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An H, Jang Y, Choi J, Hur J, Kim S, Kwon Y. New Insights into AMPK, as a Potential Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease and Hepatic Fibrosis. Biomol Ther (Seoul) 2025; 33:18-38. [PMID: 39702310 PMCID: PMC11704404 DOI: 10.4062/biomolther.2024.188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
AMP-activated protein kinase (AMPK) activators have garnered significant attention for their potential to prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) into liver fibrosis and to fundamentally improve liver function. The broad spectrum of pathways regulated by AMPK activators makes them promising alternatives to conventional liver replacement therapies and the limited pharmacological treatments currently available. In this study, we aim to illustrate the newly detailed multiple mechanisms of MASLD progression based on the multiple-hit hypothesis. This model posits that impaired lipid metabolism, combined with insulin resistance and metabolic imbalance, initiates inflammatory cascades, gut dysbiosis, and the accumulation of toxic metabolites, ultimately promoting fibrosis and accelerating MASLD progression to irreversible hepatocellular carcinoma (HCC). AMPK plays a multifaceted protective role against these pathological conditions by regulating several key downstream signaling pathways. It regulates biological effectors critical to metabolic and inflammatory responses, such as SIRT1, Nrf2, mTOR, and TGF-β, through complex and interrelated mechanisms. Due to these intricate connections, AMPK's role is pivotal in managing metabolic and inflammatory disorders. In this review, we demonstrate the specific roles of AMPK and its related pathways. Several agents directly activate AMPK by binding as agonists, while some others indirectly activate AMPK by modulating upstream molecules, including adiponectin, LKB1, and the AMP: ATP ratio. As AMPK activators can target each stage of MASLD progression, the development of AMPK activators offers immense potential to expand therapeutic strategies for liver diseases such as MASH, MASLD, and liver fibrosis.
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Affiliation(s)
- Haeun An
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Yerin Jang
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jungin Choi
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Juhee Hur
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Seojeong Kim
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Youngjoo Kwon
- College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
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Chen T, Yang W, Dong R, Yao H, Sun M, Wang J, Zhou Q, Xu J. The effect and application of adiponectin in hepatic fibrosis. Gastroenterol Rep (Oxf) 2024; 12:goae108. [PMID: 39737222 PMCID: PMC11683834 DOI: 10.1093/gastro/goae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/04/2024] [Accepted: 09/24/2024] [Indexed: 01/01/2025] Open
Abstract
Hepatic fibrosis, a degenerative liver lesion, significantly contributes to the deterioration and mortality among patients with chronic liver diseases. The condition arises from various factors including toxins, such as alcohol, infections like different types of viral hepatitis, and metabolic diseases. Currently, there are no effective treatments available for liver fibrosis. Recent research has shown that adiponectin (ADPN) exhibits inhibitory effects on hepatic fibrosis. ADPN, an adipocytokine secreted by mature adipocytes, features receptors that are widely distributed across multiple tissues, especially the liver. In the liver, direct effects of ADPN on liver fibrosis include reducing inflammation and regulating hepatic stellate cell proliferation and migration. And its indirect effects include alleviating hepatic endoplasmic reticulum stress and reducing inflammation in hepatic lobules, thereby mitigating hepatic fibrosis. This review aims to elucidate the regulatory role of ADPN in liver fibrosis, explore how ADPN and its receptors alleviate endoplasmic reticulum stress, summarize ADPN detection methods, and discuss its potential as a novel marker and therapeutic agent in combating hepatic fibrosis.
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Affiliation(s)
- Taoran Chen
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Wenjing Yang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Rongrong Dong
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Han Yao
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Miao Sun
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiaxin Wang
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Qi Zhou
- Department of Pediatrics, First Hospital of Jilin University, Changchun, Jilin, P. R. China
| | - Jiancheng Xu
- Department of Laboratory Medicine, First Hospital of Jilin University, Changchun, Jilin, P. R. China
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de Luxán-Delgado B, Potes Y, Rubio-González A, Solano JJ, Boga JA, Antuña E, Cachán-Vega C, Bermejo-Millo JC, Menéndez-Coto N, García-González C, Pereira GC, Caballero B, Coto-Montes A, Vega-Naredo I. Melatonin Alleviates Liver Mitochondrial Dysfunction in Leptin-Deficient Mice. Int J Mol Sci 2024; 25:8677. [PMID: 39201365 PMCID: PMC11354344 DOI: 10.3390/ijms25168677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 08/02/2024] [Indexed: 09/02/2024] Open
Abstract
Despite efforts to elucidate the cellular adaptations induced by obesity, cellular bioenergetics is currently considered a crucial target. New strategies to delay the onset of the hazardous adaptations induced by obesity are needed. Therefore, we evaluated the effects of 4 weeks of melatonin treatment on mitochondrial function and lipid metabolism in the livers of leptin-deficient mice. Our results revealed that the absence of leptin increased lipid storage in the liver and induced significant mitochondrial alterations, which were ultimately responsible for defective ATP production and reactive oxygen species overproduction. Moreover, leptin deficiency promoted mitochondrial biogenesis, fusion, and outer membrane permeabilization. Melatonin treatment reduced the bioenergetic deficit found in ob/ob mice, alleviating some mitochondrial alterations in the electron transport chain machinery, biogenesis, dynamics, respiration, ATP production, and mitochondrial outer membrane permeabilization. Given the role of melatonin in maintaining mitochondrial homeostasis, it could be used as a therapeutic agent against adipogenic steatosis.
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Affiliation(s)
- Beatriz de Luxán-Delgado
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
| | - Yaiza Potes
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Adrian Rubio-González
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Juan José Solano
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Geriatrics Service, Monte Naranco Hospital, 33012 Oviedo, Spain
| | - José Antonio Boga
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Microbiology Department, Hospital Universitario Central de Asturias, Avenida de Roma s/n, 33011 Oviedo, Spain
| | - Eduardo Antuña
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Cristina Cachán-Vega
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Juan Carlos Bermejo-Millo
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Nerea Menéndez-Coto
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
| | - Claudia García-González
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
| | - Gonçalo C. Pereira
- School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, UK;
| | - Beatriz Caballero
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Ana Coto-Montes
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
| | - Ignacio Vega-Naredo
- Department of Morphology and Cell Biology, University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain; (B.d.L.-D.); (Y.P.); (A.R.-G.); (E.A.); (J.C.B.-M.); (N.M.-C.); (B.C.); (A.C.-M.)
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. Del Hospital Universitario, 33011 Oviedo, Spain; (J.J.S.); (J.A.B.)
- Instituto de Neurociencias del Principado de Asturias (INEUROPA), University of Oviedo, Julián Clavería s/n, 33006 Oviedo, Spain
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Bo T, Gao L, Yao Z, Shao S, Wang X, Proud CG, Zhao J. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease. Cell Metab 2024; 36:947-968. [PMID: 38718757 DOI: 10.1016/j.cmet.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/26/2024]
Abstract
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
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Affiliation(s)
- Tao Bo
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ling Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Zhenyu Yao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Shanshan Shao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Xuemin Wang
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia
| | - Christopher G Proud
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia.
| | - Jiajun Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
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5
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Klobučar I, Habisch H, Klobučar L, Trbušić M, Pregartner G, Berghold A, Kostner GM, Scharnagl H, Madl T, Frank S, Degoricija V. Serum Levels of Adiponectin Are Strongly Associated with Lipoprotein Subclasses in Healthy Volunteers but Not in Patients with Metabolic Syndrome. Int J Mol Sci 2024; 25:5050. [PMID: 38732266 PMCID: PMC11084877 DOI: 10.3390/ijms25095050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024] Open
Abstract
Metabolic syndrome (MS) is a widespread disease in developed countries, accompanied, among others, by decreased adiponectin serum levels and perturbed lipoprotein metabolism. The associations between the serum levels of adiponectin and lipoproteins have been extensively studied in the past under healthy conditions, yet it remains unexplored whether the observed associations also exist in patients with MS. Therefore, in the present study, we analyzed the serum levels of lipoprotein subclasses using nuclear magnetic resonance spectroscopy and examined their associations with the serum levels of adiponectin in patients with MS in comparison with healthy volunteers (HVs). In the HVs, the serum levels of adiponectin were significantly negatively correlated with the serum levels of large buoyant-, very-low-density lipoprotein, and intermediate-density lipoprotein, as well as small dense low-density lipoprotein (LDL) and significantly positively correlated with large buoyant high-density lipoprotein (HDL). In patients with MS, however, adiponectin was only significantly correlated with the serum levels of phospholipids in total HDL and large buoyant LDL. As revealed through logistic regression and orthogonal partial least-squares discriminant analyses, high adiponectin serum levels were associated with low levels of small dense LDL and high levels of large buoyant HDL in the HVs as well as high levels of large buoyant LDL and total HDL in patients with MS. We conclude that the presence of MS weakens or abolishes the strong associations between adiponectin and the lipoprotein parameters observed in HVs and disturbs the complex interplay between adiponectin and lipoprotein metabolism.
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Affiliation(s)
- Iva Klobučar
- Department of Cardiology, Sisters of Charity University Hospital Centre, 10000 Zagreb, Croatia; (I.K.); (M.T.)
| | - Hansjörg Habisch
- Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria; (H.H.); (T.M.)
| | - Lucija Klobučar
- Department of Medicine, University Hospital Centre Osijek, 31000 Osijek, Croatia;
| | - Matias Trbušić
- Department of Cardiology, Sisters of Charity University Hospital Centre, 10000 Zagreb, Croatia; (I.K.); (M.T.)
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Gudrun Pregartner
- Institute for Medical Informatics, Statistics, and Documentation, Medical University of Graz, 8036 Graz, Austria; (G.P.); (A.B.)
| | - Andrea Berghold
- Institute for Medical Informatics, Statistics, and Documentation, Medical University of Graz, 8036 Graz, Austria; (G.P.); (A.B.)
| | - Gerhard M. Kostner
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria;
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria;
| | - Tobias Madl
- Otto Loewi Research Center, Medicinal Chemistry, Medical University of Graz, 8010 Graz, Austria; (H.H.); (T.M.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Saša Frank
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria;
- BioTechMed-Graz, 8010 Graz, Austria
| | - Vesna Degoricija
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Department of Medicine, Sisters of Charity University Hospital Centre, 10000 Zagreb, Croatia
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Zhou N, Gong L, Zhang E, Wang X. Exploring exercise-driven exerkines: unraveling the regulation of metabolism and inflammation. PeerJ 2024; 12:e17267. [PMID: 38699186 PMCID: PMC11064867 DOI: 10.7717/peerj.17267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/28/2024] [Indexed: 05/05/2024] Open
Abstract
Exercise has many beneficial effects that provide health and metabolic benefits. Signaling molecules are released from organs and tissues in response to exercise stimuli and are widely termed exerkines, which exert influence on a multitude of intricate multi-tissue processes, such as muscle, adipose tissue, pancreas, liver, cardiovascular tissue, kidney, and bone. For the metabolic effect, exerkines regulate the metabolic homeostasis of organisms by increasing glucose uptake and improving fat synthesis. For the anti-inflammatory effect, exerkines positively influence various chronic inflammation-related diseases, such as type 2 diabetes and atherosclerosis. This review highlights the prospective contribution of exerkines in regulating metabolism, augmenting the anti-inflammatory effects, and providing additional advantages associated with exercise. Moreover, a comprehensive overview and analysis of recent advancements are provided in this review, in addition to predicting future applications used as a potential biomarker or therapeutic target to benefit patients with chronic diseases.
