1,25(OH)2D3/VDR on brown adipocyte differentiation and mitochondrial respiration have not been reported. METHODS mRNA expression of VDR and the metabolizing enzymes 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) were examined in BAT of mice models of obesity and during brown adipocyte differentiation. The effects of 1,25(OH)2D3 and VDR over-expression on brown adipocyte differentiation and functional outcomes were evaluated. RESULTS No significant changes in mRNA of VDR and CYP27B1 were noted in both diet-induced obese (DIO) and ob/ob mice, whereas uncoupling protein 1 mRNA was downregulated in BAT of ob/ob, but not DIO mice when compared to the controls. In contrast, mRNA of VDR, CYP24A1, and CYP27B1 were downregulated during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, accompanied by suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Further, both 1,25(OH)2D3 and VDR over-expression suppressed PPARγ transactivation in brown preadipocytes. CONCLUSION Our results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)2D3/VDR system in regulating BAT development and function in obesity warrant further investigation.
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Affiliation(s)
- Carolyn J Ricciardi
- Department of Nutrition, University of Tennessee, 1215 W. Cumberland Ave, Knoxville, TN, 37996, USA
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Li HB, Jin C, Chen Y, Flavell RA. Inflammasome activation and metabolic disease progression. Cytokine Growth Factor Rev 2014; 25:699-706. [PMID: 25156419 DOI: 10.1016/j.cytogfr.2014.07.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Innate pattern recognition receptors NLRs are cytosolic sensors that detect endogenous metabolic stress and form a multiprotein complex called the inflammasome, that recruits and activates caspase enzymes mediating the activation of the cytokines IL-1β and IL-18. The innate immune system and metabolic system are evolutionarily conserved, intimately integrated, and functionally dependent. In recent decades, obesity-associated metabolic diseases have been become a worldwide epidemic. Here we review recent evidence that demonstrates the important roles of NLRs and inflammasomes in response to metabolic stress in different tissues.
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Affiliation(s)
- Hua-Bing Li
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Chengcheng Jin
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Yuanyuan Chen
- Institute of Surgical Research, Daping Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, USA.
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Abstract
Maternal peripheral insulin resistance and increased inflammation are two features of pregnancies, complicated by gestational diabetes mellitus (GDM). The nucleotide-binding oligomerisation domain (NOD) intracellular molecules recognise a wide range of microbial products, as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor κB (NFκB). The aim of this study was to determine whether levels of NOD1 and NOD2 are increased in adipose tissue of women with GDM. The effect of NOD1 and NOD2 activation on inflammation and the insulin signalling pathway was also assessed. NOD1, but not NOD2, expression was higher in omental and subcutaneous adipose tissues obtained from women with GDM when compared with those from women with normal glucose tolerance (NGT). In both omental and subcutaneous adipose tissues from NGT and GDM women, the NOD1 ligand g-d-glutamyl-meso-diaminopimelic acid (iE-DAP) significantly induced the expression and secretion of the pro-inflammatory cytokine interleukin 6 (IL6) and chemokine IL8; COX2 (PTGS2) gene expression and subsequent prostaglandin production; the expression and secretion of the extracellular matrix remodelling enzyme matrix metalloproteinase 9 (MMP9) and the gene expression and secretion of the adhesion molecules ICAM1 and VCAM1. There was no effect of the NOD2 ligand muramyl dipeptide on any of the endpoints tested. The effects of the NOD1 ligand iE-DAP were mediated via NFκB, as the NFκB inhibitor BAY 11-7082 significantly attenuated iE-DAP-induced expression and secretion of pro-inflammatory cytokines, COX2 gene expression and subsequent prostaglandin production, MMP9 expression and secretion and ICAM1 and VCAM1 gene expression and secretion. In conclusion, the present findings describe an important role for NOD1 in the development of insulin resistance and inflammation in pregnancies complicated by GDM.
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Affiliation(s)
- Martha Lappas
- ObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, AustraliaMercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, AustraliaObstetricsNutrition and Endocrinology Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Level 4/163 Studley Road, Heidelberg, Victoria 3084, AustraliaMercy Perinatal Research CentreMercy Hospital for Women, Heidelberg, Victoria, Australia
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Bae J, Ricciardi CJ, Esposito D, Komarnytsky S, Hu P, Curry BJ, Brown PL, Gao Z, Biggerstaff JP, Chen J, Zhao L. Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. Am J Physiol Cell Physiol 2014; 306:C918-30. [DOI: 10.1152/ajpcell.00249.2013] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide-oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are recently found to be present in adult humans, has not been studied. Here we report that mRNA of TLR4, TLR2, NOD1, and NOD2 is upregulated, paralleled with upregulated mRNA of inflammatory cytokines and chemokines in the brown adipose tissue (BAT) of the obese mice. During brown adipocyte differentiation, mRNA and protein expression of NOD1 and TLR4, but not TLR2 and NOD2, is also increased. Activation of TLR4, TLR2, or NOD1 in brown adipocytes induces activation of NF-κB and MAPK signaling pathways, leading to inflammatory cytokine/chemokine mRNA expression and/or protein secretion. Moreover, activation of TLR4, TLR2, or NOD1 attenuates both basal and isoproterenol-induced uncoupling protein 1 (UCP-1) expression without affecting mitochondrial biogenesis and lipid accumulation in brown adipocytes. Cellular bioenergetics measurements confirm that attenuation of UCP-1 expression by PRR activation is accompanied by suppression of both basal and isoproterenol-stimulated oxygen consumption rates and isoproterenol-induced uncoupled respiration from proton leak; however, maximal respiration and ATP-coupled respiration are not changed. Further, the attenuation of UCP-1 by PRR activation appears to be mediated through downregulation of the UCP-1 promoter activities. Taken together, our results demonstrate the role of selected PRR activation in inducing inflammation and downregulation of UCP-1 expression and mitochondrial respiration in brown adipocytes. Our results uncover novel targets in BAT for obesity treatment and prevention.
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Affiliation(s)
- Jiyoung Bae
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
| | | | - Debora Esposito
- Plants for Human Health Institute, North Carolina Research Campus, North Carolina State University, Kannapolis, North Carolina
- Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina; and
| | - Slavko Komarnytsky
- Plants for Human Health Institute, North Carolina Research Campus, North Carolina State University, Kannapolis, North Carolina
- Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina; and
| | - Pan Hu
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
| | - Benjamin J. Curry
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
| | - Patricia L. Brown
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
| | - Zhanguo Gao
- Pennington Biomedical Research Center, Baton Rouge, Louisiana
| | - John P. Biggerstaff
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
- Center for Environmental Biotechnology, University of Tennessee, Knoxville, Tennessee
| | - Jiangang Chen
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
- Department of Public Health, University of Tennessee, Knoxville, Tennessee
| | - Ling Zhao
- Department of Nutrition, University of Tennessee, Knoxville, Tennessee
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