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Wang T, Zhou D, Hong Z. Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2025; 6:e70030. [PMID: 39764565 PMCID: PMC11702502 DOI: 10.1002/mco2.70030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 03/17/2025] Open
Abstract
Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.
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Affiliation(s)
- Tiantian Wang
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
| | - Dong Zhou
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
| | - Zhen Hong
- Department of NeurologyWest China Hospital of Sichuan UniversityChengduSichuanChina
- Institute of Brain Science and Brain‐Inspired Technology of West China HospitalSichuan UniversityChengduSichuanChina
- Department of NeurologyChengdu Shangjin Nanfu HospitalChengduSichuanChina
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Luo W, Zhou Y, Wang LY, Ai L. Interactions between myoblasts and macrophages under high glucose milieus result in inflammatory response and impaired insulin sensitivity. World J Diabetes 2024; 15:1589-1602. [PMID: 39099815 PMCID: PMC11292338 DOI: 10.4239/wjd.v15.i7.1589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 04/28/2024] [Accepted: 05/20/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Skeletal muscle handles about 80% of insulin-stimulated glucose uptake and become the major organ occurring insulin resistance (IR). Many studies have confirmed the interactions between macrophages and skeletal muscle regulated the inflammation and regeneration of skeletal muscle. However, despite of the decades of research, whether macrophages infiltration and polarization in skeletal muscle under high glucose (HG) milieus results in the development of IR is yet to be elucidated. C2C12 myoblasts are well-established and excellent model to study myogenic regulation and its responses to stimulation. Further exploration of macrophages' role in myoblasts IR and the dynamics of their infiltration and polarization is warranted. AIM To evaluate interactions between myoblasts and macrophages under HG, and its effects on inflammation and IR in skeletal muscle. METHODS We detected the polarization status of macrophages infiltrated to skeletal muscles of IR mice by hematoxylin and eosin and immunohistochemical staining. Then, we developed an in vitro co-culture system to study the interactions between myoblasts and macrophages under HG milieus. The effects of myoblasts on macrophages were explored through morphological observation, CCK-8 assay, Flow Cytometry, and enzyme-linked immunosorbent assay. The mediation of macrophages to myogenesis and insulin sensitivity were detected by morphological observation, CCK-8 assay, Immunofluorescence, and 2-NBDG assay. RESULTS The F4/80 and co-localization of F4/80 and CD86 increased, and the myofiber size decreased in IR group (P < 0.01, g = 6.26). Compared to Mc group, F4/80+CD86+CD206- cells, tumor necrosis factor-α (TNFα), inerleukin-1β (IL-1β) and IL-6 decreased, and IL-10 increased in McM group (P < 0.01, g > 0.8). In McM + HG group, F4/80+CD86+CD206- cells, monocyte chemoattractant protein 1, TNFα, IL-1β and IL-6 were increased, and F4/80+CD206+CD86- cells and IL-10 were decreased compared with Mc + HG group and McM group (P < 0.01, g > 0.8). Compered to M group, myotube area, myotube number and E-MHC were increased in MMc group (P < 0.01, g > 0.8). In MMc + HG group, myotube area, myotube number, E-MHC, GLUT4 and glucose uptake were decreased compared with M + HG group and MMc group (P < 0.01, g > 0.8). CONCLUSION Interactions between myoblasts and macrophages under HG milieus results in inflammation and IR, which support that the macrophage may serve as a promising therapeutic target for skeletal muscle atrophy and IR.
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Affiliation(s)
- Wei Luo
- Department of Sports and Health Sciences, Nanjing Sport Institute, Nanjing 210014, Jiangsu Province, China
| | - Yue Zhou
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Li-Ying Wang
- Department of Exercise Physiology, Beijing Sport University, Beijing 100084, China
| | - Lei Ai
- Department of Sports Physiology Research, Jiangsu Research Institute of Sports Science, Nanjing 210033, Jiangsu Province, China
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Hutchinson AL, Liddle DM, Monk JM, Ma DWL, Robinson LE. n-3 and n-6 Polyunsaturated Fatty Acids Modulate Macrophage-Myocyte Inflammatory Crosstalk and Improve Myocyte Insulin Sensitivity. Nutrients 2024; 16:2086. [PMID: 38999834 PMCID: PMC11243049 DOI: 10.3390/nu16132086] [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: 06/07/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/14/2024] Open
Abstract
In obesity, circulating saturated fatty acids (SFAs) and inflammatory cytokines interfere with skeletal muscle insulin signaling, leading to whole body insulin resistance. Further, obese skeletal muscle is characterized by macrophage infiltration and polarization to the inflammatory M1 phenotype, which is central to the development of local inflammation and insulin resistance. While skeletal muscle-infiltrated macrophage-myocyte crosstalk is exacerbated by SFA, the effects of other fatty acids, such as n-3 and n-6 polyunsaturated fatty acids (PUFAs), are less studied. Thus, the objective of this study was to determine the effects of long-chain n-3 and n-6 PUFAs on macrophage M1 polarization and subsequent effects on myocyte inflammation and metabolic function compared to SFA. Using an in vitro model recapitulating obese skeletal muscle cells, differentiated L6 myocytes were cultured for 24 h with RAW 264.7 macrophage-conditioned media (MCM), followed by insulin stimulation (100 nM, 20 min). MCM was generated by pre-treating macrophages for 24 h with 100 μM palmitic acid (16:0, PA-control), arachidonic acid (20:4n-6, AA), or docosahexaenoic acid (22:6n-3, DHA). Next, macrophage cultures were stimulated with a physiological dose (10 ng/mL) of lipopolysaccharide for an additional 12 h to mimic in vivo obese endotoxin levels. Compared to PA, both AA and DHA reduced mRNA expression and/or secreted protein levels of markers for M1 (TNFα, IL-6, iNOS; p < 0.05) and increased those for M2 (IL-10, TGF-β; p < 0.05) macrophage polarization. In turn, AA- and DHA-derived MCM reduced L6 myocyte-secreted cytokines (TNFα, IL-6; p < 0.05) and chemokines (MCP-1, MIP-1β; p < 0.05). Only AA-derived MCM increased L6-myocyte phosphorylation of Akt (p < 0.05), yet this was inconsistent with improved insulin signaling, as only DHA-derived MCM improved L6 myocyte glucose uptake (p < 0.05). In conclusion, dietary n-3 and n-6 PUFAs may be a useful strategy to modulate macrophage-myocyte inflammatory crosstalk and improve myocyte insulin sensitivity in obesity.
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Affiliation(s)
| | | | | | | | - Lindsay E. Robinson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada (J.M.M.); (D.W.L.M.)
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Zhu Y, Hu Y, Pan Y, Li M, Niu Y, Zhang T, Sun H, Zhou S, Liu M, Zhang Y, Wu C, Ma Y, Guo Y, Wang L. Fatty infiltration in the musculoskeletal system: pathological mechanisms and clinical implications. Front Endocrinol (Lausanne) 2024; 15:1406046. [PMID: 39006365 PMCID: PMC11241459 DOI: 10.3389/fendo.2024.1406046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/10/2024] [Indexed: 07/16/2024] Open
Abstract
Fatty infiltration denotes the anomalous accrual of adipocytes in non-adipose tissue, thereby generating toxic substances with the capacity to impede the ordinary physiological functions of various organs. With aging, the musculoskeletal system undergoes pronounced degenerative alterations, prompting heightened scrutiny regarding the contributory role of fatty infiltration in its pathophysiology. Several studies have demonstrated that fatty infiltration affects the normal metabolism of the musculoskeletal system, leading to substantial tissue damage. Nevertheless, a definitive and universally accepted generalization concerning the comprehensive effects of fatty infiltration on the musculoskeletal system remains elusive. As a result, this review summarizes the characteristics of different types of adipose tissue, the pathological mechanisms associated with fatty infiltration in bone, muscle, and the entirety of the musculoskeletal system, examines relevant clinical diseases, and explores potential therapeutic modalities. This review is intended to give researchers a better understanding of fatty infiltration and to contribute new ideas to the prevention and treatment of clinical musculoskeletal diseases.
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Affiliation(s)
- Yihua Zhu
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yue Hu
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yalan Pan
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Traditional Chinese Medicine (TCM) Nursing Intervention Laboratory of Chronic Disease Key Laboratory, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Muzhe Li
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yuanyuan Niu
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Tianchi Zhang
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Haitao Sun
- Department of Orthopedic Surgery, Affiliated Huishan Hospital of Xinglin College of Nantong University, Wuxi, Jiangsu, China
| | - Shijie Zhou
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Mengmin Liu
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yili Zhang
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chengjie Wu
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yong Ma
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng TCM Hospital, Yancheng, Jiangsu, China
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, Jiangsu, China
| | - Yang Guo
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, Jiangsu, China
| | - Lining Wang
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & Orthopedics, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Chinese Medicine Centre (International Collaboration between Western Sydney University and Beijing University of Chinese Medicine), Western Sydney University, Sydney, Australia
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Akieda-Asai S, Ma H, Han W, Nagata J, Yamaguchi F, Date Y. Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet. Sci Rep 2024; 14:7670. [PMID: 38561446 PMCID: PMC10984920 DOI: 10.1038/s41598-024-57727-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic β-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6-STAT3-SOCS3 and ubiquitin-proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.
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Affiliation(s)
- Sayaka Akieda-Asai
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan.
| | - Hao Ma
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Wanxin Han
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Junko Nagata
- Department of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Fumitake Yamaguchi
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan
- Department of Nursing, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Yukari Date
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan.
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Wang Y, Wang J, Tao SY, Liang Z, Xie R, Liu NN, Deng R, Zhang Y, Deng D, Jiang G. Mitochondrial damage-associated molecular patterns: A new insight into metabolic inflammation in type 2 diabetes mellitus. Diabetes Metab Res Rev 2024; 40:e3733. [PMID: 37823338 DOI: 10.1002/dmrr.3733] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 07/18/2023] [Accepted: 09/08/2023] [Indexed: 10/13/2023]
Abstract
The pathogenesis of diabetes is accompanied by increased levels of inflammatory factors, also known as "metabolic inflammation", which runs through the whole process of the occurrence and development of the disease. Mitochondria, as the key site of glucose and lipid metabolism, is often accompanied by mitochondrial function damage in type 2 diabetes mellitus (T2DM). Damaged mitochondria release pro-inflammatory factors through damage-related molecular patterns that activate inflammation pathways and reactions to oxidative stress, further aggravate metabolic disorders, and form a vicious circle. Currently, the pathogenesis of diabetes is still unclear, and clinical treatment focuses primarily on symptomatic intervention of the internal environment of disorders of glucose and lipid metabolism with limited clinical efficacy. The proinflammatory effect of mitochondrial damage-associated molecular pattern (mtDAMP) in T2DM provides a new research direction for exploring the pathogenesis and intervention targets of T2DM. Therefore, this review covers the most recent findings on the molecular mechanism and related signalling cascades of inflammation caused by mtDAMP in T2DM and discusses its pathogenic role of it in the pathological process of T2DM to search potential intervention targets.
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Affiliation(s)
- Yan Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Jingwu Wang
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Si-Yu Tao
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | | | - Rong Xie
- Xinjiang Medical University, Urumqi, China
| | - Nan-Nan Liu
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ruxue Deng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Yuelin Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Deqiang Deng
- Department of Endocrinology, Urumqi Hospital of Traditional Chinese Medicine, Urumqi, China
| | - Guangjian Jiang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Yazıcı D, Demir SÇ, Sezer H. Insulin Resistance, Obesity, and Lipotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:391-430. [PMID: 39287860 DOI: 10.1007/978-3-031-63657-8_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.