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Affiliation(s)
- Nihong Zhou
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing, China
- School of Sport Science, Beijing Sport University, Beijing, China
| | - Lijing Gong
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing, China
- Key Laboratory for Performance Training & Recovery of General Administration of Sport, Beijing Sport University, Beijing, China
| | - Enming Zhang
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
- NanoLund Center for NanoScience, Lund University, Lund, Sweden
| | - Xintang Wang
- Key Laboratory for Performance Training & Recovery of General Administration of Sport, Beijing Sport University, Beijing, China
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
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Guerra-Ávila PL, Guzmán TJ, Vargas-Guerrero B, Domínguez-Rosales JA, Cervantes-Garduño AB, Salazar-Montes AM, Sánchez-Orozco LV, Gurrola-Díaz CM. Comparative Screening of the Liver Gene Expression Profiles from Type 1 and Type 2 Diabetes Rat Models. Int J Mol Sci 2024; 25:4151. [PMID: 38673735 PMCID: PMC11050131 DOI: 10.3390/ijms25084151] [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: 02/26/2024] [Revised: 04/04/2024] [Accepted: 04/06/2024] [Indexed: 04/28/2024] Open
Abstract
Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350-450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <-2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function.
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Affiliation(s)
- Paloma Lucía Guerra-Ávila
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Tereso J. Guzmán
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
- Department of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, 48149 Münster, Germany
| | - Belinda Vargas-Guerrero
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - José Alfredo Domínguez-Rosales
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Alejandra Beatriz Cervantes-Garduño
- Laboratorio de Genómica Clínica, Facultad de Odontología, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México C.P. 04510, Mexico;
| | - Adriana María Salazar-Montes
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Laura Verónica Sánchez-Orozco
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Carmen Magdalena Gurrola-Díaz
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
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8
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Ma K, Zhang Y, Zhao J, Zhou L, Li M. Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue. Front Immunol 2024; 15:1381227. [PMID: 38638434 PMCID: PMC11024263 DOI: 10.3389/fimmu.2024.1381227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Accepted: 03/25/2024] [Indexed: 04/20/2024] Open
Abstract
Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes.
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Affiliation(s)
| | | | | | | | - Min Li
- Institute of Metabolic Diseases, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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9
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Xie L, Wang H, Hu J, Liu Z, Hu F. The role of novel adipokines and adipose-derived extracellular vesicles (ADEVs): Connections and interactions in liver diseases. Biochem Pharmacol 2024; 222:116104. [PMID: 38428826 DOI: 10.1016/j.bcp.2024.116104] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 02/01/2024] [Accepted: 02/27/2024] [Indexed: 03/03/2024]
Abstract
Adipose tissues (AT) are an important endocrine organ that secretes various functional adipokines, peptides, non-coding RNAs, and acts on AT themselves or other distant tissues or organs through autocrine, paracrine, or endocrine manners. An accumulating body of evidence has suggested that many adipokines play an important role in liver metabolism. Besides the traditional adipokines such as adiponectin and leptin, many novel adipokines have recently been identified to have regulatory effects on the liver. Additionally, AT can produce extracellular vesicles (EVs) that act on peripheral tissues. However, under pathological conditions, such as obesity and diabetes, dysregulation of adipokines is associated with functional changes in AT, which may cause liver diseases. In this review, we focus on the newly discovered adipokines and EVs secreted by AT and highlight their actions on the liver under the context of obesity, nonalcoholic fatty liver diseases (NAFLD), and some other liver diseases. Clarifying the action of adipokines and adipose tissue-derived EVs on the liver would help to identify novel therapeutic targets or biomarkers for metabolic diseases.
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Affiliation(s)
- Lijun Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Huiying Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jinying Hu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Zhuoying Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; Health Law Research Center, School of Law, Central South University, Changsha, China.
| | - Fang Hu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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10
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Schwärzler J, Grabherr F, Grander C, Adolph TE, Tilg H. The pathophysiology of MASLD: an immunometabolic perspective. Expert Rev Clin Immunol 2024; 20:375-386. [PMID: 38149354 DOI: 10.1080/1744666x.2023.2294046] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/08/2023] [Indexed: 12/28/2023]
Abstract
INTRODUCTION Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease - MASLD; metabolic dysfunction-associated steatohepatitis - MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts. AREAS COVERED We summarize the pathophysiologic concepts of MASLD and its transition to MASH and subsequent advanced sequelae of diseases. Furthermore, we highlight how dietary constituents, microbes and associated metabolites, metabolic perturbations, and immune dysregulation fuel lipotoxicity, hepatic inflammation, liver injury, insulin resistance, and systemic inflammation. Deciphering the intricate pathophysiologic processes that contribute to the development and progression of MASLD is essential to develop targeted therapeutic approaches to combat this escalating burden for health-care systems. EXPERT OPINION The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease challenges health-care systems worldwide. Understanding pathophysiologic traits is crucial to improve the prevention and treatment of this disorder and to slow progression into advanced sequelae such as cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
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11
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Ramirez Bustamante CE, Agarwal N, Cox AR, Hartig SM, Lake JE, Balasubramanyam A. Adipose Tissue Dysfunction and Energy Balance Paradigms in People Living With HIV. Endocr Rev 2024; 45:190-209. [PMID: 37556371 PMCID: PMC10911955 DOI: 10.1210/endrev/bnad028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 07/09/2023] [Accepted: 08/07/2023] [Indexed: 08/11/2023]
Abstract
Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.
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Affiliation(s)
- Claudia E Ramirez Bustamante
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Neeti Agarwal
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Aaron R Cox
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sean M Hartig
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jordan E Lake
- Division of Infectious Diseases, Department of Internal Medicine, McGovern Medical School at UTHealth, Houston, TX 77030, USA
| | - Ashok Balasubramanyam
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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12
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Włodarczyk M, Włodarczyk J, Maryńczak K, Waśniewska-Włodarczyk A, Doboszewska U, Wlaź P, Dziki Ł, Fichna J. Role of Adipose Tissue Hormones in Pathogenesis of Cryptoglandular Anal Fistula. Int J Mol Sci 2024; 25:1501. [PMID: 38338780 PMCID: PMC10855462 DOI: 10.3390/ijms25031501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/21/2023] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
The cryptoglandular perianal fistula is a common benign anorectal disorder that is managed mainly with surgery and in some cases may be an extremely challenging condition. Perianal fistulas are often characterized by significantly decreased patient quality of life. Lack of fully recognized pathogenesis of this disease makes it difficult to treat it properly. Recently, adipose tissue hormones have been proposed to play a role in the genesis of cryptoglandular anal fistulas. The expression of adipose tissue hormones and epithelial-to-mesenchymal transition (EMT) factors were characterized based on 30 samples from simple fistulas and 30 samples from complex cryptoglandular perianal fistulas harvested during surgery. Tissue levels of leptin, resistin, MMP2, and MMP9 were significantly elevated in patients who underwent operations due to complex cryptoglandular perianal fistulas compared to patients with simple fistulas. Adiponectin and E-cadherin were significantly lowered in samples from complex perianal fistulas in comparison to simple fistulas. A negative correlation between leptin and E-cadherin levels was observed. Resistin and MMP2 levels, as well as adiponectin and E-cadherin levels, were positively correlated. Complex perianal cryptoglandular fistulas have a reduced level of the anti-inflammatory adipokine adiponectin and have an increase in the levels of proinflammatory resistin and leptin. Abnormal secretion of these adipokines may affect the integrity of the EMT in the fistula tract. E-cadherin, MMP2, and MMP9 expression levels were shifted in patients with more advanced and complex perianal fistulas. Our results supporting the idea of using mesenchymal stem cells in the treatment of cryptoglandular perianal fistulas seem reasonable, but further studies are warranted.
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Affiliation(s)
- Marcin Włodarczyk
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Jakub Włodarczyk
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | - Kasper Maryńczak
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Anna Waśniewska-Włodarczyk
- Department of Normal and Clinical Anatomy, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland
| | - Urszula Doboszewska
- Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland
| | - Łukasz Dziki
- Department of General and Oncological Surgery, Faculty of Medicine, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
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13
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Chen X, Peng R, Peng D, Xiao J, Liu D, Li R. An update: is there a relationship between H. pylori infection and nonalcoholic fatty liver disease? why is this subject of interest? Front Cell Infect Microbiol 2023; 13:1282956. [PMID: 38145041 PMCID: PMC10739327 DOI: 10.3389/fcimb.2023.1282956] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/21/2023] [Indexed: 12/26/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is thought to impact various extragastric diseases, including nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease. Meanwhile, the pathogenesis of NAFLD needs further research, and effective treatment for this disease remains elusive. In this mini-review, we enumerate and ponder on the evidence demonstrating an association between H. pylori infection and NAFLD. Primarily, we delve into high-quality meta-analyses and clinical randomized controlled trials focusing on the association studies between the two. We also discuss clinical studies that present opposite conclusions. In addition, we propose a mechanism through which H. pylori infection aggravates NAFLD: inflammatory cytokines and adipocytokines, insulin resistance, lipid metabolism, intestinal barrier and microbiota, H. pylori outer membrane vesicles and H. pylori-infected cell-extracellular vesicles. This mini-review aims to further explore NAFLD pathogenesis and extragastric disease mechanisms caused by H. pylori infection.
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Affiliation(s)
- Xingcen Chen
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Ruyi Peng
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Dongzi Peng
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Jia Xiao
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Deliang Liu
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
| | - Rong Li
- Department of Gastroenterology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- Research Center of Digestive Diseases, Central South University, Changsha, Hunan, China
- Clinical Research Center, Digestive Diseases of Hunan Province, Changsha, Hunan, China
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14
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Begum M, Choubey M, Tirumalasetty MB, Arbee S, Mohib MM, Wahiduzzaman M, Mamun MA, Uddin MB, Mohiuddin MS. Adiponectin: A Promising Target for the Treatment of Diabetes and Its Complications. Life (Basel) 2023; 13:2213. [PMID: 38004353 PMCID: PMC10672343 DOI: 10.3390/life13112213] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 10/30/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, presents a formidable global health challenge with its associated complications. Adiponectin, an adipocyte-derived hormone, has emerged as a significant player in glucose metabolism and insulin sensitivity. Beyond its metabolic effects, adiponectin exerts anti-inflammatory, anti-oxidative, and vasoprotective properties, making it an appealing therapeutic target for mitigating diabetic complications. The molecular mechanisms by which adiponectin impacts critical pathways implicated in diabetic nephropathy, retinopathy, neuropathy, and cardiovascular problems are thoroughly examined in this study. In addition, we explore possible treatment options for increasing adiponectin levels or improving its downstream signaling. The multifaceted protective roles of adiponectin in diabetic complications suggest its potential as a novel therapeutic avenue. However, further translational studies and clinical trials are warranted to fully harness the therapeutic potential of adiponectin in the management of diabetic complications. This review highlights adiponectin as a promising target for the treatment of diverse diabetic complications and encourages continued research in this pivotal area of diabetes therapeutics.
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Affiliation(s)
- Mahmuda Begum
- Department of Internal Medicine, HCA-St David’s Medical Center, 919 E 32nd St, Austin, TX 78705, USA;
| | - Mayank Choubey
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, 101 Mineola Blvd, Mineola, NY 11501, USA; (M.C.); (M.B.T.); (M.W.)
| | - Munichandra Babu Tirumalasetty
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, 101 Mineola Blvd, Mineola, NY 11501, USA; (M.C.); (M.B.T.); (M.W.)
| | - Shahida Arbee
- Institute for Molecular Medicine, Aichi Medical University, 1-Yazako, Karimata, Aichi, Nagakute 480-1103, Japan;
| | - Mohammad Mohabbulla Mohib
- Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg, Magdeburger Straße 6, 06112 Halle, Germany;
| | - Md Wahiduzzaman
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, 101 Mineola Blvd, Mineola, NY 11501, USA; (M.C.); (M.B.T.); (M.W.)
| | - Mohammed A. Mamun
- CHINTA Research Bangladesh, Savar 1342, Bangladesh;
- Department of Public Health and Informatics, Jahangirnagar University, Savar 1342, Bangladesh
| | - Mohammad Borhan Uddin
- Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh;
| | - Mohammad Sarif Mohiuddin
- Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, 101 Mineola Blvd, Mineola, NY 11501, USA; (M.C.); (M.B.T.); (M.W.)
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15
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Zheng Y, Ye C, He M, Ko WKW, Chan YW, Wong AOL. Goldfish adiponectin: (I) molecular cloning, tissue distribution, recombinant protein expression, and novel function as a satiety factor in fish model. Front Endocrinol (Lausanne) 2023; 14:1283298. [PMID: 38027109 PMCID: PMC10643153 DOI: 10.3389/fendo.2023.1283298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/06/2023] [Indexed: 12/01/2023] Open
Abstract
Adiponectin (AdipoQ) is an adipokine involved in glucose homeostasis and lipid metabolism. In mammals, its role in appetite control is highly controversial. To shed light on the comparative aspects of AdipoQ in lower vertebrates, goldfish was used as a model to study feeding regulation by AdipoQ in fish species. As a first step, goldfish AdipoQ was cloned and found to be ubiquitously expressed at the tissue level. Using sequence alignment, protein modeling, phylogenetic analysis and comparative synteny, goldfish AdipoQ was shown to be evolutionarily related to its fish counterparts and structurally comparable with AdipoQ in higher vertebrates. In our study, recombinant goldfish AdipoQ was expressed in E. coli, purified by IMAC, and confirmed to be bioactive via activation of AdipoQ receptors expressed in HepG2 cells. Feeding in goldfish revealed that plasma levels of AdipoQ and its transcript expression in the liver and brain areas involved in appetite control including the telencephalon, optic tectum, and hypothalamus could be elevated by food intake. In parallel studies, IP and ICV injection of recombinant goldfish AdipoQ in goldfish was effective in reducing foraging behaviors and food consumption. Meanwhile, transcript expression of orexigenic factors (NPY, AgRP, orexin, and apelin) was suppressed with parallel rises in anorexigenic factors (POMC, CART, CCK, and MCH) in the telencephalon, optic tectum and/or hypothalamus. In these brain areas, transcript signals for leptin receptor were upregulated with concurrent drops in the NPY receptor and ghrelin receptors. In the experiment with IP injection of AdipoQ, transcript expression of leptin was also elevated with a parallel drop in ghrelin mRNA in the liver. These findings suggest that AdipoQ can act as a novel satiety factor in goldfish. In this case, AdipoQ signals (both central and peripheral) can be induced by feeding and act within the brain to inhibit feeding behaviors and food intake via differential regulation of orexigenic/anorexigenic factors and their receptors. The feeding inhibition observed may also involve the hepatic action of AdipoQ by modulation of feeding regulators expressed in the liver.
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Affiliation(s)
| | | | | | | | | | - Anderson O. L. Wong
- School of Biological Sciences, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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16
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Nikolettos K, Nikolettos N, Vlahos N, Pagonopoulou O, Asimakopoulos B. Role of leptin, adiponectin, and kisspeptin in polycystic ovarian syndrome pathogenesis. Minerva Obstet Gynecol 2023; 75:460-467. [PMID: 36255161 DOI: 10.23736/s2724-606x.22.05139-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
INTRODUCTION Polycystic ovarian syndrome (PCOS) affects 5-20% of females and is the most common cause of anovulatory infertility. Leptin seems to have an important role in reproduction. Many reproductive pathologies such as preeclampsia, PCOS, and endometriosis are associated to plasma adiponectin levels. Kisspeptin levels are increased in PCOS women. EVIDENCE ACQUISITION A review of the literature was completed through the PubMed database aiming to find articles regarding leptin, adiponectin and kisspeptin and if they are related to PCOS pathogenesis. EVIDENCE SYNTHESIS Even today it is not clear what is the role of leptin in women with PCOS, although most of the researchers found increased levels of leptin as well as leptin resistance in PCOS (both obese and lean individuals). Many more longitudinal studies should be done to discover the usefulness of measuring adiponectin in prepubertal women who apparently have a possibility to develop PCOS to find out if they finally develop PCOS. Most of the researchers found that PCOS women have decreased levels of adiponectin unrelated to BMI levels. Nevertheless, not all studies had the same result. Moreover, it is necessary more studies to be made to investigate the connection between kisspeptin and other metabolic factors such as LH and insulin resistance. CONCLUSIONS In general, it remains inconclusive whether leptin, adiponectin, and kisspeptin can be used as clinical and/or biochemical markers of PCOS. Therefore, it is essential to review the current data with regards to the association between PCOS and circulating leptin, adiponectin, and kisspeptin in women with PCOS.
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Affiliation(s)
- Konstantinos Nikolettos
- Obstetric and Gynecologic Clinic, Medical School, Democritus University of Thrace, Alexandroupolis, Greece -
| | - Nikos Nikolettos
- Obstetric and Gynecologic Clinic, Medical School, Democritus University of Thrace, Alexandroupolis, Greece
| | - Nikolaos Vlahos
- Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, School of Medicine, Aretaieion Hospital, Athens, Greece
| | - Olga Pagonopoulou
- Laboratory of Physiology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Byron Asimakopoulos
- Laboratory of Physiology, Faculty of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
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Sun H, Kemper JK. MicroRNA regulation of AMPK in nonalcoholic fatty liver disease. Exp Mol Med 2023; 55:1974-1981. [PMID: 37653034 PMCID: PMC10545736 DOI: 10.1038/s12276-023-01072-3] [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: 04/19/2023] [Revised: 06/10/2023] [Accepted: 06/13/2023] [Indexed: 09/02/2023] Open
Abstract
Obesity-associated nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is the leading cause of liver failure and death. The function of AMP-activated protein kinase (AMPK), a master energy sensor, is aberrantly reduced in NAFLD, but the underlying mechanisms are not fully understood. Increasing evidence indicates that aberrantly expressed microRNAs (miRs) are associated with impaired AMPK function in obesity and NAFLD. In this review, we discuss the emerging evidence that miRs have a role in reducing AMPK activity in NAFLD and nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. We also discuss the underlying mechanisms of the aberrant expression of miRs that can negatively impact AMPK, as well as the therapeutic potential of targeting the miR-AMPK pathway for NAFLD/NASH.
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Affiliation(s)
- Hao Sun
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA
| | - Jongsook Kim Kemper
- Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
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Lim JY, Kim E. The Role of Organokines in Obesity and Type 2 Diabetes and Their Functions as Molecular Transducers of Nutrition and Exercise. Metabolites 2023; 13:979. [PMID: 37755259 PMCID: PMC10537761 DOI: 10.3390/metabo13090979] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/22/2023] [Accepted: 08/24/2023] [Indexed: 09/28/2023] Open
Abstract
Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.
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Affiliation(s)
- Ji Ye Lim
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., Houston, TX 77030, USA
| | - Eunju Kim
- Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., Houston, TX 77030, USA
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Hinrichs H, Faerber A, Young M, Ballentine SJ, Thompson MD. Maternal Exercise Protects Male Offspring From Maternal Diet-Programmed Nonalcoholic Fatty Liver Disease Progression. Endocrinology 2023; 164:6991827. [PMID: 36655378 PMCID: PMC10091505 DOI: 10.1210/endocr/bqad010] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/09/2023] [Accepted: 01/12/2023] [Indexed: 01/20/2023]
Abstract
Maternal obesity programs the risk for development of nonalcoholic fatty liver disease (NAFLD) in offspring. Maternal exercise is a potential intervention to prevent developmentally programmed phenotypes. We hypothesized that maternal exercise would protect from progression of NAFLD in offspring previously exposed to a maternal obesogenic diet. Female mice were fed chow (CON) or high fat, fructose, cholesterol (HFFC) and bred with lean males. A subset had an exercise wheel introduced 4 weeks after starting the diet to allow for voluntary exercise. The offspring were weaned to the HFFC diet for 7 weeks to induce NAFLD. Serum, adipose, and liver tissue were collected for metabolic, histologic, and gene expression analyses. Cecal contents were collected for 16S sequencing. Global metabolomics was performed on liver. Female mice fed the HFFC diet had increased body weight prior to adding an exercise wheel. Female mice fed the HFFC diet had an increase in exercise distance relative to CON during the preconception period. Exercise distance was similar between groups during pregnancy and lactation. CON-active and HFFC-active offspring exhibited decreased inflammation compared with offspring from sedentary dams. Fibrosis increased in offspring from HFFC-sedentary dams compared with CON-sedentary. Offspring from exercised HFFC dams exhibited less fibrosis than offspring from sedentary HFFC dams. While maternal diet significantly affected the microbiome of offspring, the effect of maternal exercise was minimal. Metabolomics analysis revealed shifts in multiple metabolites including several involved in bile acid, 1-carbon, histidine, and acylcarnitine metabolism. This study provides preclinical evidence that maternal exercise is a potential approach to prevent developmentally programmed liver disease progression in offspring.