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Affiliation(s)
- Dilek Yazıcı
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey.
| | - Selin Çakmak Demir
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
| | - Havva Sezer
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
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Boonlaos A, Uddin MJ, Temyord K, Jattawa D, Kayan A. Muscle fiber characteristics and expression level of Troponin T3, Toll-like receptor 2, and Toll-like receptor 4 genes in chicken meat with white striping. Vet World 2023; 16:1415-1420. [PMID: 37621550 PMCID: PMC10446722 DOI: 10.14202/vetworld.2023.1415-1420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 05/31/2023] [Indexed: 08/26/2023] Open
Abstract
Background and Aim The poultry industry faces an emerging muscular defect in chicken meat called white striping (WS). The biological processes associated with WS myopathy are immune system activation, angiogenesis, hypoxia, cell death, and striated muscle contraction. We examined the Troponin T3 (TNNT3), Toll-like receptor 2 (TLR2), and Toll-like receptor 4 (TLR4) genes based on their functions related to muscle contraction and the innate immune system. This study aimed to determine the muscle fiber characteristics (MFCs) and expression level of TNNT3, TLR2, and TLR4 genes in white striping chicken meat (WSCM). Materials and Methods A total of 428 breast samples were randomly collected from a commercial poultry processing plant. The samples were classified into four levels: 0 (normal), 1 (moderate WS), 2 (severe WS), and 3 (extreme WS). Five samples per group were selected to evaluate MFCs, including total number of muscle fibers, muscle fiber diameter, cross-sectional area, endomysium thickness, and perimysium thickness. Five samples per group were selected for ribonucleic acid (RNA) isolation to evaluate the messenger RNA (mRNA) expression levels of TNNT3, TLR2, and TLR4 genes related to WS. Results Statistical analysis revealed that the total number of fibers, endomysium thickness, and perimysium thickness significantly differed between groups (p < 0.05). Muscle fiber diameter and cross-sectional area did not significantly differ (p > 0.05). The expression of the TNNT3 gene did not significantly differ among groups (p > 0.05). Toll-like receptor 2 and TLR4 mRNA expression significantly differed among groups (p < 0.05). Conclusion These detailed MFCs will provide baseline information to observe WS in chicken meat. Toll-like receptor 2 and TLR4 genes may play a role in the occurrence of WS in chicken meat through non-specific immune reactions.
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Affiliation(s)
- Antika Boonlaos
- Department of Animal Science, Faculty of Agriculture, Kasetsart University, Bangkok, Thailand
| | - Muhammad Jasim Uddin
- School of Veterinary Medicine, Murdoch University, Western Australia, Australia
- Center for Biosecurity and One Health, Harry Butler Institute, Murdoch University, Murdoch, Australia
| | - Katchaporn Temyord
- Bureau of Livestock Standard and Certification, Department of Livestock Development, Bangkok, Thailand
| | - Danai Jattawa
- Department of Animal Science, Faculty of Agriculture, Kasetsart University, Bangkok, Thailand
| | - Autchara Kayan
- Department of Animal Science, Faculty of Agriculture, Kasetsart University, Bangkok, Thailand
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Bikbova G, Oshitari T, Bikbov M. Diabetic Neuropathy of the Retina and Inflammation: Perspectives. Int J Mol Sci 2023; 24:ijms24119166. [PMID: 37298118 DOI: 10.3390/ijms24119166] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/21/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
A clear connection exists between diabetes and atherosclerotic cardiovascular disease. Consequently, therapeutic approaches that target both diseases are needed. Clinical trials are currently underway to explore the roles of obesity, adipose tissue, gut microbiota, and pancreatic beta cell function in diabetes. Inflammation plays a key role in diabetes pathophysiology and associated metabolic disorders; thus, interest has increased in targeting inflammation to prevent and control diabetes. Diabetic retinopathy is known as a neurodegenerative and vascular disease that occurs after some years of poorly controlled diabetes. However, increasing evidence points to inflammation as a key figure in diabetes-associated retinal complications. Interconnected molecular pathways, such as oxidative stress, and the formation of advanced glycation end-products, are known to contribute to the inflammatory response. This review describes the possible mechanisms of the metabolic changes in diabetes that involve inflammatory pathways.
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Affiliation(s)
- Guzel Bikbova
- Department of Ophthalmology and Visual Science, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan
- Ufa Eye Research Institute, Pushkin Street 90, Ufa 450077, Russia
| | - Toshiyuki Oshitari
- Department of Ophthalmology and Visual Science, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan
- Department of Ophthalmology, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita 286-8686, Japan
| | - Mukharram Bikbov
- Ufa Eye Research Institute, Pushkin Street 90, Ufa 450077, Russia
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Wang HW, Tang J, Sun L, Li Z, Deng M, Dai Z. Mechanism of immune attack in the progression of obesity-related type 2 diabetes. World J Diabetes 2023; 14:494-511. [PMID: 37273249 PMCID: PMC10236992 DOI: 10.4239/wjd.v14.i5.494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity and overweight are widespread issues in adults, children, and adolescents globally, and have caused a noticeable rise in obesity-related complications such as type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is an important promotor of the pathogenesis of obesity-related T2DM. This proinflammatory activation occurs in multiple organs and tissues. Immune cell-mediated systemic attack is considered to contribute strongly to impaired insulin secretion, insulin resistance, and other metabolic disorders. This review focused on highlighting recent advances and underlying mechanisms of immune cell infiltration and inflammatory responses in the gut, islet, and insulin-targeting organs (adipose tissue, liver, skeletal muscle) in obesity-related T2DM. There is current evidence that both the innate and adaptive immune systems contribute to the development of obesity and T2DM.
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Affiliation(s)
- Hua-Wei Wang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jun Tang
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li Sun
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhen Li
- Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ming Deng
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhe Dai
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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11
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Della Guardia L, Codella R. Exercise Restores Hypothalamic Health in Obesity by Reshaping the Inflammatory Network. Antioxidants (Basel) 2023; 12:antiox12020297. [PMID: 36829858 PMCID: PMC9951965 DOI: 10.3390/antiox12020297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Obesity and overnutrition induce inflammation, leptin-, and insulin resistance in the hypothalamus. The mediobasal hypothalamus responds to exercise enabling critical adaptions at molecular and cellular level that positively impact local inflammation. This review discusses the positive effect of exercise on obesity-induced hypothalamic dysfunction, highlighting the mechanistic aspects related to the anti-inflammatory effects of exercise. In HFD-fed animals, both acute and chronic moderate-intensity exercise mitigate microgliosis and lower inflammation in the arcuate nucleus (ARC). Notably, this associates with restored leptin sensitivity and lower food intake. Exercise-induced cytokines IL-6 and IL-10 mediate part of these positive effect on the ARC in obese animals. The reduction of obesity-associated pro-inflammatory mediators (e.g., FFAs, TNFα, resistin, and AGEs), and the improvement in the gut-brain axis represent alternative paths through which regular exercise can mitigate hypothalamic inflammation. These findings suggest that the regular practice of exercise can restore a proper functionality in the hypothalamus in obesity. Further analysis investigating the crosstalk muscle-hypothalamus would help toward a deeper comprehension of the subject.
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Affiliation(s)
- Lucio Della Guardia
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy
| | - Roberto Codella
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan, Italy
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, 20138 Milan, Italy
- Correspondence: ; Tel.: +39-02-50330356
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12
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Aldahhan RA, Motawei KH, Al-Hariri MT. Lipotoxicity-related sarcopenia: a review. J Med Life 2022; 15:1334-1339. [PMID: 36567835 PMCID: PMC9762358 DOI: 10.25122/jml-2022-0157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/27/2022] [Indexed: 12/27/2022] Open
Abstract
A body of literature supports the postulation that a persistent lipid metabolic imbalance causes lipotoxicity, "an abnormal fat storage in the peripheral organs". Hence, lipotoxicity could somewhat explain the process of sarcopenia, an aging-related, gradual, and involuntary decline in skeletal muscle strength and mass associated with several health complications. This review focuses on the recent mechanisms underlying lipotoxicity-related sarcopenia. A vicious cycle occurs between sarcopenia and ectopic fat storage via a complex interplay of mitochondrial dysfunction, pro-inflammatory cytokine production, oxidative stress, collagen deposition, extracellular matrix remodeling, and life habits. The repercussions of lipotoxicity exacerbation of sarcopenia can include increased disability, morbidity, and mortality. This suggests that appropriate lipotoxicity management should be considered the primary target for the prevention and/or treatment of chronic musculoskeletal and other aging-related disorders. Further advanced research is needed to understand the molecular details of lipotoxicity and its consequences for sarcopenia and sarcopenia-related comorbidities.
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Affiliation(s)
| | - Kamaluddin Hasan Motawei
- Department of Anatomy, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohammed Taha Al-Hariri
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia,Corresponding Author: Mohammed Taha Al-Hariri, Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. E-mail:
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13
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Li H, Meng Y, He S, Tan X, Zhang Y, Zhang X, Wang L, Zheng W. Macrophages, Chronic Inflammation, and Insulin Resistance. Cells 2022; 11:cells11193001. [PMID: 36230963 PMCID: PMC9562180 DOI: 10.3390/cells11193001] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/08/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
The prevalence of obesity has reached alarming levels, which is considered a major risk factor for several metabolic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver, atherosclerosis, and ischemic cardiovascular disease. Obesity-induced chronic, low-grade inflammation may lead to insulin resistance, and it is well-recognized that macrophages play a major role in such inflammation. In the current review, the molecular mechanisms underlying macrophages, low-grade tissue inflammation, insulin resistance, and T2D are described. Also, the role of macrophages in obesity-induced insulin resistance is presented, and therapeutic drugs and recent advances targeting macrophages for the treatment of T2D are introduced.
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Affiliation(s)
- He Li
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Ya Meng
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Shuwang He
- Shandong DYNE Marine Biopharmaceutical Co., Ltd., Rongcheng 264300, China
| | - Xiaochuan Tan
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yujia Zhang
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Xiuli Zhang
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Lulu Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
- Correspondence: (L.W.); (W.Z.); Tel.: +86-010-63165233 (W.Z.)
| | - Wensheng Zheng
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Correspondence: (L.W.); (W.Z.); Tel.: +86-010-63165233 (W.Z.)
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14
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Fanalli SL, da Silva BPM, Gomes JD, de Almeida VV, Freitas FAO, Moreira GCM, Silva-Vignato B, Afonso J, Reecy J, Koltes J, Koltes D, de Almeida Regitano LC, Garrick DJ, de Carvalho Balieiro JC, Meira AN, Freitas L, Coutinho LL, Fukumasu H, Mourão GB, de Alencar SM, Luchiari Filho A, Cesar ASM. Differential Gene Expression Associated with Soybean Oil Level in the Diet of Pigs. Animals (Basel) 2022; 12:1632. [PMID: 35804531 PMCID: PMC9265114 DOI: 10.3390/ani12131632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 12/21/2022] Open
Abstract
The aim of this study was to identify the differentially expressed genes (DEG) from the skeletal muscle and liver samples of animal models for metabolic diseases in humans. To perform the study, the fatty acid (FA) profile and RNA sequencing (RNA-Seq) data of 35 samples of liver tissue (SOY1.5, n = 17 and SOY3.0, n = 18) and 36 samples of skeletal muscle (SOY1.5, n = 18 and SOY3.0, n = 18) of Large White pigs were analyzed. The FA profile of the tissues was modified by the diet, mainly those related to monounsaturated (MUFA) and polyunsaturated (PUFA) FA. The skeletal muscle transcriptome analysis revealed 45 DEG (FDR 10%), and the functional enrichment analysis identified network maps related to inflammation, immune processes, and pathways associated with oxidative stress, type 2 diabetes, and metabolic dysfunction. For the liver tissue, the transcriptome profile analysis revealed 281 DEG, which participate in network maps related to neurodegenerative diseases. With this nutrigenomics study, we verified that different levels of soybean oil in the pig diet, an animal model for metabolic diseases in humans, affected the transcriptome profile of skeletal muscle and liver tissue. These findings may help to better understand the biological mechanisms that can be modulated by the diet.
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Affiliation(s)
- Simara Larissa Fanalli
- Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga 13635-900, SP, Brazil; (S.L.F.); (B.P.M.d.S.); (H.F.)
| | - Bruna Pereira Martins da Silva
- Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga 13635-900, SP, Brazil; (S.L.F.); (B.P.M.d.S.); (H.F.)
| | - Julia Dezen Gomes
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Vivian Vezzoni de Almeida
- College of Veterinary Medicine and Animal Science, Federal University of Goiás, Goiânia 74690-900, GO, Brazil;
| | - Felipe André Oliveira Freitas
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | | | - Bárbara Silva-Vignato
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Juliana Afonso
- Embrapa Pecuária Sudeste, São Carlos 70770-901, SP, Brazil; (J.A.); (L.C.d.A.R.)
| | - James Reecy
- College of Agriculture and Life Sciences, Iowa State University, Ames, IA 50011, USA; (J.R.); (J.K.); (D.K.)
| | - James Koltes
- College of Agriculture and Life Sciences, Iowa State University, Ames, IA 50011, USA; (J.R.); (J.K.); (D.K.)
| | - Dawn Koltes
- College of Agriculture and Life Sciences, Iowa State University, Ames, IA 50011, USA; (J.R.); (J.K.); (D.K.)
| | | | - Dorian John Garrick
- AL Rae Centre for Genetics and Breeding, Massey University, Hamilton 3214, New Zealand;
| | | | - Ariana Nascimento Meira
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Luciana Freitas
- DB Genética de Suínos, Patos de Minas 38706-000, MG, Brazil;
| | - Luiz Lehmann Coutinho
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Heidge Fukumasu
- Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga 13635-900, SP, Brazil; (S.L.F.); (B.P.M.d.S.); (H.F.)
| | - Gerson Barreto Mourão
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Severino Matias de Alencar
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Albino Luchiari Filho
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
| | - Aline Silva Mello Cesar
- Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga 13635-900, SP, Brazil; (S.L.F.); (B.P.M.d.S.); (H.F.)