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Affiliation(s)
- Holly Hinrichs
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Austin Faerber
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Monica Young
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Samuel J Ballentine
- Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Michael D Thompson
- Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA
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20
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Sahu B, Bal NC. Adipokines from white adipose tissue in regulation of whole body energy homeostasis. Biochimie 2023; 204:92-107. [PMID: 36084909 DOI: 10.1016/j.biochi.2022.09.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 08/08/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023]
Abstract
Diseases originating from altered energy homeostasis including obesity, and type 2 diabetes are rapidly increasing worldwide. Research in the last few decades on animal models and humans demonstrates that the white adipose tissue (WAT) is critical for energy balance and more than just an energy storage site. WAT orchestrates the whole-body metabolism through inter-organ crosstalk primarily mediated by cytokines named "Adipokines". The adipokines influence metabolism and fuel selection of the skeletal muscle and liver thereby fine-tuning the load on WAT itself in physiological conditions like starvation, exercise and cold. In addition, adipokine secretion is influenced by various pathological conditions like obesity, inflammation and diabetes. In this review, we have surveyed the current state of knowledge on important adipokines and their significance in regulating energy balance and metabolic diseases. Furthermore, we have summarized the interplay of pro-inflammatory and anti-inflammatory adipokines in the modulation of pathological conditions.
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Affiliation(s)
- Bijayashree Sahu
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
| | - Naresh C Bal
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
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21
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Pathophysiology of obesity and its associated diseases. Acta Pharm Sin B 2023. [DOI: 10.1016/j.apsb.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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22
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Lactation alters the relationship between liver lipid synthesis and hepatic fat stores in the postpartum period. J Lipid Res 2022; 63:100288. [PMID: 36162520 PMCID: PMC9619182 DOI: 10.1016/j.jlr.2022.100288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
In mothers who are nursing their infants, increased clearance of plasma metabolites into the mammary gland may reduce ectopic lipid in the liver. No study to date has investigated the role of lactation on liver lipid synthesis in humans, and we hypothesized that lactation would modify fatty acid and glucose handling to support liver metabolism in a manner synchronized with the demands of milk production. Lactating (n = 18) and formula-feeding women (n = 10) underwent metabolic testing at 6-week postpartum to determine whether lactation modified intrahepatic triacylglycerols (IHTGs), measured by proton magnetic resonance spectroscopy. Subjects ingested oral deuterated water to measure fractional de novo lipogenesis (DNL) in VLDL-TG during fasting and during an isotope-labeled clamp at an insulin infusion rate of 10 mU/m2/min. Compared with formula-feeding women, we found that lactating women exhibited lower plasma VLDL-TG concentrations, similar IHTG content and similar contribution of DNL to total VLDL-TG production. These findings suggest that lactation lowers plasma VLDL-TG concentrations for reasons that are unrelated to IHTG and DNL. Surprisingly, we determined that the rate of appearance of nonesterified fatty acids was not related to IHTG in either group, and the expected positive association between DNL and IHTG was only significant in formula-feeding women. Further, in lactating women only, the higher the prolactin concentration, the lower the IHTG, while greater DNL strongly associated with elevations in VLDL-TG. In conclusion, we suggest that future studies should investigate the role of lactation and prolactin in liver lipid secretion and metabolism.
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Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile, Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum. Int J Mol Sci 2022; 23:ijms23179807. [PMID: 36077198 PMCID: PMC9456344 DOI: 10.3390/ijms23179807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 12/04/2022] Open
Abstract
Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes (ALT, AST, GGT and ALP) in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D.
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Contribution of Adiponectin/Carnitine Palmityl Transferase 1A-Mediated Fatty Acid Metabolism during the Development of Idiopathic Pulmonary Fibrosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5265616. [PMID: 36035217 PMCID: PMC9402305 DOI: 10.1155/2022/5265616] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/14/2022] [Accepted: 07/25/2022] [Indexed: 11/18/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that leads rapidly to death. The present study is aimed at discovering the in-depth pathogenesis of IPF, exploring the role of adiponectin/carnitine palmityl transferase 1A- (APN/CPT1A-) mediated fatty acid metabolism during the development of IPF, and excavating its potential mechanism. Here, THP-1 cells were differentiated into M0 macrophages, followed by polarization to M1 macrophages upon hypoxia. Subsequently, lung fibroblast HFL-1 cells were stimulated by M1 macrophages to simulate hypoxia-related IPF condition in vitro. It was discovered that the stimulation of M1 macrophages promoted fibroblast proliferation and fibrosis formation in vitro, accompanied with a disorder of the APN/CPT1A pathway, an overproduction of lipid peroxides, and a low level of autophagy in HFL-1 cells. Thereafter, APN treatment or CPT1A overexpression greatly suppressed above lipid peroxide accumulation, fibroblast proliferation, and fibrosis but activated autophagy in vitro. Furthermore, an in vivo IPF rat model was established by injection of bleomycin (BLM). Consistently, CPT1A overexpression exerted a protective role against pulmonary fibrosis in vivo; however, the antifibrosis property of CPT1A was partly abolished by 3-methyladenine (an autophagy inhibitor). In summary, APN/CPT1A-mediated fatty acid metabolism exerted its protective role in IPF partly through activating autophagy, shedding a new prospective for the treatment of IPF.
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Celecoxib-mediated attenuation of non-alcoholic steatohepatitis is potentially relevant to redistributing the expression of adiponectin receptors in rats. Heliyon 2022; 8:e09872. [PMID: 35832345 PMCID: PMC9272346 DOI: 10.1016/j.heliyon.2022.e09872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/20/2022] [Accepted: 06/30/2022] [Indexed: 11/23/2022] Open
Abstract
Pharmacological inhibition of cyclooxygenase-2 (COX-2) activity ameliorated the severity of non-alcoholic steatohepatitis (NASH) rats. It is not completely understood that the role of COX-2 inhibitor celecoxib on adiponectin receptors (Adipo-R1/R2) expression in different tissues in NASH rats. Sprague-Dawley male NASH rats induced by a high-fat diet (HFD) were administrated with or without celecoxib for 8 weeks. Biochemical parameters of liver function, glucose, and lipid metabolism, and the levels of adiponectin, tumor necrosis factor-alpha (TNF-α), prostaglandin E2 (PGE2) in the serum or liver were collected according to the standard protocols. The mRNA and protein levels of Adipo-R1, Adipo-R2, and COX-2 in the liver, muscle, and visceral fat were performed by quantitative real-time polymerase chain reaction (q-PCR) and Western blot analysis, respectively. The results showed that celecoxib ameliorated the various clinical indicators and pathological characteristics in the NASH rats, including body weight, liver function, liver index, and redox activities in serum and hepatic samples. The serum concentrations of adiponectin and TNF-α and PGE2 were negatively correlated. As expected, these ameliorative effects of celecoxib were associated with the gene and protein levels up-regulation of Adipo-R1, Adipo-R2 in the liver and visceral fat tissues, and seeming to be compensatory down-regulation expression in muscle tissues (P <0.05). Additionally, COX-2 protein expression was negatively correlated with serum adiponectin levels, protein expression of adiponectin receptors from the liver and visceral fat, conversely, positively correlated with those from the muscle. Our current study demonstrate that celecoxib might effectively alleviate NASH rats in a unique manner closely relevant to redistributing the expression of adiponectin receptors in the liver, visceral fat, and muscle. However, the precise molecular mechanism needs further study.
NASH is a watershed in the progression of NAFLD. Finding a therapy for NASH is in urgent need. Pharmacological inhibition of COX-2 activity ameliorated the severity of NASH. Low-dose celecoxib, a COX-2 inhibitor, can improve NASH by redistributing the expression of adiponectin receptors.
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Li Y, Zhang S, Zhu Z, Zhou R, Xu P, Zhou L, Kan Y, Li J, Zhao J, Fang P, Yu X, Shang W. Upregulation of adiponectin by Ginsenoside Rb1 contributes to amelioration of hepatic steatosis induced by high fat diet. J Ginseng Res 2022; 46:561-571. [PMID: 35818425 PMCID: PMC9270646 DOI: 10.1016/j.jgr.2021.10.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Ginsenoside Rb1 (GRb1) is capable of regulating lipid and glucose metabolism through its action on adipocytes. However, the beneficial role of GRb1-induced up-regulation of adiponectin in liver steatosis remains unelucidated. Thus, we tested whether GRb1 ameliorates liver steatosis and insulin resistance by promoting the expression of adiponectin. METHODS 3T3-L1 adipocytes and hepatocytes were used to investigate GRb1's action on adiponectin expression and triglyceride (TG) accumulation. Wild type (WT) mice and adiponectin knockout (KO) mice fed high fat diet were treated with GRb1 for 2 weeks. Hepatic fat accumulation and function as well as insulin sensitivity was measured. The activation of AMPK was also detected in the liver and hepatocytes. RESULTS GRb1 reversed the reduction of adiponectin secretion in adipocytes. The conditioned medium (CM) from adipocytes treated with GRb1 reduced TG accumulation in hepatocytes, which was partly attenuated by the adiponectin antibody. In the KO mice, the GRb1-induced significant decrease of TG content, ALT and AST was blocked by the deletion of adiponectin. The elevations of GRb1-induced insulin sensitivity indicated by OGTT, ITT and HOMA-IR were also weakened in the KO mice. The CM treatment significantly enhanced the phosphorylation of AMPK in hepatocytes, but not GRb1 treatment. Likewise, the phosphorylation of AMPK in liver of the WT mice was increased by GRb1, but not in the KO mice. CONCLUSIONS The up-regulation of adiponectin by GRb1 contributes to the amelioration of liver steatosis and insulin resistance, which further elucidates a new mechanism underlying the beneficial effects of GRb1 on obesity.