- Luiz de Queiroz College of Agriculture, University of São Paulo, Piracicaba 13418-900, SP, Brazil; (J.D.G.); (F.A.O.F.); (B.S.-V.); (A.N.M.); (L.L.C.); (G.B.M.); (S.M.d.A.); (A.L.F.)
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15
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Rome S. Muscle and Adipose Tissue Communicate with Extracellular Vesicles. Int J Mol Sci 2022; 23:ijms23137052. [PMID: 35806052 PMCID: PMC9266961 DOI: 10.3390/ijms23137052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 02/05/2023] Open
Abstract
In numerous body locations, muscle and adipose tissue are in close contact. Both tissues are endocrine organs that release cytokines, playing a crutial role in the control of tissue homeostasis in health and diseases. Within this context, the identification of the signals involved in muscle–fat crosstalk has been a hot topic over the last 15 years. Recently, it has been discovered that adipose tissue and muscles can release information embedded in lipid-derived nanovesicles called ‘extracellular vesicles’ (EVs), which can modulate the phenotype and the homeostasis of neighboring recipient cells. This article reviews knowledge on EVs and their involvement in the communication between adipose tissue and muscle in several body locations. Even if the works are scarce, they have revolutionized our vision in the field of metabolic and cardiovascular diseases.
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Affiliation(s)
- Sophie Rome
- CarMeN Laboratory, INSERM 1060/INRAE 1397, Lyon-Sud Faculty of Medicine, LYON 1 University, 69301 Pierre Bénite, France
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16
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Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity 2022; 55:31-55. [PMID: 35021057 PMCID: PMC8773457 DOI: 10.1016/j.immuni.2021.12.013] [Citation(s) in RCA: 827] [Impact Index Per Article: 275.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 01/13/2023]
Abstract
Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.
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Affiliation(s)
- Theresa V. Rohm
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Daniel T. Meier
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland
| | - Jerrold M. Olefsky
- Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Marc Y. Donath
- Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland.,Department of Biomedicine (DBM), University of Basel, University Hospital Basel, CH-4031 Basel, Switzerland.,Correspondence:
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17
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Dungan CM, Murach KA, Zdunek CJ, Tang ZJ, Nolt GL, Brightwell CR, Hettinger Z, Englund D, Liu Z, Fry CS, Filareto A, Franti M, Peterson CA. Deletion of SA β-Gal+ cells using senolytics improves muscle regeneration in old mice. Aging Cell 2022; 21:e13528. [PMID: 34904366 PMCID: PMC8761017 DOI: 10.1111/acel.13528] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 10/05/2021] [Accepted: 11/21/2021] [Indexed: 12/11/2022] Open
Abstract
Systemic deletion of senescent cells leads to robust improvements in cognitive, cardiovascular, and whole-body metabolism, but their role in tissue reparative processes is incompletely understood. We hypothesized that senolytic drugs would enhance regeneration in aged skeletal muscle. Young (3 months) and old (20 months) male C57Bl/6J mice were administered the senolytics dasatinib (5 mg/kg) and quercetin (50 mg/kg) or vehicle bi-weekly for 4 months. Tibialis anterior (TA) was then injected with 1.2% BaCl2 or PBS 7- or 28 days prior to euthanization. Senescence-associated β-Galactosidase positive (SA β-Gal+) cell abundance was low in muscle from both young and old mice and increased similarly 7 days following injury in both age groups, with no effect of D+Q. Most SA β-Gal+ cells were also CD11b+ in young and old mice 7- and 14 days following injury, suggesting they are infiltrating immune cells. By 14 days, SA β-Gal+/CD11b+ cells from old mice expressed senescence genes, whereas those from young mice expressed higher levels of genes characteristic of anti-inflammatory macrophages. SA β-Gal+ cells remained elevated in old compared to young mice 28 days following injury, which were reduced by D+Q only in the old mice. In D+Q-treated old mice, muscle regenerated following injury to a greater extent compared to vehicle-treated old mice, having larger fiber cross-sectional area after 28 days. Conversely, D+Q blunted regeneration in young mice. In vitro experiments suggested D+Q directly improve myogenic progenitor cell proliferation. Enhanced physical function and improved muscle regeneration demonstrate that senolytics have beneficial effects only in old mice.
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Affiliation(s)
- Cory M. Dungan
- Department of Physical TherapyCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
- Sanders‐Brown Center on AgingUniversity of KentuckyLexingtonKentuckyUSA
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Kevin A. Murach
- Department of Physical TherapyCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
- Present address:
Department of Health, Human Performance, and Recreation, and Cell and Molecular Biology ProgramUniversity of ArkansasFayettevilleArkansasUSA
| | | | - Zuo Jian Tang
- Computational BiologyGCBDSBoehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | - Georgia L. Nolt
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Camille R. Brightwell
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
- Department of Athletic Training and Clinical NutritionCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
| | - Zachary Hettinger
- Department of Physical TherapyCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Davis A. Englund
- Department of Physical TherapyCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
| | - Zheng Liu
- Computational BiologyGCBDSBoehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | - Christopher S. Fry
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
- Department of Athletic Training and Clinical NutritionCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
| | - Antonio Filareto
- Regenerative MedicineBoehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | - Michael Franti
- Regenerative MedicineBoehringer Ingelheim Pharmaceuticals Inc.RidgefieldConnecticutUSA
| | - Charlotte A. Peterson
- Department of Physical TherapyCollege of Health SciencesUniversity of KentuckyLexingtonKentuckyUSA
- The Center for Muscle BiologyUniversity of KentuckyLexingtonKentuckyUSA
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18
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Della Guardia L, Codella R. Exercise tolls the bell for key mediators of low-grade inflammation in dysmetabolic conditions. Cytokine Growth Factor Rev 2021; 62:83-93. [PMID: 34620559 DOI: 10.1016/j.cytogfr.2021.09.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/30/2021] [Accepted: 09/10/2021] [Indexed: 12/15/2022]
Abstract
Metabolic conditions share a common low-grade inflammatory milieu, which represents a key-factor for their ignition and maintenance. Exercise is instrumental for warranting systemic cardio-metabolic balance, owing to its regulatory effect on inflammation. This review explores the effect of physical activity in the modulation of sub-inflammatory framework characterizing dysmetabolic conditions. Regular exercise suppresses plasma levels of TNFα, IL-1β, FFAs and MCP-1, in dysmetabolic subjects. In addition, a single session of training increases the anti-inflammatory IL-10, IL-1 receptor antagonist (IL-1ra), and muscle-derived IL-6, mitigating low-grade inflammation. Resting IL-6 levels are decreased in trained-dysmetabolic subjects, compared to sedentary. On the other hand, the acute release of muscle-IL-6, after exercise, seems to exert a regulatory effect on the metabolic and inflammatory balance. In fact, muscle-released IL-6 is presumably implicated in fat loss and boosts plasma levels of IL-10 and IL-1ra. The improvement of adipose tissue functionality, following regular exercise, is also critical for the mitigation of sub-inflammation. This effect is likely mediated by muscle-released IL-15 and IL-6 and partly relies on the brown-shifting of white adipocytes, induced by exercise. In obese-dysmetabolic subjects, moderate training is shown to restore gut-microbiota health, and this mitigates the translocation of bacterial-LPS into bloodstream. Finally, regular exercise can lower plasma advanced glycated endproducts. The articulated physiology of circulating mediators and the modulating effect of the pathophysiological background, render the comprehension of the exercise-regulatory effect on sub-inflammation a key issue, in dysmetabolism.
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Affiliation(s)
- Lucio Della Guardia
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Via Fratelli Cervi 93, Segrate, 20090 Milano, Italy
| | - Roberto Codella
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Via Fratelli Cervi 93, Segrate, 20090 Milano, Italy; Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milano, Italy.
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19
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Han JH, Kim W. Peripheral CB1R as a modulator of metabolic inflammation. FASEB J 2021; 35:e21232. [PMID: 33715173 DOI: 10.1096/fj.202001960r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/30/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022]
Abstract
Obesity is associated with chronic inflammation in insulin-sensitive tissues, including liver and adipose tissue, and causes hormonal/metabolic complications, such as insulin resistance. There is growing evidence that peripheral cannabinoid-type 1 receptor (CB1R) is a crucial participant in obesity-induced pro-inflammatory responses in insulin-target tissues, and its selective targeting could be a novel therapeutic strategy to break the link between insulin resistance and metabolic inflammation. In this review, we introduce the role of peripheral CB1R in metabolic inflammation and as a mediator of hormonal/metabolic complications that underlie metabolic syndrome, including fatty liver, insulin resistance, and dyslipidemia. We also discuss the therapeutic potential of second- and third-generation peripherally restricted CB1R antagonists for treating obesity-induced metabolic inflammation without eliciting central CB1R-mediated neurobehavioral effects, predictive of neuropsychiatric side effects, in humans.
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Affiliation(s)
- Ji Hye Han
- Department of Molecular Science & Technology, Ajou University, Suwon, South Korea
| | - Wook Kim
- Department of Molecular Science & Technology, Ajou University, Suwon, South Korea
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20
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Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus. J Neuroinflammation 2021; 18:140. [PMID: 34154608 PMCID: PMC8218389 DOI: 10.1186/s12974-021-02183-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. Systemic inflammation is caused by macrophages that infiltrate obese adipose tissues. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia. Since this infiltration contributes to neuroinflammation and neuronal impairment, herein we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice. METHODS C57BL/6J mice were fed HFD (60% kcal from fat) or control diet with matching sucrose levels, for 12-16 weeks. Males and females were analyzed separately to determine sex-specific responses to HFD. Differences in hypothalamic gene expression in HFD-fed male and female mice, compared to their lean controls, in two different areas of the hypothalamus, were determined using the NanoString neuroinflammation panel. Phenotypic changes in macrophages that infiltrated the hypothalamus in HFD-fed mice were determined by analyzing cell surface markers using flow cytometry and compared to changes in macrophages from the adipose tissue and peritoneal cavity. Adipose tissue transplantation was performed to determine the source of hypothalamic macrophages. RESULTS We determined that hypothalamic gene expression profiles demonstrate sex-specific and region-specific diet-induced changes. Sex-specific changes included larger changes in males, while region-specific changes included larger changes in the area surrounding the median eminence. Several genes were identified that may provide partial protection to female mice. We also identified diet-induced changes in macrophage migration into the hypothalamus, adipose tissue, and peritoneal cavity, specifically in males. Further, we determined that hypothalamus-infiltrating macrophages express pro-inflammatory markers and markers of metabolically activated macrophages that were identical to markers of adipose tissue macrophages in HFD-fed mice. Employing adipose tissue transplant, we demonstrate that hypothalamic macrophages can originate from the visceral adipose tissue. CONCLUSION HFD-fed males experience higher neuroinflammation than females, likely because they accumulate more visceral fat, which provides a source of pro-inflammatory macrophages that migrate to other tissues, including the hypothalamus. Our findings may explain the male bias for neuroinflammation and the metabolic syndrome. Together, our results demonstrate a new connection between the adipose tissue and the hypothalamus in obesity that contributes to neuroinflammation and hypothalamic pathologies.
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21
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Fletcher E, Gordon PM. Obesity-induced alterations to the immunoproteasome: a potential link to intramuscular lipotoxicity. Appl Physiol Nutr Metab 2021; 46:485-493. [PMID: 33186056 DOI: 10.1139/apnm-2020-0655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Although the mechanisms are unclear, inflammation and/or lipotoxicity likely contribute to obese muscle pathology. The immunoproteasome is known to respond to inflammation and oxidative damage and may aid muscle regeneration. We sought to determine whether diet-induced obesity (DIO) influences the immunoproteasome subunits LMP7 and MECL-1 in mouse muscle with and without exercise-induced muscle damage (EIMD). Muscle mass, regeneration, macrophage content and lipid peroxidation (8-isoprostane) were also assessed. Sixty male, 4-week-old C57BL/6J mice were fed a high-fat (HFD) or low-fat diet for 12 weeks. Mice were then subdivided into EIMD or no muscle damage (NMD) groups. The gastrocnemius muscle was excised 1 or 5 days after EIMD, producing 6 groups (n = 10/group). Body mass was greater; however, relative gastrocnemius mass was lower in HFD-fed mice. Despite no macrophage or MECL-1 alterations, LMP7 and 8-isoprostane were increased in obese mice in the NMD and 1 day post-EIMD groups. However, 8-isoprostane was reduced in obese mice 5 days post-EIMD, and accompanied by increased muscle LMP7, MECL-1 and macrophage content. Consequently, DIO may impair the immunoproteasome's ability to control muscle lipid peroxidation but is reversed with eccentric exercise. Although muscle regeneration was unchanged, immunoproteasome dysregulation occurs in obese muscle and may contribute to muscle pathology. Novelty: DIO may impair the intramuscular immunoproteasome response to lipid peroxidation. Acute eccentric exercise may protect obese individuals from muscle lipotoxicity via immunoproteasome upregulation.