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Affiliation(s)
- Yaru Li
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuchen Zhang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ziwei Zhu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ruonan Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Pingyuan Xu
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lingyan Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Kan
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiao Li
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Zhao
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Penghua Fang
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xizhong Yu
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenbin Shang
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Kanbay M, Copur S, Demiray A, Sag AA, Covic A, Ortiz A, Tuttle KR. Fatty kidney: A possible future for chronic kidney disease research. Eur J Clin Invest 2022; 52:e13748. [PMID: 35040119 DOI: 10.1111/eci.13748] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/15/2022] [Accepted: 01/16/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Metabolic syndrome is a growing twenty-first century pandemic associated with multiple clinical comorbidities ranging from cardiovascular diseases, non-alcoholic fatty liver disease and polycystic ovary syndrome to kidney dysfunction. A novel area of research investigates the concept of fatty kidney in the pathogenesis of chronic kidney disease, especially in patients with diabetes mellitus or metabolic syndrome. AIM To review the most updated literature on fatty kidney and provide future research, diagnostic and therapeutic perspectives on a disease increasingly affecting the contemporary world. MATERIALS AND METHOD We performed an extensive literature search through three databases including Embase (Elsevier) and the Cochrane Central Register of Controlled Trials (Wiley) and PubMed/Medline Web of Science in November 2021 by using the following terms and their combinations: 'fatty kidney', 'ectopic fat', 'chronic kidney disease', 'cardiovascular event', 'cardio-metabolic risk', 'albuminuria' and 'metabolic syndrome'. Each study has been individually assessed by the authors. RESULTS Oxidative stress and inflammation, Klotho deficiency, endoplasmic reticulum stress, mitochondrial dysfunction and disruption of cellular energy balance appear to be the main pathophysiological mechanisms leading to tissue damage following fat accumulation. Despite the lack of large-scale comprehensive studies in this novel field of research, current clinical trials demonstrate fatty kidney as an independent risk factor for the development of chronic kidney disease and cardiovascular events. CONCLUSION The requirement for future studies investigating the pathophysiology, clinical outcomes and therapeutics of fatty kidney is clear.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Atalay Demiray
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Alan A Sag
- Division of Vascular and Interventional Radiology, Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa' University of Medicine, Iasi, Romania
| | - Alberto Ortiz
- Department of Medicine, Universidad Autonoma de Madrid and IIS-Fundacion Jimenez Diaz, Madrid, Spain
| | - Kathherine R Tuttle
- Division of Nephrology, University of Washington, Seattle, Washington, USA.,Providence Medical Research Center, Providence Health Care, Spokane, Washington, USA
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Matsuoka R, Miki M, Mizuno S, Ito Y, Yamada C, Suzuki A. MTCL2 promotes asymmetric microtubule organization by crosslinking microtubules on the Golgi membrane. J Cell Sci 2022; 135:275616. [PMID: 35543016 DOI: 10.1242/jcs.259374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 04/20/2022] [Indexed: 11/20/2022] Open
Abstract
The Golgi complex plays an active role in organizing asymmetric microtubule arrays essential for polarized vesicle transport. The coiled-coil protein MTCL1 stabilizes microtubules nucleated from the Golgi membrane. Here, we report an MTCL1 paralog, MTCL2, which preferentially acts on the perinuclear microtubules accumulated around the Golgi. MTCL2 associates with the Golgi membrane through the N-terminal coiled-coil region and directly binds microtubules through the conserved C-terminal domain without promoting microtubule stabilization. Knockdown of MTCL2 significantly impaired microtubule accumulation around the Golgi as well as the compactness of the Golgi ribbon assembly structure. Given that MTCL2 forms parallel oligomers through homo-interaction of the central coiled-coil motifs, our results indicate that MTCL2 promotes asymmetric microtubule organization by crosslinking microtubules on the Golgi membrane. Results of in vitro wound healing assays further suggest that this function of MTCL2 enables integration of the centrosomal and Golgi-associated microtubules on the Golgi membrane, supporting directional migration. Additionally, the results demonstrated the involvement of CLASPs and giantin in mediating the Golgi association of MTCL2.
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Affiliation(s)
- Risa Matsuoka
- Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Masateru Miki
- Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Sonoko Mizuno
- Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Yurina Ito
- Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Chihiro Yamada
- Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
| | - Atsushi Suzuki
- Molecular Cellular Biology Laboratory, Yokohama City University Graduate School of Medical Life Science, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
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Ladwa M, Bello O, Hakim O, Boselli ML, Shojaee-Moradie F, Umpleby AM, Peacock J, Amiel SA, Bonadonna RC, Goff LM. Exploring the determinants of ethnic differences in insulin clearance between men of Black African and White European ethnicity. Acta Diabetol 2022; 59:329-337. [PMID: 34661756 PMCID: PMC8863750 DOI: 10.1007/s00592-021-01809-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 10/03/2021] [Indexed: 11/27/2022]
Abstract
AIM People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. METHODS BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic-euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. RESULTS Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation. CONCLUSION These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties.
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Affiliation(s)
- Meera Ladwa
- Diabetes Research Group, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, Franklin-Wilkins Building, Room 3.87, Waterloo Campus, London, SE1 9NH, UK
| | - Oluwatoyosi Bello
- Diabetes Research Group, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, Franklin-Wilkins Building, Room 3.87, Waterloo Campus, London, SE1 9NH, UK
| | - Olah Hakim
- Diabetes Research Group, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, Franklin-Wilkins Building, Room 3.87, Waterloo Campus, London, SE1 9NH, UK
| | - Maria Linda Boselli
- Division of Endocrinology and Metabolic Disease, University of Verona School of Medicine, Verona, Italy
| | | | - A Margot Umpleby
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Janet Peacock
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Stephanie A Amiel
- Diabetes Research Group, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, Franklin-Wilkins Building, Room 3.87, Waterloo Campus, London, SE1 9NH, UK
| | - Riccardo C Bonadonna
- Department of Medicine and Surgery, University of Parma and Azienda Ospedaliera Universitaria di Parma, Parma, Italy
| | - Louise M Goff
- Diabetes Research Group, Department of Nutritional Sciences, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King's College London, Franklin-Wilkins Building, Room 3.87, Waterloo Campus, London, SE1 9NH, UK.
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Mleczko J, Royo F, Samuelson I, Clos‐Garcia M, Williams C, Cabrera D, Azparren‐Angulo M, Gonzalez E, Garcia‐Vallicrosa C, Carobbio S, Rodriguez‐Cuenca S, Azkargorta M, van Liempd S, Elortza F, Vidal‐Puig A, Mora S, Falcon‐Perez J. Extracellular vesicles released by steatotic hepatocytes alter adipocyte metabolism. JOURNAL OF EXTRACELLULAR BIOLOGY 2022; 1:e32. [PMID: 38938664 PMCID: PMC11080919 DOI: 10.1002/jex2.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/13/2022] [Accepted: 01/26/2022] [Indexed: 06/29/2024]
Abstract
The composition of extracellular vesicles (EVs) is altered in many pathological conditions, and their molecular content provides essential information on features of parent cells and mechanisms of crosstalk between cells and organs. Metabolic Syndrome (MetS) is a cluster of clinical manifestations including obesity, insulin resistance, dyslipidemia and hypertension that increases the risk of cardiovascular disease and type 2 diabetes mellitus. Here, we investigated the crosstalk between liver and adipocytes by characterizing EVs secreted by primary hepatocytes isolated from Zucker rat model, and studied the effect they have on 3T3-L1 adipocytes. We found that steatotic hepatocytes secrete EVs with significantly reduced exosomal markers in comparison with their lean counterpart. Moreover, proteomic analysis revealed that those EVs reflect the metabolic state of the parent cell in that the majority of proteins upregulated relate to fat metabolism, fatty acid synthesis, glycolysis, and pentose phosphate pathway. In addition, hepatocytes-secreted EVs influenced lipolysis and insulin sensitivity in recipient 3T3-L1 adipocytes. Untargeted metabolomic analysis detected alterations in different adipocyte metabolic pathways in cells treated with hepatic EVs. In summary, our work showed that steatosis has a significant impact in the amount and composition of EVs secreted by hepatocytes. Moreover, our data point to the involvement of hepatic-EVs in the development of pathologies associated with MetS.
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Affiliation(s)
- J.E. Mleczko
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
- Department of NeurologyAlzheimer's Disease Research CenterIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - F. Royo
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
- Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd)Instituto de Salud Carlos IIIMadridSpain
| | - I. Samuelson
- TVP LabWellcome/MRC Institute of Metabolic ScienceMRC Metabolic Diseases Unit – Metabolic Research LaboratoriesUniversity of CambridgeCambridgeUK
| | - M. Clos‐Garcia
- Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR)Faculty of Health and medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - C. Williams
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - D. Cabrera
- Metabolomics PlatformCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - M. Azparren‐Angulo
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - E. Gonzalez
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - C. Garcia‐Vallicrosa
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - S. Carobbio
- TVP LabWellcome/MRC Institute of Metabolic ScienceMRC Metabolic Diseases Unit – Metabolic Research LaboratoriesUniversity of CambridgeCambridgeUK
| | - S. Rodriguez‐Cuenca
- TVP LabWellcome/MRC Institute of Metabolic ScienceMRC Metabolic Diseases Unit – Metabolic Research LaboratoriesUniversity of CambridgeCambridgeUK
| | - M. Azkargorta
- Proteomics PlatformCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - S. van Liempd
- Metabolomics PlatformCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - F. Elortza
- Proteomics PlatformCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
| | - A. Vidal‐Puig
- TVP LabWellcome/MRC Institute of Metabolic ScienceMRC Metabolic Diseases Unit – Metabolic Research LaboratoriesUniversity of CambridgeCambridgeUK
| | - S. Mora
- Department of Biochemistry and Molecular BiomedicineUniversity of BarcelonaBarcelonaSpain
| | - J.M. Falcon‐Perez
- Exosomes LaboratoryCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
- Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas (CIBERehd)Instituto de Salud Carlos IIIMadridSpain
- Metabolomics PlatformCenter for Cooperative Research in Biosciences (CIC bioGUNE)Basque Research and Technology Alliance (BRTA)DerioBizkaiaSpain
- IKERBASQUEBasque Foundation for ScienceBilbaoBizkaiaSpain
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31
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Jung HN, Jung CH. The Role of Anti-Inflammatory Adipokines in Cardiometabolic Disorders: Moving beyond Adiponectin. Int J Mol Sci 2021; 22:ijms222413529. [PMID: 34948320 PMCID: PMC8707770 DOI: 10.3390/ijms222413529] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023] Open
Abstract
The global burden of obesity has multiplied owing to its rapidly growing prevalence and obesity-related morbidity and mortality. In addition to the classic role of depositing extra energy, adipose tissue actively interferes with the metabolic balance by means of secreting bioactive compounds called adipokines. While most adipokines give rise to inflammatory conditions, the others with anti-inflammatory properties have been the novel focus of attention for the amelioration of cardiometabolic complications. This review compiles the current evidence on the roles of anti-inflammatory adipokines, namely, adiponectin, vaspin, the C1q/TNF-related protein (CTRP) family, secreted frizzled-related protein 5 (SFRP5), and omentin-1 on cardiometabolic health. Further investigations on the mechanism of action and prospective human trials may pave the way to their clinical application as innovative biomarkers and therapeutic targets for cardiovascular and metabolic disorders.
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Affiliation(s)
- Han Na Jung
- Asan Medical Center, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Asan Diabetes Center, Asan Medical Center, Seoul 05505, Korea
| | - Chang Hee Jung
- Asan Medical Center, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul 05505, Korea;
- Asan Diabetes Center, Asan Medical Center, Seoul 05505, Korea
- Correspondence:
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32
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Piquet M, Martínez MC, Romacho T. Inter-Organ Crosstalk in the Development of Obesity-Associated Insulin Resistance. Handb Exp Pharmacol 2021; 274:205-226. [PMID: 34853949 DOI: 10.1007/164_2021_564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The epidemics of obesity and type 2 diabetes have led to intensive investigation of the underlying mechanisms of these diseases and their main complications such as cardiovascular diseases and non-alcoholic fatty liver disease. This search has contributed to better understand how organs and tissues communicate with each other in the so-called inter-organ crosstalk. Adipose tissue, the liver, or skeletal muscle can actively release secreted factors termed "organokines" which can interact with other distant targets in complex networks. More recently, other novel mediators of inter-organ crosstalk such as extracellular vesicles and their non-traditional cargoes as miRNAs and lncRNAs are gaining importance and represent potential therapeutic targets. In the present chapter we summarize some of the current knowledge on inter-organ communication with a focus on adipose tissue-released factors and their modulation on other organs and tissues like pancreas, liver, skeletal muscle, the cardiovascular system, and the gut in the context of obesity and its progression to insulin resistance. We also provide a perspective on mediators of inter-organ crosstalk as potential therapeutic targets.