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Affiliation(s)
- Emma Fletcher
- Department of Health, Human Performance and Recreation, Baylor University, Waco, TX 76798, USA
- Department of Health, Human Performance and Recreation, Baylor University, Waco, TX 76798, USA
| | - Paul M Gordon
- Department of Health, Human Performance and Recreation, Baylor University, Waco, TX 76798, USA
- Department of Health, Human Performance and Recreation, Baylor University, Waco, TX 76798, USA
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Pahk K, Kim EJ, Kwon HW, Joung C, Seo HS, Kim S. Association of Inflammatory Metabolic Activity of Psoas Muscle and Acute Myocardial Infarction: A Preliminary Observational Study with 18F-FDG PET/CT. Diagnostics (Basel) 2021; 11:diagnostics11030511. [PMID: 33805700 PMCID: PMC7999462 DOI: 10.3390/diagnostics11030511] [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: 02/14/2021] [Revised: 03/11/2021] [Accepted: 03/11/2021] [Indexed: 11/23/2022] Open
Abstract
Inflamed skeletal muscle promotes chronic inflammation in atherosclerotic plaques, thereby contributing to the increased risk of coronary artery disease (CAD). In this study, we evaluated the metabolic activity of psoas muscle, using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), and its association with carotid artery inflammation and acute myocardial infarction (AMI). In total, 90 participants (32 AMI, 33 chronic stable angina (CSA), and 25 control) were enrolled in this prospective study. Metabolic activity of skeletal muscle (SM) was measured by using maximum standardized uptake value (SUVmax) of psoas muscle, and corresponding psoas muscle area (SM area) was also measured. Carotid artery inflammation was evaluated by using the target-to background ratio (TBR) of carotid artery. SM SUVmax was highest in AMI, intermediate in CSA, and lowest in control group. SM SUVmax was significantly correlated with carotid artery TBR and systemic inflammatory surrogate markers. Furthermore, SM SUVmax was independently associated with carotid artery TBR and showed better predictability than SM area for the prediction of AMI. Metabolic activity of psoas muscle assessed by 18F-FDG PET/CT was associated with coronary plaque vulnerability and synchronized with the carotid artery inflammation in the participants with CAD. Furthermore, it may also be useful to predict AMI.
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Affiliation(s)
- Kisoo Pahk
- Department of Nuclear Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (K.P.); (H.W.K.)
| | - Eung Ju Kim
- Department of Cardiovascular Center, Korea University Guro Hospital, Seoul 08308, Korea;
| | - Hyun Woo Kwon
- Department of Nuclear Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (K.P.); (H.W.K.)
| | - Chanmin Joung
- Institute for Inflammation Control, Korea University, Seoul 02841, Korea;
| | - Hong Seog Seo
- Department of Cardiovascular Center, Korea University Guro Hospital, Seoul 08308, Korea;
- Correspondence: (H.S.S.); (S.K.); Tel.:+82-2-2626-3018 (H.S.S.); +82-2-920-5540 (S.K.)
| | - Sungeun Kim
- Department of Nuclear Medicine, Korea University Anam Hospital, Seoul 02841, Korea; (K.P.); (H.W.K.)
- Correspondence: (H.S.S.); (S.K.); Tel.:+82-2-2626-3018 (H.S.S.); +82-2-920-5540 (S.K.)
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23
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Seyhanli Z, Seyhanli A, Aksun S, Pamuk BO. Evaluation of serum Angiopoietin-like protein 2 (ANGPTL-2), Angiopoietin-like protein 8 (ANGPTL-8), and high-sensitivity C-reactive protein (hs-CRP) levels in patients with gestational diabetes mellitus and normoglycemic pregnant women. J Matern Fetal Neonatal Med 2021; 35:5647-5652. [PMID: 33615956 DOI: 10.1080/14767058.2021.1888919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE In the present study, we aimed to investigate the role of the fasting serum levels of Anjiopoetın 2 - like protein (ANGPTL2), Anjiopoetın 8-like protein (ANGPTL8), and high-sensitivity C-reactive protein (hs-CRP) in the etiopathogenesis of gestational diabetes mellitus (GDM), and analyze the relationships between insulin resistance parameters. MATERIAL AND METHOD The 90 individuals admitted to İzmir Katip Celebi University Hospital Internal Medicine, Endocrinology and Obstetrics, and gynecology outpatient clinic were included in the study of similar ages and similar demographic characteristics. Forty-five women with diet-controlled GDM and 45 women with normoglycemic pregnancy were enrolled. ANGPTL-2, ANGPTL-8, hs-CRP, creatinine, ALT, GGT, lipid profile, HBA1c(%), and serum insülin, c-peptide levels were studied in the fasting serum samples of research groups. All individuals had 75-g OGTT testing. GDM screening was performed at 24-28 weeks' gestation. Exclusion criteria were as follows: Age <18 years or >40 years, pregestational diabetes (type 1 or 2), drug or alcohol abuse, thyroid dysfunction, Hepatitis B, and other infectious diseases (Herpes virus, Streptococcus B carriers, Chlamydia and Candida), Thalassemia carriers or other significant medical conditions, the use of any medication that interferes with lipid or glucose metabolism that would affect glucose regulation. RESULT Forty-five women with GDM and for the control group, 45 women with normoglycemic pregnant women were identified. The mean gestational age was 30.7 (18-38) for GDM and 29.6 (24-39) for the control group. Serum ANGPTL-8 (GDM =19.5 ± 93 Control = 0.73 ± 3.78 p = <.001). There was a statistically significant difference between the case and control groups for serum ANGPTL-8 levels. Serum ANGPTL-2 (GDM =19.9 ± 23.1 Control = 26.0 ± 23.4 p = .105) and serum hs-CRP(GDM =106 ± 65.1 Control =98.2 ± 87.3 p = .768). There was no statistically significant difference between the case and control groups for serum ANGPTL-2 and hsCRP levels. Serum ANGPTL8 levels were positively correlated with FPG (r = 0.391, p = <.001), FPI (r = 0.212, p = .045), 1-h PPG (r = 0.514, p = <.001), 2-h PPG (r = 0.502, p = <.001), HOMA-IR) score (r = 0.310, p = .003), TG (r = 0.245, p = .020); they were not except for BMI, hs-CRP levels and ANGPTL2 levels. CONCLUSIONS ANGPTL8 levels were significantly higher in GDM than in healthy control group. ANGPTL2 levels and hs-CRP levels were similar to the healthy control group. Elevated serum ANGPTL8 levels were correlated significantly with insulin resistance parameters, the main component of GDM pathophysiology. Our data showed that ANGPTL8 could be a new biomarker for diagnosing GDM.
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Affiliation(s)
- Zeynep Seyhanli
- Obstetrics and Gynaecology, Izmir Gaziemir Nevvar Salih Isgoren State Hospital, Izmir, Turkey
| | - Ahmet Seyhanli
- Department of Internal Medicine (Hematology), Sivas Numune Hastanesi, Sivas, Turkey
| | - Saliha Aksun
- Biochemistry Department, Izmir Katip Celebi University Atatürk Training and Research Hospital, Izmir, Turkey
| | - Baris Onder Pamuk
- Endocrine and Metabolic Diseases Department Izmir, Izmir Katip Celebi University, Atatürk Training and Research Hospital, Izmir, Turkey
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24
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Effect of Exercise on Inflamed Psoas Muscle in Women with Obesity: A Pilot Prospective 18F-FDG PET/CT Study. Diagnostics (Basel) 2021; 11:diagnostics11020164. [PMID: 33498898 PMCID: PMC7912214 DOI: 10.3390/diagnostics11020164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 11/16/2022] Open
Abstract
Obesity increases inflammation in skeletal muscle thereby promoting systemic inflammation which leads to increased risk of cardiometabolic disease. This prospective study aimed to evaluate whether the metabolic activity of psoas muscle (PM) was associated with systemic inflammation, and whether physical exercise could reduce the PM metabolic activity evaluated by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in women with obesity. A total of 23 women with obesity who participated in a 3-month physical exercise program were enrolled. 18F-FDG PET/CT was performed before the start of the program (baseline) and after completion of the program. The maximum standardized uptake value of psoas muscle (PM SUVmax) was used for the PM metabolic activity. The SUVmax of spleen and bone marrow, and the high-sensitivity C-reactive protein were used to evaluate the systemic inflammation. At baseline, PM SUVmax was strongly correlated with the systemic inflammation. The exercise program significantly reduced the PM SUVmax, in addition to adiposity and systemic inflammation. Furthermore, we found that the association between PM SUVmax and the systemic inflammation disappeared after completion of the exercise program. In women with obesity, PM SUVmax, assessed by 18F-FDG PET/CT, was associated with obesity-induced systemic inflammation and exercise reduced the PM SUVmax and eliminated its association with systemic inflammation.
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25
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Armandi A, Rosso C, Caviglia GP, Ribaldone DG, Bugianesi E. The Impact of Dysmetabolic Sarcopenia Among Insulin Sensitive Tissues: A Narrative Review. Front Endocrinol (Lausanne) 2021; 12:716533. [PMID: 34858322 PMCID: PMC8631324 DOI: 10.3389/fendo.2021.716533] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 10/12/2021] [Indexed: 12/25/2022] Open
Abstract
Sarcopenia is a common muscular affection among elderly individuals. More recently, it has been recognized as the skeletal muscle (SM) expression of the metabolic syndrome. The prevalence of sarcopenia is increasing along with visceral obesity, to which it is tightly associated. Nonetheless, it is a still underreported entity by clinicians, despite the worsening in disease burden and reduced patient quality of life. Recognition of sarcopenia is clinically challenging, and variability in study populations and diagnostic methods across the clinical studies makes it hard to reach a strong evidence. Impaired insulin activity in SM is responsible for the altered molecular pathways and clinical manifestations of sarcopenia, which is morphologically expressed by myosteatosis. Lipotoxicity, oxidative stress and adipose tissue-derived inflammation lead to both alterations in glucose disposal and protein synthesis in SM, with raising insulin resistance (IR) and SM atrophy. In particular, hyperleptinemia and leptin resistance interfere directly with SM activity, but also with the release of Growth Hormone from the hypohysis, leading to a lack in its anabolic effect on SM. Moreover, sarcopenia is independently associated to liver fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD), which in turn worsens SM functionality through the secretion of proinflammatory heptokines. The cross-talk between the liver and SM in the IR setting is of crucial relevance, given the high prevalence of NAFLD and the reciprocal impact of insulin-sensitive tissues on the overall disease burden. Along with the efforts of non-invasive diagnostic approaches, irisin and myostatin are two myokines currently evaluated as potential biomarkers for diagnosis and prognostication. Decreased irisin levels seem to be potentially associated to sarcopenia, whereas increased myostatin has shown to negatively impact on sarcopenia in pre-clinical studies. Gene variants in irisin have been explored with regard to the impact on the liver disease phenotype, with conflicting results. The gut-muscle axis has gain relevance with the evidence that insulin resistance-derived gut dysbiosis is responsible for increased endotoxemia and reduction in short-chain free fatty acids, directly affecting and predisposing to sarcopenia. Based on the current evidence, more efforts are needed to increase awareness and improve the management of sarcopenic patients.
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26
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Chen KHE, Lainez NM, Coss D. Sex Differences in Macrophage Responses to Obesity-Mediated Changes Determine Migratory and Inflammatory Traits. THE JOURNAL OF IMMUNOLOGY 2020; 206:141-153. [PMID: 33268480 DOI: 10.4049/jimmunol.2000490] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 11/02/2020] [Indexed: 12/18/2022]
Abstract
The mechanisms whereby obesity differentially affects males and females are unclear. Because macrophages are functionally the most important cells in obesity-induced inflammation, we sought to determine reasons for male-specific propensity in macrophage migration. We previously determined that male mice fed a high-fat diet exhibit macrophage infiltration into the hypothalamus, whereas females were protected irrespective of ovarian estrogen, in this study, we show that males accumulate more macrophages in adipose tissues that are also more inflammatory. Using bone marrow cells or macrophages differentiated in vitro from male and female mice fed control or high-fat diet, we demonstrated that macrophages derived from male mice are intrinsically more migratory. We determined that males have higher levels of leptin in serum and adipose tissue. Serum CCL2 levels, however, are the same in males and females, although they are increased in obese mice compared with lean mice of both sexes. Leptin receptor and free fatty acid (FFA) receptor, GPR120, are upregulated only in macrophages derived from male mice when cultured in the presence of FFA to mimic hyperlipidemia of obesity. Unless previously stimulated with LPS, CCL2 did not cause migration of macrophages. Leptin, however, elicited migration of macrophages from both sexes. Macrophages from male mice maintained migratory capacity when cultured with FFA, whereas female macrophages failed to migrate. Therefore, both hyperlipidemia and hyperleptinemia contribute to male macrophage-specific migration because increased FFA induce leptin receptors, whereas higher leptin causes migration. Our results may explain sex differences in obesity-mediated disorders caused by macrophage infiltration.
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Affiliation(s)
- Kuan-Hui Ethan Chen
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521
| | - Nancy M Lainez
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521
| | - Djurdjica Coss
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA 92521
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27
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Haigh JL, New LE, Filippi BM. Mitochondrial Dynamics in the Brain Are Associated With Feeding, Glucose Homeostasis, and Whole-Body Metabolism. Front Endocrinol (Lausanne) 2020; 11:580879. [PMID: 33240218 PMCID: PMC7680879 DOI: 10.3389/fendo.2020.580879] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
The brain is responsible for maintaining whole-body energy homeostasis by changing energy input and availability. The hypothalamus and dorsal vagal complex (DVC) are the primary sites of metabolic control, able to sense both hormones and nutrients and adapt metabolism accordingly. The mitochondria respond to the level of nutrient availability by fusion or fission to maintain energy homeostasis; however, these processes can be disrupted by metabolic diseases including obesity and type II diabetes (T2D). Mitochondrial dynamics are crucial in the development and maintenance of obesity and T2D, playing a role in the control of glucose homeostasis and whole-body metabolism across neurons and glia in the hypothalamus and DVC.
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Affiliation(s)
| | | | - Beatrice M. Filippi
- Faculty of Biological Sciences, School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
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28
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Miyamoto JÉ, Reginato A, Portovedo M, Dos Santos RM, Stahl MA, Le Stunff H, Latorraca MQ, de Barros Reis MA, Arantes VC, Doneda DL, Ignacio-Souza LM, Torsoni AS, Grimaldi R, Ribeiro APB, Torsoni MA, Milanski M. Interesterified palm oil impairs glucose homeostasis and induces deleterious effects in liver of Swiss mice. Metabolism 2020; 112:154350. [PMID: 32910938 DOI: 10.1016/j.metabol.2020.154350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/30/2020] [Accepted: 08/30/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Interesterified fats have largely replaced the partially hydrogenated oils which are the main dietary source of trans fat in industrialized food. This process promotes a random rearrangement of the native fatty acids and the results are different triacylglycerol (TAG) molecules without generating trans isomers. The role of interesterified fats in metabolism remains unclear. We evaluated metabolic parameters, glucose homeostasis and inflammatory markers in mice fed with normocaloric and normolipidic diets or hypercaloric and high-fat diet enriched with interesterified palm oil. METHODS Male Swiss mice were randomly divided into four experimental groups and submitted to either normolipidic palm oil diet (PO), normolipidic interesterified palm oil diet (IPO), palm oil high-fat diet (POHF) or interesterified palm oil high-fat diet (IPOHF) during an 8 weeks period. RESULTS When compared to the PO group, IPO group presented higher body mass, hyperglycemia, impaired glucose tolerance, evidence of insulin resistance and greater production of glucose in basal state during pyruvate in situ assay. We also observed higher protein content of hepatic PEPCK and increased cytokine mRNA expression in the IPO group when compared to PO. Interestingly, IPO group showed similar parameters to POHF and IPOHF groups. CONCLUSION The results indicate that substitution of palm oil for interesterified palm oil even on normocaloric and normolipidic diet could negatively modulate metabolic parameters and glucose homeostasis as well as cytokine gene expression in the liver and white adipose tissue. This data support concerns about the effects of interesterified fats on health and could promote further discussions about the safety of the utilization of this unnatural fat by food industry.
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Affiliation(s)
- Josiane Érica Miyamoto
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | - Andressa Reginato
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | - Mariana Portovedo
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | - Raísa Magno Dos Santos
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | | | - Hervé Le Stunff
- Paris-Saclay Institute of Neuroscience, CNRS UMR 9197, Université Paris-Sud, University Paris Saclay, Orsay, France
| | | | | | | | - Diego Luiz Doneda
- Physiology Laboratory, Department of Basic Health Sciences, Federal University of Mato Grosso, Cuiabá, Brazil
| | - Leticia Martins Ignacio-Souza
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | - Adriana Souza Torsoni
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | - Renato Grimaldi
- School of Food Engineering, University of Campinas, UNICAMP, Campinas, Brazil
| | | | - Marcio Alberto Torsoni
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil
| | - Marciane Milanski
- School of Applied Sciences, University of Campinas, UNICAMP, Limeira, Brazil; Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas, Brazil.
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Abstract
Nutrient content and nutrient timing are considered key regulators of human health and a variety of diseases and involve complex interactions with the mucosal immune system. In particular, the innate immune system is emerging as an important signaling hub that modulates the response to nutritional signals, in part via signaling through the gut microbiota. In this review we elucidate emerging evidence that interactions between innate immunity and diet affect human metabolic health and disease, including cardiometabolic disorders, allergic diseases, autoimmune disorders, infections, and cancers. Furthermore, we discuss the potential modulatory effects of the gut microbiota on interactions between the immune system and nutrition in health and disease, namely how it relays nutritional signals to the innate immune system under specific physiological contexts. Finally, we identify key open questions and challenges to comprehensively understanding the intersection between nutrition and innate immunity and how potential nutritional, immune, and microbial therapeutics may be developed into promising future avenues of precision treatment.
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Affiliation(s)
- Samuel Philip Nobs
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel;
| | - Niv Zmora
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel;
- Research Center for Digestive Tract and Liver Diseases and Internal Medicine Division, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6423906, Israel
| | - Eran Elinav
- Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel;
- Cancer-Microbiome Research Division, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany;
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30
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Bitsi S. The chemokine CXCL16 can rescue the defects in insulin signaling and sensitivity caused by palmitate in C2C12 myotubes. Cytokine 2020; 133:155154. [PMID: 32535333 DOI: 10.1016/j.cyto.2020.155154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/13/2020] [Accepted: 06/03/2020] [Indexed: 11/25/2022]
Abstract
In obesity, macrophages infiltrate peripheral tissues and secrete pro-inflammatory cytokines that impact local insulin sensitivity. Lipopolysaccharide (LPS) and the saturated fatty acid (FA) palmitate polarise macrophages towards a pro-inflammatory phenotype in vitro and indirectly cause insulin resistance (IR) in myotubes. In contrast, unsaturated FAs confer an anti-inflammatory phenotype and counteract the actions of palmitate. To explore paracrine mechanisms of interest, J774 macrophages were exposed to palmitate ± palmitoleate or control medium and the conditioned media generated were screened using a cytokine array. Of the 62 cytokines examined, 8 were significantly differentially expressed following FA treatments. Notably, CXCL16 secretion was downregulated by palmitate. In follow-up experiments using ELISAs, this downregulation was confirmed and reversed by simultaneous addition of palmitoleate or oleate, while LPS also diminished CXCL16 secretion. To dissect potential effects of CXCL16, C2C12 myotubes were treated with palmitate to induce IR, recombinant soluble CXCL16 (sCXCL16), combined treatment, or control medium. Palmitate caused the expected reduction of insulin-stimulated Akt activation and glycogen synthesis, whereas simultaneous treatment with sCXCL16 attenuated these effects. These data indicate a putative role for CXCL16 in preservation of Akt activation and insulin signaling in the context of chronic low-grade inflammation in skeletal muscle.
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Affiliation(s)
- Stavroula Bitsi
- Comparative Biomedical Sciences Department, Royal Veterinary College, London NW1 0TU, United Kingdom.
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31
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González F, Considine RV, Abdelhadi OA, Acton AJ. Inflammation Triggered by Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2020; 105:5788228. [PMID: 32140727 PMCID: PMC7150616 DOI: 10.1210/clinem/dgaa108] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/29/2020] [Accepted: 02/28/2020] [Indexed: 12/18/2022]
Abstract
CONTEXT Inflammation and insulin resistance are often present in polycystic ovary syndrome (PCOS). OBJECTIVE We determined the effect of saturated fat ingestion on mononuclear cell (MNC) nuclear factor-κB (NFκB) activation; NFκB, inhibitory-κBα (IκBα), and tumor necrosis factor-α (TNFα) gene expression; and circulating C-reactive protein (CRP) in women with PCOS. DESIGN Cross-sectional study. SETTING Academic medical center. PATIENTS Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity). MAIN OUTCOME MEASURES Activated NFκB, NFκB heterodimer subunits, IκBα and TNFα messenger ribonucleic acid content and NFκB p65 and IκBα protein content were quantified in mononuclear cells (MNC), and CRP was measured in plasma from blood drawn fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from oral glucose tolerance testing (ISOGTT). Androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. RESULTS In response to saturated fat ingestion, women with PCOS regardless of weight class exhibited lipid-induced increases in activated NFκB, NFκB, and TNFα gene expression and plasma CRP and decreases in IκBα protein compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. Lipid-stimulated NFκB activation was negatively correlated with ISOGTT, and positively correlated with HCG-stimulated androgen secretion. CONCLUSION In PCOS, increases in NFκB activation and circulating CRP and decreases in IκBα protein following saturated fat ingestion are independent of obesity. Circulating MNC and excess adipose tissue are separate and distinct contributors to inflammation in this disorder.
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Affiliation(s)
- Frank González
- Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, IL
- Correspondence and Reprint Requests: Frank González, MD, University of Illinois at Chicago College of Medicine, Department of Obstetrics and Gynecology, 820 S. Wood Street m/c 808, CSN 276, Chicago, IL 60612. E-mail:
| | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ola A Abdelhadi
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN
| | - Anthony J Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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32
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Honma K, Machida C, Mochizuki K, Goda T. Glucose and TNF enhance expression of TNF and IL1B, and histone H3 acetylation and K4/K36 methylation, in juvenile macrophage cells. Gene 2020; 763S:100034. [PMID: 32550560 PMCID: PMC7285958 DOI: 10.1016/j.gene.2020.100034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 12/14/2022]
Abstract
Hyperglycemia activates innate leukocytes such as monocytes and induces pro-inflammatory cytokine expression, resulting in increased monocyte adhesion to aortic endothelial cells. In this study, we investigated whether high glucose and/or tumor necrosis factor (TNF) would enhance pro-inflammatory cytokine expression of tumor necrosis factor (TNF) and interleukin (IL)-1β (IL1B) by altering histone modifications in U937, a juvenile macrophage cell line. The mRNA levels of TNF and IL1B in U937 cells were significantly affected by glucose concentration and TNF treatment. Mono-methylated histone H3K4 signals around TNF and IL1B were lower in cells treated with high glucose compared with low glucose. Conversely, tri-methylated histone H3K4 and H3K36 signals were higher in cells treated with high glucose compared with low glucose. TNF treatment of U937 cells cultured in high glucose enhanced histone H3K36 tri-methylation, particularly around the gene regions of TNF and IL1B. Histone acetylation was induced by treatment with TNF in high-glucose medium. The induction of acetylation and tri-methylation of K4 and K36 of histone H3 around TNF and IL1B by treatment with high glucose and/or TNF was positively associated with the induction of these genes in juvenile macrophage U937 cells.
Culture with high glucose induced TNF and IL1B expression in U937 cells. TNF treatment enhanced high glucose inducible TNF expression in U937 cells. H3K4me3 around TNF and IL1B was induced by high glucose treatment. TNF treatment enhanced H3Ac in the gene body region of TNF and IL1B.