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Affiliation(s)
- Megan Piquet
- SOPAM, U1063, INSERM, UNIV Angers, SFR ICAT, Angers, France
| | | | - Tania Romacho
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
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Shklyaev SS, Melnichenko GA, Volevodz NN, Falaleeva NA, Ivanov SA, Kaprin AD, Mokrysheva NG. Adiponectin: a pleiotropic hormone with multifaceted roles. PROBLEMY ENDOKRINOLOGII 2021; 67:98-112. [PMID: 35018766 PMCID: PMC9753852 DOI: 10.14341/probl12827] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 10/22/2021] [Indexed: 05/28/2023]
Abstract
Adipose tissue mostly composed of different types of fat is one of the largest endocrine organs in the body playing multiple intricate roles including but not limited to energy storage, metabolic homeostasis, generation of heat, participation in immune functions and secretion of a number of biologically active factors known as adipokines. The most abundant of them is adiponectin. This adipocite-derived hormone exerts pleiotropic actions and exhibits insulin-sensitizing, antidiabetic, anti-obesogenic, anti-inflammatory, antiatherogenic, cardio- and neuroprotective properties. Contrariwise to its protective effects against various pathological events in different cell types, adiponectin may have links to several systemic diseases and malignances. Reduction in adiponectin levels has an implication in COVID-19-associated respiratory failure, which is attributed mainly to a phenomenon called 'adiponectin paradox'. Ample evidence about multiple functions of adiponectin in the body was obtained from animal, mostly rodent studies. Our succinct review is entirely about multifaceted roles of adiponectin and mechanisms of its action in different physiological and pathological states.
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Affiliation(s)
- S. S. Shklyaev
- National Research Center for Endocrinology of the Ministry of Health of the Russian Federation;
A. Tsyb Medical Radiological Research Center — Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation
| | - G. A. Melnichenko
- National Research Center for Endocrinology of the Ministry of Health of the Russian Federatio
| | - N. N. Volevodz
- National Research Center for Endocrinology of the Ministry of Health of the Russian Federatio
| | - N. A. Falaleeva
- A. Tsyb Medical Radiological Research Center — Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation
| | - S. A. Ivanov
- A. Tsyb Medical Radiological Research Center — Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation
| | - A. D. Kaprin
- A. Tsyb Medical Radiological Research Center — Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation
| | - N. G. Mokrysheva
- National Research Center for Endocrinology of the Ministry of Health of the Russian Federation
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Liu B, Zheng H, Liu G, Li Z. Adiponectin is Inversely Associated with Insulin Resistance in Adolescents with Nonalcoholic Fatty Liver Disease. Endocr Metab Immune Disord Drug Targets 2021; 22:631-639. [PMID: 34579641 DOI: 10.2174/1871530321666210927153831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Insulin resistance(IR) is confirmed as a key feature of nonalcoholic fatty liver disease (NAFLD) in children and adolescents. Numerous studies report that adiponectin (APN) levels are inversely associated with the status of IR in adults with NAFLD. This study aimed to investigate the relationship between serum total APNand homeostasis model assessment insulin resistance(HOMA-IR) in adolescents with NAFLD. METHODS 382 newly-diagnosed NAFLD adolescents, aged 9-16 years old, were enrolled and divided into 3 subgroups according to the APNtertile. Simple and multiple linear regression analyses were performed to assess the correlation between HOMA-IR and APN in boys and girls, respectively. RESULTS The HOMA-IR values tended to decrease in boys according to APN tertiles: 5.6(4.4-7.3) vs. 5.2(4.6-6.9) vs. 4.9(4.1-5.8) (P<0.01), and there was a significant difference in the HOMA-IR values among three APN tertile subgroups in girls(P<0.01).Univariate analysis showed thatbody mass index, waist circumference, weight-to-height ratio, fasting blood glucose, insulin, triglyceride, and APN were significantly associated with HOMA-IR in boys (P<0.05). In girls, body mass index, fasting blood glucose, insulin, total cholesterol, triglyceride, and APN were significantly associated with HOMA-IR (P<0.05).APN was found to be a significant determinant for HOMA-IR only in boys (β=-0.147, P<0.01). CONCLUSION Our findings showed that APN was an independent and significant determinant for increased HOMA-IR in boys with NAFLD. Further studies are needed to explore the underlying mechanisms.
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Affiliation(s)
- Bin Liu
- Department of Neurology, Shanghai Minhang Hospital, Fudan University, Shanghai. China
| | - Huan Zheng
- Department of Cardiology, Worldpath Clinic International, Shanghai. China
| | - Guanghui Liu
- Department of Endocrinology, Tongji Hospital, School of Medicine, Tongji University, Shanghai. China
| | - Zhiling Li
- Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai. China
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35
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Veronda AC, Kline CE, Irish LA. The impact of circadian timing on energy balance: an extension of the energy balance model. Health Psychol Rev 2021; 16:161-203. [PMID: 34387140 DOI: 10.1080/17437199.2021.1968310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
A significant proportion of the population is classified as having overweight or obesity. One framework which has attempted to explain biobehavioral mechanisms influencing the development of overweight and obesity is the energy balance model. According to this model, the body continually attempts to balance energy intake with energy expenditure. When energy intake and energy expenditure become imbalanced, there is an increase in homeostatic and allostatic pressure, generally to either increase energy intake or decrease energy expenditure, so as to restore energy homeostasis.Recent research has indicated that circadian aspects of energy intake and energy expenditure may influence energy balance. This paper provides a narrative review of existing evidence of the role of circadian timing on components of energy balance. Research on the timing of food intake, physical activity, and sleep indicates that unhealthy timing is likely to increase risk of weight gain. Public health guidelines focus on how much individuals eat and sleep, what foods are consumed, and the type and frequency of exercise, but the field of circadian science has begun to demonstrate that when these behaviors occur may also influence overweight and obesity prevention and treatment efforts.
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Affiliation(s)
- Allison C Veronda
- Department of Psychology, North Dakota State University, Fargo, ND, USA
| | - Christopher E Kline
- Department of Health and Human Development, University of Pittsburgh, Pittsburgh, PA, USA
| | - Leah A Irish
- Department of Psychology, North Dakota State University, Fargo, ND, USA.,Sanford Center for Biobehavioral Research, Sanford Research, Fargo, ND, USA
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36
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Ryu J, Hadley JT, Li Z, Dong F, Xu H, Xin X, Zhang Y, Chen C, Li S, Guo X, Zhao JL, Leach RJ, Abdul-Ghani MA, DeFronzo RA, Kamat A, Liu F, Dong LQ. Adiponectin Alleviates Diet-Induced Inflammation in the Liver by Suppressing MCP-1 Expression and Macrophage Infiltration. Diabetes 2021; 70:1303-1316. [PMID: 34162682 PMCID: PMC8275886 DOI: 10.2337/db20-1073] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 03/10/2021] [Indexed: 01/21/2023]
Abstract
Adiponectin is an adipokine that exerts insulin-sensitizing and anti-inflammatory roles in insulin target tissues including liver. While the insulin-sensitizing function of adiponectin has been extensively investigated, the precise mechanism by which adiponectin alleviates diet-induced hepatic inflammation remains elusive. Here, we report that hepatocyte-specific knockout (KO) of the adaptor protein APPL2 enhanced adiponectin sensitivity and prevented mice from developing high-fat diet-induced inflammation, insulin resistance, and glucose intolerance, although it caused fatty liver. The improved anti-inflammatory and insulin-sensitizing effects in the APPL2 hepatocyte-specific KO mice were largely reversed by knocking out adiponectin. Mechanistically, hepatocyte APPL2 deficiency enhances adiponectin signaling in the liver, which blocks TNF-α-stimulated MCP-1 expression via inhibiting the mTORC1 signaling pathway, leading to reduced macrophage infiltration and thus reduced inflammation in the liver. With results taken together, our study uncovers a mechanism underlying the anti-inflammatory role of adiponectin in the liver and reveals the hepatic APPL2-mTORC1-MCP-1 axis as a potential target for treating overnutrition-induced inflammation in the liver.
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Affiliation(s)
- Jiyoon Ryu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Jason T Hadley
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Zhi Li
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Feng Dong
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Huan Xu
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Xiaoban Xin
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Ye Zhang
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Cang Chen
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Senlin Li
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Xiaoning Guo
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Jared L Zhao
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Robin J Leach
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Muhammad A Abdul-Ghani
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Ralph A DeFronzo
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Amrita Kamat
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
- Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX
| | - Feng Liu
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Lily Q Dong
- Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX
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Roy B, Palaniyandi SS. Tissue-specific role and associated downstream signaling pathways of adiponectin. Cell Biosci 2021; 11:77. [PMID: 33902691 PMCID: PMC8073961 DOI: 10.1186/s13578-021-00587-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
According to the World Health Organization, metabolic syndrome (MetS) can be defined as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. The incidence of MetS keeps rising, as at least 35% of the USA population suffers from MetS. One of the worst comorbidities of metabolic syndrome are cardiovascular diseases that significantly amplifies the mortality associated with this syndrome. There is an urgent need to understand the pathophysiology of MetS to find novel diagnosis, treatment and management to mitigate the MetS and associated complications. Altered circulatory adiponectin levels have been implicated in MetS. Adiponectin has numerous biologic functions including antioxidative, anti-nitrative, anti-inflammatory, and cardioprotective effects. Being a pleiotropic hormone of multiple tissues, tissue-specific key signaling pathways of adiponectin will help finding specific target/s to blunt the pathophysiology of metabolic syndrome and associated disorders. The purpose of this review is to elucidate tissue-specific signaling pathways of adiponectin and possibly identify potential therapeutic targets for MetS as well as to evaluate the potential of adiponectin as a biomarker/therapeutic option in MetS.