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Affiliation(s)
- Kazue Honma
- Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Chie Machida
- Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Kazuki Mochizuki
- Laboratory of Food and Nutritional Sciences, Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi, Japan
| | - Toshinao Goda
- Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
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Zatterale F, Longo M, Naderi J, Raciti GA, Desiderio A, Miele C, Beguinot F. Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front Physiol 2020; 10:1607. [PMID: 32063863 PMCID: PMC7000657 DOI: 10.3389/fphys.2019.01607] [Citation(s) in RCA: 585] [Impact Index Per Article: 117.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022] Open
Abstract
Obesity is one of the major health burdens of the 21st century as it contributes to the growing prevalence of its related comorbidities, including insulin resistance and type 2 diabetes. Growing evidence suggests a critical role for overnutrition in the development of low-grade inflammation. Specifically, chronic inflammation in adipose tissue is considered a crucial risk factor for the development of insulin resistance and type 2 diabetes in obese individuals. The triggers for adipose tissue inflammation are still poorly defined. However, obesity-induced adipose tissue expansion provides a plethora of intrinsic signals (e.g., adipocyte death, hypoxia, and mechanical stress) capable of initiating the inflammatory response. Immune dysregulation in adipose tissue of obese subjects results in a chronic low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immune cells. Macrophages are the most abundant innate immune cells infiltrating and accumulating into adipose tissue of obese individuals; they constitute up to 40% of all adipose tissue cells in obesity. In obesity, adipose tissue macrophages are polarized into pro-inflammatory M1 macrophages and secrete many pro-inflammatory cytokines capable of impairing insulin signaling, therefore promoting the progression of insulin resistance. Besides macrophages, many other immune cells (e.g., dendritic cells, mast cells, neutrophils, B cells, and T cells) reside in adipose tissue during obesity, playing a key role in the development of adipose tissue inflammation and insulin resistance. The association of obesity, adipose tissue inflammation, and metabolic diseases makes inflammatory pathways an appealing target for the treatment of obesity-related metabolic complications. In this review, we summarize the molecular mechanisms responsible for the obesity-induced adipose tissue inflammation and progression toward obesity-associated comorbidities and highlight the current therapeutic strategies.
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Affiliation(s)
- Federica Zatterale
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Michele Longo
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Jamal Naderi
- URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy.,Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Caserta, Italy
| | - Gregory Alexander Raciti
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Antonella Desiderio
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Claudia Miele
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
| | - Francesco Beguinot
- Department of Translational Medicine, University of Naples Federico II, Naples, Italy.,URT Genomic of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy
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Cui C, Driscoll RK, Piao Y, Chia CW, Gorospe M, Ferrucci L. Skewed macrophage polarization in aging skeletal muscle. Aging Cell 2019; 18:e13032. [PMID: 31478346 PMCID: PMC6826159 DOI: 10.1111/acel.13032] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 07/02/2019] [Accepted: 08/05/2019] [Indexed: 12/15/2022] Open
Abstract
Skeletal muscle aging is a major cause of disability and frailty in the elderly. The progressive impairment of skeletal muscle function with aging was recently linked to a disequilibrium between damage and repair. Macrophages participate in muscle tissue repair, first as pro-inflammatory M1 subtype and then as anti-inflammatory M2 subtype. However, information on the presence of macrophages in skeletal muscle is still sporadic and the effect of aging on macrophage phenotype remains unknown. In this study, we sought to characterize the polarization status of macrophages in skeletal muscle of persons across a wide range of ages. We found that most macrophages in human skeletal muscle are M2, and that this number increased with advancing age. On the contrary, M1 macrophages declined with aging, making the total number of macrophages invariant with older age. Notably, M2 macrophages colocalized with increasing intermuscular adipose tissue (IMAT) in aging skeletal muscle. Similarly, aged BALB/c mice showed increased IMAT and M2 macrophages in skeletal muscle, accompanied by slightly increased collagen protein production. Collectively, we report that polarization of macrophages to the major M2 subtype is associated with IMAT and propose that increased M2 in aged skeletal muscle may impact upon muscle metabolism associated with aging.
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Affiliation(s)
- Chang‐Yi Cui
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program National Institutes of Health Baltimore MD USA
| | - Riley K. Driscoll
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program National Institutes of Health Baltimore MD USA
| | - Yulan Piao
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program National Institutes of Health Baltimore MD USA
| | - Chee W. Chia
- Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program National Institutes of Health Baltimore MD USA
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program National Institutes of Health Baltimore MD USA
| | - Luigi Ferrucci
- Translational Gerontology Branch, National Institute on Aging Intramural Research Program National Institutes of Health Baltimore MD USA
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miR-1185-1 and miR-548q Are Biomarkers of Response to Weight Loss and Regulate the Expression of GSK3B. Cells 2019; 8:cells8121548. [PMID: 31801236 PMCID: PMC6953011 DOI: 10.3390/cells8121548] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 11/26/2019] [Accepted: 11/27/2019] [Indexed: 12/12/2022] Open
Abstract
The aim of the present investigation was to identify putative miRNAs involved in the response to weight loss. Reverse-transcribed RNA isolated from white blood cells (WBCs) of a subpopulation from the Reduction of the Metabolic Syndrome in Navarra-Spain (RESMENA-S) study (low-responders (LR) and high-responders (HR)) was hybridized in a gene expression microarray. Moreover, miRNAs were sequenced by miRNA-Seq. It was found that miR-548q and miR-1185-1 were overexpressed in HR, both in the microarray and in the miRNA-Seq. A bioinformatic prediction of putative target genes of the selected miRNAs found that GSK3B, a putative target for miR-548q and miR-1185-1, was downregulated in HR. Particular 3′-UTR binding regions of GSK3B were cloned downstream of the firefly luciferase gene. HEK-293T cells were co-transfected with either 0.25 μg of empty pmiR-GLO or pmiR-GLO-548q-3′-UTR/pmiR-GLO-1185-1-3′-UTR, and 7.5 pmol of miR-548q/miR-1185-1 mimics, demonstrating that miR-1185-1 bound to the 3′-UTR region of GSK3B. THP-1 cells were transfected with either 20/40 nM of miR-548q/miR-1185-1 mimics, evidencing that miR-1185-1inhibited the expression of the gene when transfected at doses of 20/40 nM, whereas miR-548q inhibited GSK3B expression at a dose of 40 nM. As a conclusion, miR-548q and miR-1185-1 levels in WBCs are biomarkers of response to weight-loss diets and could be involved in the regulation of the proinflammatory gene GSK3B.
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Rudrapatna S, Bhatt M, Wang KW, Bierbrier R, Wang PW, Banfield L, Elsheikh W, Sims ED, Peterson D, Thabane L, Tarnopolsky MA, Steinberg GR, Samaan MC. Obesity and muscle-macrophage crosstalk in humans and mice: A systematic review. Obes Rev 2019; 20:1572-1596. [PMID: 31410961 DOI: 10.1111/obr.12922] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/08/2019] [Accepted: 07/09/2019] [Indexed: 12/12/2022]
Abstract
Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes (T2D). The role of the immune system in skeletal muscle (SM) inflammation and insulin sensitivity is not yet well characterized. As SM IR is an important determinant of glycaemia, it is critical that the muscle-immune phenotype is mapped to help design interventions to target T2D. This systematic review synthesized the evidence for SM macrophage content and phenotype in humans and murine models of obesity, and the association of muscle macrophage content and phenotype with IR. Results were synthesized narratively, as we were unable to conduct a meta-analysis. We included 28 studies (n=10 human, n=18 murine), and all studies detected macrophage markers in SM. Macrophage content was positively associated with IR. In humans and mice, there was variability in muscle macrophage content and phenotype in obesity. Overall certainty in the evidence was low due to heterogeneity in detection methods and incompleteness of data reporting. Macrophages are detected in human and murine SM in obesity and a positive association between macrophage content and IR is noted; however, the standardization of markers, detection methods, and reporting of study details is warranted to accurately characterize macrophages and improve the potential for creating specific and targeted immune-based therapies in obesity.
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Affiliation(s)
- Srikesh Rudrapatna
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada
| | - Meha Bhatt
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Kuan-Wen Wang
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada
| | - Rachel Bierbrier
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada.,Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Pei-Wen Wang
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada
| | - Laura Banfield
- Health Science Library, McMaster University, Hamilton, Ontario, Canada
| | - Wagdi Elsheikh
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
| | - E Danielle Sims
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada
| | - Devin Peterson
- Division of Orthopedics, Department of Pediatric Surgery, McMaster University, Hamilton, Ontario, Canada
| | - Lehana Thabane
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.,Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada.,Centre for Evaluation of Medicines, Hamilton, Ontario, Canada.,Biostatistics Init, St Joseph's Healthcare-Hamilton, Hamilton, Ontario, Canada
| | - Mark A Tarnopolsky
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | | | - M Constantine Samaan
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.,Division of Pediatric Endocrinology, McMaster Children's Hospital, Hamilton, Ontario, Canada.,Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
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González F, Considine RV, Abdelhadi OA, Acton AJ. Oxidative Stress in Response to Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2019; 104:5360-5371. [PMID: 31298704 PMCID: PMC6773460 DOI: 10.1210/jc.2019-00987] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 07/08/2019] [Indexed: 12/29/2022]
Abstract
CONTEXT Oxidative stress and insulin resistance are often present in polycystic ovary syndrome (PCOS). OBJECTIVE We determined the effect of saturated fat ingestion on leukocytic reactive oxygen species (ROS) generation, p47phox expression, and circulating thiobarbituric acid-reactive substances (TBARS) in women with PCOS. DESIGN Cross-sectional study. SETTING Academic medical center. PATIENTS Twenty women of reproductive age with PCOS (10 lean, 10 with obesity) and 19 ovulatory control subjects (10 lean, 9 with obesity). MAIN OUTCOME MEASURES ROS generation and p47phox mRNA and protein content were quantified in leukocytes, and TBARS was measured in plasma from blood drawn while the subjects were fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while the subjects were fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. RESULTS Regardless of weight class, women with PCOS exhibited lipid-induced increases in leukocytic ROS generation and p47phox mRNA and protein content as well as plasma TBARS compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The ROS generation, p47phox, and TBARS responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. CONCLUSION In PCOS, increases in ROS generation, p47phox gene expression, and circulating TBARS in response to saturated fat ingestion are independent of obesity. Circulating mononuclear cells and excess adipose tissue are separate and distinct contributors to oxidative stress in this disorder.
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Affiliation(s)
- Frank González
- Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, Illinois
- Correspondence and Reprint Requests: Frank González, MD, University of Illinois at Chicago College of Medicine, Department of Obstetrics and Gynecology, 820 South Wood Street m/c 808, CSN W233, Chicago, Illinois 60612. E-mail:
| | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ola A Abdelhadi
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Anthony J Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Sadeghi A, Shabani M, Alizadeh S, Meshkani R. Interplay between oxidative stress and autophagy function and its role in inflammatory cytokine expression induced by palmitate in skeletal muscle cells. Cytokine 2019; 125:154835. [PMID: 31479873 DOI: 10.1016/j.cyto.2019.154835] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/05/2019] [Accepted: 08/27/2019] [Indexed: 02/07/2023]
Abstract
Autophagy is a cellular process activated in response to various stresses such as starvation, hypoxia, and oxidative stress. Autophagy was reported to modulate the inflammatory pathways. However, whether autophagy is involved in regulation of palmitate-induced inflammation of skeletal muscle C2C12 cells is still unknown. The present study aimed to investigate the autophagic pathway in C2C12 cells treated with 0.5 mM palmitate. The results showed that the protein levels of LC3BII and P62 were increased in C2C12 cells after 12 h palmitate treatment. Besides, inhibition of autophagy by chloroquine or 3-methyladenin and its activation by rapamycin were associated with elevated mRNA and protein levels of IL-6 and TNF-α inflammatory cytokines in C2C12 cells. To study the mechanism by which autophagy impairment leads to activation of inflammatory responses, reactive oxygen species (ROS) levels in palmitate-treated cells were measured. The results showed that while palmitate stimulates ROS production, pretreatment of the cells with N-acetyl cysteine (NAC), a ROS scavenger, reduced inflammatory responses and also improved LC3-BII and P62 protein in the C2C12 cells exposed to palmitate. These findings suggest that palmitate-induced defect of autophagic flux leads to elevated inflammatory cytokine expression in the skeletal muscle cells by regulating the oxidative stress process.
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Affiliation(s)
- Asie Sadeghi
- Student Research Committee, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Maryam Shabani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Alizadeh
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Tsalamandris S, Antonopoulos AS, Oikonomou E, Papamikroulis GA, Vogiatzi G, Papaioannou S, Deftereos S, Tousoulis D. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur Cardiol 2019; 14:50-59. [PMID: 31131037 PMCID: PMC6523054 DOI: 10.15420/ecr.2018.33.1] [Citation(s) in RCA: 772] [Impact Index Per Article: 128.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.
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Affiliation(s)
- Sotirios Tsalamandris
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Alexios S Antonopoulos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Evangelos Oikonomou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - George-Aggelos Papamikroulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Georgia Vogiatzi
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyridon Papaioannou
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Spyros Deftereos
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
| | - Dimitris Tousoulis
- First Cardiology Clinic, Hippokration General Hospital, National and Kapodistrian University of Athens, School of Medicine Athens, Greece
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Mannino MH, Patel RS, Eccardt AM, Perez Magnelli RA, Robinson CLC, Janowiak BE, Warren DE, Fisher JS. Myoglobin as a versatile peroxidase: Implications for a more important role for vertebrate striated muscle in antioxidant defense. Comp Biochem Physiol B Biochem Mol Biol 2019; 234:9-17. [PMID: 31051268 DOI: 10.1016/j.cbpb.2019.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/29/2019] [Accepted: 04/23/2019] [Indexed: 12/17/2022]
Abstract
Myoglobins (Mb) are ubiquitous proteins found in striated muscle of nearly all vertebrate taxa. Although their function is most commonly associated with facilitating oxygen storage and diffusion, Mb has also been implicated in cellular antioxidant defense. The oxidized (Fe3+) form of Mb (metMB) can react with hydrogen peroxide (H2O2) to produce ferrylMb. FerrylMb can be reduced back to metMb for another round of reaction with H2O2. In the present study, we have shown that horse skeletal muscle Mb displays peroxidase activity using 2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) and 3,3',5,5'-tetramethylbenzidine (TMB) as reducing substrates, as well as the biologically-relevant substrates NADH/NADPH, ascorbate, caffeic acid, and resveratrol. We have also shown that ferrylMb can be reduced by both ethanol and acetaldehyde, which are known to accumulate in some vertebrate tissues under anaerobic conditions, such as anoxic goldfish and crucian carp, implying a potential mechanism for ethanol detoxification in striated muscle. We found that metMb peroxidase activity is pH-dependent, increasing as pH decreases from 7.4 to 6.1, which is biologically relevant to anaerobic vertebrate muscle when incurring intracellular lactic acidosis. Finally, we found that metMb reacts with hypochlorite in a heme-dependent fashion, indicating that Mb could play a role in hypochlorite detoxification. Taken together, these data suggest that Mb peroxidase activity might be an important antioxidant mechanism in vertebrate cardiac and skeletal muscle under a variety of physiological conditions, such as those that might occur in contracting skeletal muscle or during hypoxia.
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41
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Garneau L, Aguer C. Role of myokines in the development of skeletal muscle insulin resistance and related metabolic defects in type 2 diabetes. DIABETES & METABOLISM 2019; 45:505-516. [PMID: 30844447 DOI: 10.1016/j.diabet.2019.02.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 02/04/2019] [Accepted: 02/25/2019] [Indexed: 12/20/2022]
Abstract
Due to its mass, skeletal muscle is the major site of glucose uptake and an important tissue in the development of type 2 diabetes (T2D). Muscles of patients with T2D are affected with insulin resistance and mitochondrial dysfunction, which result in impaired glucose and fatty acid metabolism. A well-established method of managing the muscle metabolic defects occurring in T2D is physical exercise. During exercise, muscles contract and secrete factors called myokines which can act in an autocrine/paracrine fashion to improve muscle energy metabolism. In patients with T2D, plasma levels as well as muscle levels (mRNA and protein) of some myokines are upregulated, while others are downregulated. The signalling pathways of certain myokines are also altered in skeletal muscle of patients with T2D. Taken together, these findings suggest that myokine secretion is an important factor contributing to the development of muscle metabolic defects during T2D. It is also of interest considering that lack of physical activity is closely linked to the occurrence of this disease. The causal relationships between sedentary behavior, factors secreted by skeletal muscle at rest and during contraction and the development of T2D remain to be elucidated. Many myokines shown to influence muscle energy metabolism still have not been characterized in the context of T2D in skeletal muscle specifically. The purpose of this review is to highlight what is known and what remains to be determined regarding myokine secretion in patients with T2D to uncover potential therapeutic targets for the management of this disease.
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Affiliation(s)
- L Garneau
- University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON, K1H 8M5, Canada; Institut du Savoir Montfort - recherche, Ottawa, ON, K1K 0T2, Canada
| | - C Aguer
- University of Ottawa, Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, Ottawa, ON, K1H 8M5, Canada; Institut du Savoir Montfort - recherche, Ottawa, ON, K1K 0T2, Canada.
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Schneider SM, Sridhar V, Bettis AK, Heath-Barnett H, Balog-Alvarez CJ, Guo LJ, Johnson R, Jaques S, Vitha S, Glowcwski AC, Kornegay JN, Nghiem PP. Glucose Metabolism as a Pre-clinical Biomarker for the Golden Retriever Model of Duchenne Muscular Dystrophy. Mol Imaging Biol 2019; 20:780-788. [PMID: 29508262 PMCID: PMC6153676 DOI: 10.1007/s11307-018-1174-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Purpose Metabolic dysfunction in Duchenne muscular dystrophy (DMD) is characterized by reduced glycolytic and oxidative enzymes, decreased and abnormal mitochondria, decreased ATP, and increased oxidative stress. We analyzed glucose metabolism as a potential disease biomarker in the genetically homologous golden retriever muscular dystrophy (GRMD) dog with molecular, biochemical, and in vivo imaging. Procedures Pelvic limb skeletal muscle and left ventricle tissue from the heart were analyzed by mRNA profiling, qPCR, western blotting, and immunofluorescence microscopy for the primary glucose transporter (GLUT4). Physiologic glucose handling was measured by fasting glucose tolerance test (GTT), insulin levels, and skeletal and cardiac positron emission tomography/X-ray computed tomography (PET/CT) using the glucose analog 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). Results MRNA profiles showed decreased GLUT4 in the cranial sartorius (CS), vastus lateralis (VL), and long digital extensor (LDE) of GRMD vs. normal dogs. QPCR confirmed GLUT4 downregulation but increased hexokinase-1. GLUT4 protein levels were not different in the CS, VL, or left ventricle but increased in the LDE of GRMD vs. normal. Microscopy revealed diffuse membrane expression of GLUT4 in GRMD skeletal but not cardiac muscle. GTT showed higher basal glucose and insulin in GRMD but rapid tissue glucose uptake at 5 min post-dextrose injection in GRMD vs. normal/carrier dogs. PET/ CT with [18F]FDG and simultaneous insulin stimulation showed a significant increase (p = 0.03) in mean standard uptake values (SUV) in GRMD skeletal muscle but not pelvic fat at 5 min post-[18F]FDG /insulin injection. Conversely, mean cardiac SUV was lower in GRMD than carrier/normal (p < 0.01). Conclusions Altered glucose metabolism in skeletal and cardiac muscle of GRMD dogs can be monitored with molecular, biochemical, and in vivo imaging studies and potentially utilized as a biomarker for disease progression and therapeutic response. Electronic supplementary material The online version of this article (10.1007/s11307-018-1174-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sarah Morar Schneider
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA
| | - Vidya Sridhar
- Texas A&M Institute for Preclinical Studies, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA
| | - Amanda K Bettis
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA
| | - Heather Heath-Barnett
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA
| | - Cynthia J Balog-Alvarez
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA
| | - Lee-Jae Guo
- Texas A&M Institute for Preclinical Studies, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA.,Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA
| | - Rachel Johnson
- Texas A&M Institute for Preclinical Studies, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA
| | - Scott Jaques
- Texas A&M Veterinary Diagnostic Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA
| | - Stanislav Vitha
- Microscopy Imaging Center, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA
| | - Alan C Glowcwski
- Texas A&M Institute for Preclinical Studies, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843-4458, USA
| | - Joe N Kornegay
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA
| | - Peter P Nghiem
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, 77843-4458, USA.
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Walton RG, Kosmac K, Mula J, Fry CS, Peck BD, Groshong JS, Finlin BS, Zhu B, Kern PA, Peterson CA. Human skeletal muscle macrophages increase following cycle training and are associated with adaptations that may facilitate growth. Sci Rep 2019; 9:969. [PMID: 30700754 PMCID: PMC6353900 DOI: 10.1038/s41598-018-37187-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 11/23/2018] [Indexed: 12/26/2022] Open
Abstract
Skeletal muscle macrophages participate in repair and regeneration following injury. However, their role in physiological adaptations to exercise is unexplored. We determined whether endurance exercise training (EET) alters macrophage content and characteristics in response to resistance exercise (RE), and whether macrophages are associated with other exercise adaptations. Subjects provided vastus lateralis biopsies before and after one bout of RE, after 12 weeks of EET (cycling), and after a final bout of RE. M2 macrophages (CD11b+/CD206+) did not increase with RE, but increased in response to EET (P < 0.01). Increases in M2 macrophages were positively correlated with fiber hypertrophy (r = 0.49) and satellite cells (r = 0.47). M2c macrophages (CD206+/CD163+) also increased following EET (P < 0.001), and were associated with fiber hypertrophy (r = 0.64). Gene expression was quantified using NanoString. Following EET, the change in M2 macrophages was positively associated with changes in HGF, IGF1, and extracellular matrix genes. EET decreased expression of IL6 (P < 0.05), C/EBPβ (P < 0.01), and MuRF (P < 0.05), and increased expression of IL-4 (P < 0.01), TNFα (P < 0.01) and the TWEAK receptor FN14 (P < 0.05). The change in FN14 gene expression was inversely associated with changes in C/EBPβ (r = -0.58) and MuRF (r = -0.46) following EET. In cultured human myotubes, siRNA inhibition of FN14 increased expression of C/EBPβ (P < 0.05) and MuRF (P < 0.05). Our data suggest that macrophages contribute to the muscle response to EET, potentially including modulation of TWEAK-FN14 signaling.
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Affiliation(s)
- R Grace Walton
- College of Health Sciences and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA.
| | - Kate Kosmac
- College of Health Sciences and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Jyothi Mula
- College of Health Sciences and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Christopher S Fry
- Deptartment of Nutrition & Metabolism, School of Health Professions, University of Texas Medical Branch at Galveston, Galveston, Texas, USA
| | - Bailey D Peck
- College of Health Sciences and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA
| | - Jason S Groshong
- Department of Health Professions, University of Central Florida, Orlando, Florida, USA
| | - Brian S Finlin
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky, USA
| | - Beibei Zhu
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky, USA
| | - Philip A Kern
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky, USA
| | - Charlotte A Peterson
- College of Health Sciences and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky, USA
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Pothuraju R, Rachagani S, Junker WM, Chaudhary S, Saraswathi V, Kaur S, Batra SK. Pancreatic cancer associated with obesity and diabetes: an alternative approach for its targeting. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:319. [PMID: 30567565 PMCID: PMC6299603 DOI: 10.1186/s13046-018-0963-4] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure. MAIN BODY Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different molecular mechanisms. Deep understanding of these factors and causal relationship between factors and altered signaling pathways will facilitate deconvolution of disease complexity as well as lead to development of novel therapies. In the present review, we focuses on the interplay between adipocytokines, gut microbiota, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase affected by metabolic alteration and pancreatic tumor progression. CONCLUSIONS Metabolic diseases, such as obesity and T2DM, contribute PC development through altered metabolic pathways. Delineating key players in oncogenic development in pancreas due to metabolic disorder could be a beneficial strategy to combat cancers associated with metabolic diseases in particular, PC.
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Affiliation(s)
- Ramesh Pothuraju
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Satyanarayana Rachagani
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Wade M Junker
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.,Sanguine Diagnostics and Therapeutics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sanjib Chaudhary
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Viswanathan Saraswathi
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sukhwinder Kaur
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. .,Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. .,Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
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Can obesity-induced inflammation in skeletal muscle and intramuscular adipose tissue accurately detect liver fibrosis? JOURNAL OF MUSCULOSKELETAL & NEURONAL INTERACTIONS 2018; 18:509-524. [PMID: 30511955 PMCID: PMC6313048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVES Obesity is characterized by a chronic, low grade, systemic inflammation. However, little is known about the role of skeletal muscle, which represents an active metabolic organ whose activities need to be determined. The purpose of our study was to detect relationships between skeletal muscle and adipose tissue inflammation with nonalcoholic fatty liver disease (NAFLD) and diabetes, as well as to explore associations with clinicopathological parameters. METHODS Our study population consisted of 50 morbidly obese patients undergoing planned bariatric surgery. Biopsies were taken from visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), skeletal muscle (SM), extramyocellular adipose tissue (EMAT) and liver. The expression of CD68 and CD3 was assessed by immunohistochemistry. RESULTS Our findings suggest a complex inter- and intra-tissue co-expression network that links obesity-induced inflammation in adipose depots and skeletal muscle with NAFLD. A novel finding is the intricate cross-talk between SM, EMAT and the liver and the probable correlation between SM, EMAT inflammation and the presence of liver fibrosis. CONCLUSIONS Although the mechanisms of obesity-induced inflammation and its association with NAFLD and liver fibrosis are incompletely understood, our findings indicate an extensive and complex tissue network that needs to be further investigated.