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Affiliation(s)
- Bipradas Roy
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Integrative Biosciences Center (IBio), Room #3402, 6135 Woodward, Detroit, MI 48202 USA
- Department of Physiology, Wayne State University, Detroit, MI 48202 USA
| | - Suresh Selvaraj Palaniyandi
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Integrative Biosciences Center (IBio), Room #3402, 6135 Woodward, Detroit, MI 48202 USA
- Department of Physiology, Wayne State University, Detroit, MI 48202 USA
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38
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Adiponectin: Structure, Physiological Functions, Role in Diseases, and Effects of Nutrition. Nutrients 2021; 13:nu13041180. [PMID: 33918360 PMCID: PMC8066826 DOI: 10.3390/nu13041180] [Citation(s) in RCA: 164] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
Adiponectin (a protein consisting of 244 amino acids and characterized by a molecular weight of 28 kDa) is a cytokine that is secreted from adipose tissues (adipokine). Available evidence suggests that adiponectin is involved in a variety of physiological functions, molecular and cellular events, including lipid metabolism, energy regulation, immune response and inflammation, and insulin sensitivity. It has a protective effect on neurons and neural stem cells. Adiponectin levels have been reported to be negatively correlated with cancer, cardiovascular disease, and diabetes, and shown to be affected (i.e., significantly increased) by proper healthy nutrition. The present review comprehensively overviews the role of adiponectin in a range of diseases, showing that it can be used as a biomarker for diagnosing these disorders as well as a target for monitoring the effectiveness of preventive and treatment interventions.
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Sattarinezhad A, Rasekhi Kazerouni A, Omrani GR, Shams M. Determinants of serum adiponectin levels: a cross-sectional study. Horm Mol Biol Clin Investig 2021; 42:321-324. [PMID: 33787190 DOI: 10.1515/hmbci-2020-0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 03/04/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. CONTENT Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. SUMMARY AND OUTLOOK Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.
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Affiliation(s)
- Azar Sattarinezhad
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Mesbah Shams
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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40
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Zhang J, Ling N, Lei Y, Peng M, Hu P, Chen M. Multifaceted Interaction Between Hepatitis B Virus Infection and Lipid Metabolism in Hepatocytes: A Potential Target of Antiviral Therapy for Chronic Hepatitis B. Front Microbiol 2021; 12:636897. [PMID: 33776969 PMCID: PMC7991784 DOI: 10.3389/fmicb.2021.636897] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/18/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus (HBV) is considered a “metabolic virus” and affects many hepatic metabolic pathways. However, how HBV affects lipid metabolism in hepatocytes remains uncertain yet. Accumulating clinical studies suggested that compared to non-HBV-infected controls, chronic HBV infection was associated with lower levels of serum total cholesterol and triglycerides and a lower prevalence of hepatic steatosis. In patients with chronic HBV infection, high ALT level, high body mass index, male gender, or old age was found to be positively correlated with hepatic steatosis. Furthermore, mechanisms of how HBV infection affected hepatic lipid metabolism had also been explored in a number of studies based on cell lines and mouse models. These results demonstrated that HBV replication or expression induced extensive and diverse changes in hepatic lipid metabolism, by not only activating expression of some critical lipogenesis and cholesterolgenesis-related proteins but also upregulating fatty acid oxidation and bile acid synthesis. Moreover, increasing studies found some potential targets to inhibit HBV replication or expression by decreasing or enhancing certain lipid metabolism-related proteins or metabolites. Therefore, in this article, we comprehensively reviewed these publications and revealed the connections between clinical observations and experimental findings to better understand the interaction between hepatic lipid metabolism and HBV infection. However, the available data are far from conclusive, and there is still a long way to go before clarifying the complex interaction between HBV infection and hepatic lipid metabolism.
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Affiliation(s)
- Jiaxuan Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu Lei
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingli Peng
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Hu
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Wegeberg AM, Meldgaard T, Baek A, Drewes AM, Vyberg M, Jessen N, Brock B, Brock C. Subcutaneous adipose tissue composition and function are unaffected by liraglutide-induced weight loss in adults with type 1 diabetes. Basic Clin Pharmacol Toxicol 2021; 128:773-782. [PMID: 33624417 PMCID: PMC8251841 DOI: 10.1111/bcpt.13575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/16/2021] [Accepted: 02/18/2021] [Indexed: 12/18/2022]
Abstract
Adipose tissue is the primary energy reservoir of the human body, which also possesses endocrine functions. The glucagon‐like peptide agonist liraglutide produces weight loss, although the specific effects on adipose tissue are unknown. We aimed to characterize the white adipose tissue composition and pericellular fibrosis of subcutaneous adipose tissue in response to liraglutide treatment. Furthermore, we explored the level of circulating free fatty acids, cluster of differentiation 163 (CD163) macrophage marker, leptin and adiponectin. Thirty‐nine adults with type 1 diabetes and polyneuropathy were randomly assigned to 26 weeks of liraglutide or placebo treatment. Biopsies of subcutaneous tissue were formalin‐fixed stained with picrosirius red to visualize collagen or immunohistochemically stained for CD163. Serum concentrations of free fatty acids, CD163, leptin and adiponectin were assessed with immunoassays or multiplex panels. In comparison with placebo, liraglutide induced weight loss (3.38 kg, 95% CI −5.29; −1.48, P < 0.001), but did not cause any differences in cell size, distribution of CD163‐positive cells, pericellular fibrosis and serum levels of free fatty acids, CD163, leptin or adiponectin (all P < 0.1). Additionally, no associations between weight loss, cell size and serum markers were found (all P > 0.08). In conclusion, despite liraglutide's effect on weight loss, sustained alterations in subcutaneous adipose tissue did not seem to appear.
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Affiliation(s)
- Anne-Marie Wegeberg
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Theresa Meldgaard
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Amanda Baek
- The Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark.,Steno Diabetes Center North Denmark, Aalborg University Hospital and Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Mogens Vyberg
- Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Niels Jessen
- The Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Christina Brock
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark.,Steno Diabetes Center North Denmark, Aalborg University Hospital and Clinical Institute, Aalborg University, Aalborg, Denmark
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Allen SL, Quinlan JI, Dhaliwal A, Armstrong MJ, Elsharkawy AM, Greig CA, Lord JM, Lavery GG, Breen L. Sarcopenia in chronic liver disease: mechanisms and countermeasures. Am J Physiol Gastrointest Liver Physiol 2021; 320:G241-G257. [PMID: 33236953 PMCID: PMC8609568 DOI: 10.1152/ajpgi.00373.2020] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with cirrhosis and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and posttransplant complications. In chronic liver disease (CLD), sarcopenia is most commonly defined through the measurement of the skeletal muscle index of the third lumbar spine. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover, which likely occurs due to a decrease in muscle protein synthesis and an elevation in muscle protein breakdown. This imbalance is assumed to arise due to several factors including accelerated starvation, hyperammonemia, amino acid deprivation, chronic inflammation, excessive alcohol intake, and physical inactivity. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to mitochondrial dysfunction and an increase in myostatin expression. Currently, the use of nutritional interventions such as late-evening snacks, branched-chain amino acid supplementation, and physical activity have been proposed to help the management and treatment of sarcopenia. However, little evidence exists to comprehensively support their use in clinical settings. Several new pharmacological strategies, including myostatin inhibition and the nutraceutical Urolithin A, have recently been proposed to treat age-related sarcopenia and may also be of use in CLD. This review highlights the potential molecular mechanisms contributing to sarcopenia in CLD alongside a discussion of existing and potential new treatment strategies.
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Affiliation(s)
- Sophie L. Allen
- 1School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom,2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Jonathan I. Quinlan
- 1School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom,2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Amritpal Dhaliwal
- 2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,3Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom,4Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Matthew J. Armstrong
- 2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,4Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Ahmed M. Elsharkawy
- 2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,3Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom,4Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom
| | - Carolyn A. Greig
- 1School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom,2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,5MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom
| | - Janet M. Lord
- 2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,3Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom,5MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom
| | - Gareth G. Lavery
- 2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,6Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom,7Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partner, Birmingham, United Kingdom
| | - Leigh Breen
- 1School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, United Kingdom,2National Institute for Health Research, Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom,5MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, United Kingdom
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Graffmann N, Ncube A, Martins S, Fiszl AR, Reuther P, Bohndorf M, Wruck W, Beller M, Czekelius C, Adjaye J. A stem cell based in vitro model of NAFLD enables the analysis of patient specific individual metabolic adaptations in response to a high fat diet and AdipoRon interference. Biol Open 2021; 10:bio.054189. [PMID: 33372064 PMCID: PMC7860118 DOI: 10.1242/bio.054189] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease. Its development and progression depend on genetically predisposed susceptibility of the patient towards several ‘hits’ that induce fat storage first and later inflammation and fibrosis. Here, we differentiated induced pluripotent stem cells (iPSCs) derived from four distinct donors with varying disease stages into hepatocyte like cells (HLCs) and determined fat storage as well as metabolic adaptations after stimulations with oleic acid. We could recapitulate the complex networks that control lipid and glucose metabolism and we identified distinct gene expression profiles related to the steatosis phenotype of the donor. In an attempt to reverse the steatotic phenotype, cells were treated with the small molecule AdipoRon, a synthetic analogue of adiponectin. Although the responses varied between cells lines, they suggest a general influence of AdipoRon on metabolism, transport, immune system, cell stress and signalling. Summary: A stem cell based in vitro model of NAFLD recapitulates regulatory networks and suggests a steatosis associated phenotype. AdipoRon treatment influences metabolism, immune system, cell stress and signalling.
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Affiliation(s)
- Nina Graffmann
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Audrey Ncube
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Soraia Martins
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Aurelian Robert Fiszl
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Philipp Reuther
- Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich-Heine University Düsseldorf 40225, Düsseldorf, Germany
| | - Martina Bohndorf
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Wasco Wruck
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
| | - Mathias Beller
- Institute for Mathematical Modeling of Biological Systems, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.,Systems Biology of Lipid Metabolism, Heinrich-Heine University Düsseldorf 40225, Düsseldorf, Germany
| | - Constantin Czekelius
- Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich-Heine University Düsseldorf 40225, Düsseldorf, Germany
| | - James Adjaye
- Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf, Medical faculty, Moorenstrasse 5, 40225 Düsseldorf, Germany
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Vila-Bedmar R, Cruces-Sande M, Arcones AC, Willemen HLDM, Prieto P, Moreno-Indias I, Díaz-Rodríguez D, Francisco S, Jaén RI, Gutiérrez-Repiso C, Heijnen CJ, Boscá L, Fresno M, Kavelaars A, Mayor F, Murga C. GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity. Cell Mol Life Sci 2020; 77:4957-4976. [PMID: 31927610 PMCID: PMC11105060 DOI: 10.1007/s00018-019-03442-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 12/18/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023]
Abstract
Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/- mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/- mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations.