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Yoshinaga T, Niou T, Niihara T, Kajiya Y, Hori E, Tomiyoshi A, Tokudome E, Nishimata H, Takei T, Yoshida M. Angiopoietin-like Protein 2 is a Useful Biomarker for Pancreatic Cancer that is Associated with Type 2 Diabetes Mellitus and Inflammation. J Cancer 2018; 9:4736-4741. [PMID: 30588259 PMCID: PMC6299393 DOI: 10.7150/jca.25404] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is one of the tumors with the worst prognosis, with the 5-year survival rate reported to be 6%. The number of patients suffering from pancreatic cancer in recent years has continued to increase dramatically. Carbohydrate antigen 19-9 is an established biomarker of pancreatic cancer, but it does not have sufficient ability to detect pancreatic cancer at an early stage. We focused on angiopoietin-like protein 2 (ANGPTL2), which has been reported to be related to chronic inflammation and Type 2 diabetes mellitus. In this study, whether ANGPTL2 can detect early pancreatic cancer was evaluated. It was found that the concentration of serum ANGPTL2 was significantly higher in pancreatic cancer patients and tumor stage 0-I patients than in healthy individuals (5.84 ± 1.82 ng/mL vs 3.61 ± 0.64 ng/mL; P < 0.001) (5.68 ± 0.79 ng/mL vs 3.61 ± 0.64 ng/mL; P = 0.010). In addition, the diagnostic capability of serum ANGPTL2 levels for pancreatic cancer was evaluated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) for ANGPTL2 was 0.906 (95% confidence interval (CI): 0.815-0.997; P < 0.001). To identify the risk factors for pancreatic cancer, multivariate regression models were used. Ten factors were included, and increasing age (odds ratio (OR), 1.318, 95% CI, 1.058-1.642; P = 0.014) and high ANGPTL2 levels (OR, 22.219, 95% CI, 1.962-251.659, P = 0.012) were found to be independent risk factors for pancreatic cancer, with ANGPTL2 having the strongest relationship. In addition, serum ANGPTL2 levels were strongly correlated with inflammatory markers, with blood sugar levels showing the strongest correlation with serum ANGPTL2 levels. In conclusion, this study suggested that an elevated serum ANGPTL2 level has the potential to be a biomarker capable of early detection of pancreatic cancer, and it was correlated with inflammation of the pancreas and the risk of developing diabetes mellitus.
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Affiliation(s)
- Takuma Yoshinaga
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | | | - Toru Niihara
- Gastroenterology, Nanpuh Hospital, Kagoshima, Japan
| | - Yoriko Kajiya
- Department of Radiology, Nanpuh Hospital, Kagoshima, Japan
| | - Emiko Hori
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | - Ayako Tomiyoshi
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | - Erena Tokudome
- Division of Clinical Application, Nanpuh Hospital, Kagoshima, Japan
| | | | - Takayuki Takei
- Department of Chemical Engineering, Graduate School of Science and Engineering, Kagoshima, Japan
| | - Masahiro Yoshida
- Department of Chemical Engineering, Graduate School of Science and Engineering, Kagoshima, Japan
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Harmon DB, Wu C, Dedousis N, Sipula IJ, Stefanovic-Racic M, Schoiswohl G, O'Donnell CP, Alonso LC, Kershaw EE, Kelley EE, O'Doherty RM. Adipose tissue-derived free fatty acids initiate myeloid cell accumulation in mouse liver in states of lipid oversupply. Am J Physiol Endocrinol Metab 2018; 315:E758-E770. [PMID: 30086648 PMCID: PMC6293173 DOI: 10.1152/ajpendo.00172.2018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Accumulation of myeloid cells in the liver, notably dendritic cells (DCs) and monocytes/macrophages (MCs), is a major component of the metainflammation of obesity. However, the mechanism(s) stimulating hepatic DC/MC infiltration remain ill defined. Herein, we addressed the hypothesis that adipose tissue (AT) free fatty acids (FFAs) play a central role in the initiation of hepatic DC/MC accumulation, using a number of mouse models of altered FFA supply to the liver. In two models of acute FFA elevation (lipid infusion and fasting) hepatic DC/MC and triglycerides (TGs) but not AT DC/MC were increased without altering plasma cytokines (PCs; TNFα and monocyte chemoattractant protein 1) and with variable effects on oxidative stress (OxS) markers. However, fasting in mice with profoundly reduced AT lipolysis (AT-specific deletion of adipose TG lipase; AAKO) failed to elevate liver DC/MC, TG, or PC, but liver OxS increased. Livers of obese AAKO mice that are known to be resistant to steatosis were similarly protected from inflammation. In high-fat feeding studies of 1, 3, 6, or 20-wk duration, liver DC/MC accumulation dissociated from PC and OxS but tracked with liver TGs. Furthermore, decreasing OxS by ~80% in obese mice failed to decrease liver DC/MC. Therefore, FFA and more specifically AT-derived FFA stimulate hepatic DC/MC accumulation, thus recapitulating the pathology of the obese liver. In a number of cases the effects of FFA can be dissociated from OxS and PC but match well with liver TG, a marker of FFA oversupply.
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Affiliation(s)
- Daniel B Harmon
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Chao Wu
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University , Changsha , China
| | - Nikolaos Dedousis
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Ian J Sipula
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Maja Stefanovic-Racic
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Gabriele Schoiswohl
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Christopher P O'Donnell
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
- Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Laura C Alonso
- Department of Medicine, Diabetes Division, University of Massachusetts , Worcester, Massachusetts
| | - Erin E Kershaw
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Eric E Kelley
- Department of Physiology and Pharmacology, West Virginia University , Morgantown, West Virginia
| | - Robert M O'Doherty
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh , Pittsburgh, Pennsylvania
- Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
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Wang X, Zhao D, Cui Y, Lu S, Gao D, Liu J. Proinflammatory macrophages impair skeletal muscle differentiation in obesity through secretion of tumor necrosis factor‐α via sustained activation of p38 mitogen‐activated protein kinase. J Cell Physiol 2018; 234:2566-2580. [DOI: 10.1002/jcp.27012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 06/25/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Xueqiang Wang
- Center for Mitochondrial Biology and MedicineThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong UniversityXi’an China
| | - Daina Zhao
- Center for Mitochondrial Biology and MedicineThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong UniversityXi’an China
| | - Yajuan Cui
- Center for Mitochondrial Biology and MedicineThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong UniversityXi’an China
| | - Shemin Lu
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Xi’an Jiaotong University Health Science CenterXi’an China
| | - Dan Gao
- Center for Mitochondrial Biology and MedicineThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong UniversityXi’an China
| | - Jiankang Liu
- Center for Mitochondrial Biology and MedicineThe Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong UniversityXi’an China
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Hernandez-Carretero A, Weber N, LaBarge SA, Peterka V, Doan NYT, Schenk S, Osborn O. Cysteine- and glycine-rich protein 3 regulates glucose homeostasis in skeletal muscle. Am J Physiol Endocrinol Metab 2018; 315:E267-E278. [PMID: 29634311 PMCID: PMC6139493 DOI: 10.1152/ajpendo.00435.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Skeletal muscle is the major site of postprandial peripheral glucose uptake, but in obesity-induced insulin-resistant states insulin-stimulated glucose disposal is markedly impaired. Despite the importance of skeletal muscle in regulating glucose homeostasis, the specific transcriptional changes associated with insulin-sensitive vs. -resistant states in muscle remain to be fully elucidated. Herein, using an RNA-seq approach we identified 20 genes differentially expressed in an insulin-resistant state in skeletal muscle, including cysteine- and glycine-rich protein 3 ( Csrp3), which was highly expressed in insulin-sensitive conditions but significantly reduced in the insulin-resistant state. CSRP3 has diverse functional roles including transcriptional regulation, signal transduction, and cytoskeletal organization, but its role in glucose homeostasis has yet to be explored. Thus, we investigated the role of CSRP3 in the development of obesity-induced insulin resistance in vivo. High-fat diet-fed CSRP3 knockout (KO) mice developed impaired glucose tolerance and insulin resistance as well as increased inflammation in skeletal muscle compared with wild-type (WT) mice. CSRP3-KO mice had significantly impaired insulin signaling, decreased GLUT4 translocation to the plasma membrane, and enhanced levels of phospho-PKCα in muscle, which all contributed to reduced insulin-stimulated glucose disposal in muscle in HFD-fed KO mice compared with WT mice. CSRP3 is a highly inducible protein and its expression is acutely increased after fasting. After 24h fasting, glucose tolerance was significantly improved in WT mice, but this effect was blunted in CSRP3-KO mice. In summary, we identify a novel role for Csrp3 expression in skeletal muscle in the development of obesity-induced insulin resistance.
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Affiliation(s)
| | - Natalie Weber
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Samuel A LaBarge
- Department of Orthopedic Surgery, University of California, San Diego, La Jolla, California
| | - Veronika Peterka
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Nhu Y Thi Doan
- Department of Medicine, University of California, San Diego, La Jolla, California
| | - Simon Schenk
- Department of Orthopedic Surgery, University of California, San Diego, La Jolla, California
| | - Olivia Osborn
- Department of Medicine, University of California, San Diego, La Jolla, California
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50
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Rahmani E, Akbarzadeh S, Broomand A, Torabi F, Motamed N, Zohrabi M. Serum Levels of Angiopoietin-Like Protein 2 and Obestatin in Iranian Women with Polycystic Ovary Syndrome and Normal Body Mass Index. J Clin Med 2018; 7:jcm7070159. [PMID: 29932432 PMCID: PMC6069096 DOI: 10.3390/jcm7070159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/16/2018] [Accepted: 06/17/2018] [Indexed: 11/16/2022] Open
Abstract
Background: Polycystic ovary syndrome (PCOS) is a common endocrine disease in women of reproduction age and a major cause of anovulatory infertility. Insulin resistance plays an important role in the development and durability of this disorder. ANGPTL2 is known as an inflammatory mediator derived from adipose tissue that links obesity to systemic insulin resistance, and obestatin has been identified as a hormone associated with insulin resistance that suppresses food reabsorption, inhibits gastric emptying and decreases weight gain. The aim of this study was to evaluate serum levels of ANGPTL2 and obestatin in PCOS women with normal body mass index (BMI). Methods: In this case-control study, 26 PCOS women based on the Rotterdam 2003 diagnostic criteria as the case group and 26 women with normal menstrual cycles as the control group were enrolled. Serum levels of ANGPTL2, obestatin, insulin and other hormone factors related with PCOS were measured by ELISA method and biochemical parameters were measured by an autoanalyzer. Data were analyzed by independent samples-T test, Chi Square, Correlation and a single sample Kolmogrov–Smirnov test using SPSS software, version 16. Results: There were no significant variations in the amount of ANGPTL2, obestatin, cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein, cholesterol, creatinine and dehydroepiandrosterone-sulfate between the two groups. There were significant increases in serum levels of fasting blood sugar (p = 0.01), insulin (p = 0.04), homeostasis model assessments of insulin resistance (p = 0.04), testosterone (p = 0.02), luteinizing hormone (p = 0.004), luteinizing hormone/follicle stimulating hormone (p = 0.006) and prolactin (p = 0.04) in case group compared to the control group. A significant positive correlation was observed between ANGPTL2 and insulin (p = 0.02), HOMA-IR (p = 0.01) and, on the other hand, a significant negative correlation was observed between obestatin and insulin (p = 0.01), HOMA-IR (p = 0.008) in PCOS group. Conclusions: In this study, no significant variations were observed in serum levels of ANGPTL2 and obestatin in PCOS women with normal BMI.
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Affiliation(s)
- Elham Rahmani
- Department of Obstetrics and Gynecology, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Samad Akbarzadeh
- Department of Biochemistry, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Ainaz Broomand
- Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Fatemeh Torabi
- Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Niloofar Motamed
- Department of Community Medicine, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr 7518759577, Iran.
| | - Marzieh Zohrabi
- The Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514947932, Iran.
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