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Affiliation(s)
- Rocío Vila-Bedmar
- Departamento de ciencias básicas de la salud, área de Bioquímica y Biología Molecular, Universidad Rey Juan Carlos (URJC), Madrid, Spain
| | - Marta Cruces-Sande
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Alba C Arcones
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Hanneke L D M Willemen
- Laboratory of Translational Immunology (LTI), University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Patricia Prieto
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Isabel Moreno-Indias
- CIBER de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Endocrinología y Nutrición, Hospital Universitario Virgen de Victoria de Malaga, Universidad de Málaga, Málaga, Spain
| | - Daniel Díaz-Rodríguez
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain
| | - Sara Francisco
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain
| | - Rafael I Jaén
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Carolina Gutiérrez-Repiso
- CIBER de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Endocrinología y Nutrición, Hospital Universitario Virgen de Victoria de Malaga, Universidad de Málaga, Málaga, Spain
| | - Cobi J Heijnen
- University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lisardo Boscá
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
| | - Manuel Fresno
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | | | - Federico Mayor
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain.
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
| | - Cristina Murga
- Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049, Madrid, Spain.
- Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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45
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Chang ML, Yang Z, Yang SS. Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression. Int J Mol Sci 2020; 21:E8308. [PMID: 33167521 PMCID: PMC7663948 DOI: 10.3390/ijms21218308] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.
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Affiliation(s)
- Ming-Ling Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Zinger Yang
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Sien-Sing Yang
- Liver Center, Cathay General Hospital Medical Center, Taipei 10630, Taiwan;
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46
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Shabalala SC, Dludla PV, Mabasa L, Kappo AP, Basson AK, Pheiffer C, Johnson R. The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling. Biomed Pharmacother 2020; 131:110785. [PMID: 33152943 DOI: 10.1016/j.biopha.2020.110785] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, as it affects up to 30 % of adults in Western countries. Moreover, NAFLD is also considered an independent risk factor for cardiovascular diseases. Insulin resistance and inflammation have been identified as key factors in the pathophysiology of NAFLD. Although the mechanisms associated with the development of NAFLD remain to be fully elucidated, a complex interaction between adipokines and cytokines appear to play a crucial role in the development of this condition. Adiponectin is the most common adipokine known to be inversely linked with insulin resistance, lipid accumulation, inflammation and NAFLD. Consequently, the focus has been on the use of new therapies that may enhance hepatic expression of adiponectin downstream targets or increase the serum levels of adiponectin in the treatment NAFLD. While currently used therapies show limited efficacy in this aspect, accumulating evidence suggest that various dietary polyphenols may stimulate adiponectin levels, offering potential protection against the development of insulin resistance, inflammation and NAFLD as well as associated conditions of metabolic syndrome. As such, this review provides a better understanding of the role polyphenols play in modulating adiponectin signaling to protect against NAFLD. A brief discussion on the regulation of adiponectin during disease pathophysiology is also covered to underscore the potential protective effects of polyphenols against NAFLD. Some of the prominent polyphenols described in the manuscript include aspalathin, berberine, catechins, chlorogenic acid, curcumin, genistein, piperine, quercetin, and resveratrol.
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Affiliation(s)
- Samukelisiwe C Shabalala
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Department of Biochemistry and Microbiology, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa, 3886, South Africa
| | - Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy
| | - Lawrence Mabasa
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa
| | - Abidemi P Kappo
- Department of Biochemistry, Faculty of Science, University of Johannesburg, Auckland Park, 2006, South Africa
| | - Albertus K Basson
- Department of Biochemistry and Microbiology, Faculty of Science and Agriculture, University of Zululand, KwaDlangezwa, 3886, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Department of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa
| | - Rabia Johnson
- Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa; Department of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa.
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Tura A, Thieme C, Brosig A, Merz H, Ranjbar M, Vardanyan S, Zuo H, Maassen T, Kakkassery V, Grisanti S. Lower Levels of Adiponectin and Its Receptor Adipor1 in the Uveal Melanomas With Monosomy-3. Invest Ophthalmol Vis Sci 2020; 61:12. [PMID: 32396633 PMCID: PMC7405622 DOI: 10.1167/iovs.61.5.12] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Adiponectin is an insulin-sensitizing and anticarcinogenic hormone that is encoded by a gene on chromosome 3. Here, we analyzed the expression of adiponectin and its receptor Adipor1 in primary uveal melanoma (UM) with regard to the monosomy-3 status and clinical factors, as well as the physiological response of UM cells to adiponectin. Methods Immunohistochemistry was performed on the primary UM of 34 patients. Circulating melanoma cells (CMC) were isolated by immunomagnetic enrichment. Monosomy-3 was evaluated by Immuno-FISH. Gene expression was analyzed using the RNAseq data of The Cancer Genome Atlas study. Cultures of choroidal melanocytes and UM were established from the samples of two patients. The proliferative potential of the UM cell lines Mel-270 and OMM-2.5 was determined by immunocytochemistry, immunoblotting, cell cycle analysis, nucleolar staining, and adenosine triphosphate (ATP) levels. Results UM with monosomy-3 exhibited a lower immunoreactivity for adiponectin and Adipor1, which was associated with monosomy-3-positive CMC and the development of extraocular growth or metastases. Both proteins were more abundant in the irradiated tumors and present in the cultured cells. Gene expression profile indicated the impairment of adiponectin-mediated signaling in the monosomy-3 tumors. Adiponectin induced a significant decline in the ATP levels, Ki-67 expression, cells in the G2/M phase, and nucleolar integrity in UM cultures. Conclusions Adiponectin deficiency appears to enhance the metastatic potential of the UM cells with monosomy-3 and the termination of tumor dormancy. Counteracting insulin resistance and improving the serum adiponectin levels might therefore be a valuable approach to prevent or delay the UM metastases.
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48
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Zhu D, Xu L, Wei X, Xia B, Gong Y, Li Q, Chen X. PPARγ enhanced Adiponectin polymerization and trafficking by promoting RUVBL2 expression during adipogenic differentiation. Gene 2020; 764:145100. [PMID: 32877748 DOI: 10.1016/j.gene.2020.145100] [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: 06/15/2020] [Revised: 08/16/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023]
Abstract
Adipocyte differentiation is an essential part of adipose tissue development, and is closely related to obesity and obesity-related diseases. In this study, we found that the expression of PPARγ, RUVBL2 and Adiponectin were concurrently obviously increased in the 5th-7th day of 3T3-L1 cell differentiation. PPARγ overexpression or the PPARγ activator facilitated Adiponectin trafficking and secretion and upregulated RUVBL2 expression as well as AS160 phosphorylation during adipogenic differentiation of 3T3-L1 cells. Consistently RUVBL2 overexpression also enhanced the polymerization and secretion of Adiponectin, in contrast, RUVBL2 knockdown reduced Adiponectin secretion. Further, PPARγ significantly enhanced RUVBL2 promoter activity and transcription. The progressive deletions and mutations of RUVBL2 promoter for PPARγ binding sites suggested that the PPARγ binding motif situated at -804/-781 bp is an essential component required for RUVBL2 promoter activity. Chromatin immunoprecipitation (ChIP) assays determined that PPARγ can directly interact with the RUVBL2 promoter DNA. Taken together, these data suggest that PPARγ promotes the expression, polymerization and secretion of Adiponectin by activating RUVBL2 transcriptionally, which accelerates 3T3-L1 cell differentiation.
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Affiliation(s)
- Daiyun Zhu
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Le Xu
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Xuan Wei
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Benzeng Xia
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Yuqing Gong
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Qinjin Li
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, PR China
| | - Xiaodong Chen
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, PR China.
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Analysis of APPL1 Gene Polymorphisms in Patients with a Phenotype of Maturity Onset Diabetes of the Young. J Pers Med 2020; 10:jpm10030100. [PMID: 32854233 PMCID: PMC7565648 DOI: 10.3390/jpm10030100] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/03/2020] [Accepted: 08/22/2020] [Indexed: 02/06/2023] Open
Abstract
The APPL1 gene encodes a protein mediating the cross-talk between adiponectin and insulin signaling. Recently, it was found that APPL1 mutations can cause maturity onset diabetes of the young, type 14. Here, an analysis of APPL1 was performed in patients with a maturity-onset diabetes of the young (MODY) phenotype, and prevalence of these mutations was estimated in a Russian population, among type 2 diabetes mellitus (T2DM) and MODY patients. Whole-exome sequencing or targeted sequencing was performed on 151 probands with a MODY phenotype, with subsequent association analysis of one of identified variants, rs11544593, in a white population of Western Siberia (276 control subjects and 169 T2DM patients). Thirteen variants were found in APPL1, three of which (rs79282761, rs138485817, and rs11544593) are located in exons. There were no statistically significant differences in the frequencies of rs11544593 alleles and genotypes between T2DM patients and the general population. In the MODY group, AG rs11544593 genotype carriers were significantly more frequent (AG vs. AA + GG: odds ratio 1.83, confidence interval 1.15-2.90, p = 0.011) compared with the control group. An association of rs11544593 with blood glucose concentration was revealed in the MODY group. The genotyping data suggest that rs11544593 may contribute to carbohydrate metabolism disturbances.
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Yang J, Guo Y, Henning SM, Chan B, Long J, Zhong J, Acin-Perez R, Petcherski A, Shirihai O, Heber D, Li Z. Ellagic Acid and Its Microbial Metabolite Urolithin A Alleviate Diet-Induced Insulin Resistance in Mice. Mol Nutr Food Res 2020; 64:e2000091. [PMID: 32783299 DOI: 10.1002/mnfr.202000091] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 07/27/2020] [Indexed: 12/15/2022]
Abstract
SCOPE This work aims at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet-induced IR. METHODS AND RESULTS DBA2J mice are fed a high fat/high sucrose diet (HF/HS) for 8 weeks to induce IR and then 0.1% EA, UA, or EA and UA (EA+UA) are added to the HF/HS-diet for another 8 weeks. UA significantly decreases fasting glucose and increases adiponectin compared with HF/HS-controls. During intraperitoneal insulin tolerance test, EA+UA significantly improve insulin-mediated glucose lowering effects at 15 and 120 min and reduce blood triglycerides compared with HF/HS-controls. Serum free fatty acids are significantly decreased by EA, UA, and EA+UA. Differential expression of genes related to mitochondrial function by EA, UA, and EA+UA in liver and skeletal muscle is observed. Primary hepatocytes from IR-mice have higher proton leak, basal and ATP-linked oxygen consumption rates compared with healthy controls. EA and EA+UA but not UA reduce the proton leak in hepatocytes from IR-mice. CONCLUSION EA and UA induce different metabolic benefits in IR mice. The effects of EA and UA on mitochondrial function suggest a potentially novel mechanism modulating metabolism.
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Affiliation(s)
- Jieping Yang
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Yuanqiang Guo
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Susanne M Henning
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Brenda Chan
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Jianfeng Long
- Department of Clinical Nutrition, 2nd XiangYa Hospital, Central South University, Changsha, 410011, China
| | - Jin Zhong
- Department of Pathology and Laboratory Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA, 90095, USA
| | - Rebeca Acin-Perez
- Division of Endocrinology, Department of Medicine, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Anton Petcherski
- Division of Endocrinology, Department of Medicine, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Orian Shirihai
- Division of Endocrinology, Department of Medicine, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - David Heber
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Zhaoping Li
- Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.,Department of Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA, 90095, USA
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