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Ahmadi S, Ohkubo T. A Bird's-Eye Overview of Leptin and Female Reproduction -with Mammalian Comparisons. J Poult Sci 2025; 62:2025007. [PMID: 39916995 PMCID: PMC11794366 DOI: 10.2141/jpsa.2025007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/10/2025] [Indexed: 02/09/2025] Open
Abstract
Leptin, a key regulator of reproductive physiology, influences various processes in vertebrates, including oocyte proliferation, embryogenesis, the onset of puberty, ovarian function, and follicle development. In mammals, leptin affects steroidogenesis, folliculogenesis, and hormonal regulation through the hypothalamic-pituitary-gonadal axis. Instead, in avian species, leptin-controlled mechanisms are poorly understood, because birds do not produce leptin in adipocytes. In birds, leptin is expressed in the brain, pituitary glands, and gonads, where it enhances ovarian function and egg-laying performance, particularly during feed deprivation. In this review, we discuss and summarize the recently discovered role of leptin in regulating ovarian function during different life stages in birds and compare it with its function in mammals.
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Affiliation(s)
- Sadequllah Ahmadi
- College of Agriculture, Ibaraki University, 3-21-1 Chuo, Ami, Ibaraki 300-0393, Japan
- Faculty of Animal Science, Afghanistan National Agricultural Sciences and Technology University (ANASTU), Kandahar 3801, Afghanistan
| | - Takeshi Ohkubo
- College of Agriculture, Ibaraki University, 3-21-1 Chuo, Ami, Ibaraki 300-0393, Japan
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2
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Duan F, Wu J, Chang J, Peng H, Liu Z, Liu P, Han X, Sun T, Shang D, Yang Y, Li Z, Li P, Liu Y, Zhu Y, Lv Y, Guo X, Zhao Y, An Y. Deciphering endocrine function of adipose tissue and its significant influences in obesity-related diseases caused by its dysfunction. Differentiation 2025; 141:100832. [PMID: 39709882 DOI: 10.1016/j.diff.2024.100832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024]
Abstract
Current research has found that adipose tissue is not only involved in energy metabolism, but also a highly active endocrine organ that secretes various adipokines, including adiponectin, leptin, resistin and apelin, which are involved in the regulation of physiology and pathology of tissues and organs throughout the body. With the yearly increasing incidence, obesity has become a risk factor for a variety of pathological changes, including inflammation and metabolic syndrome in various system (endocrine, circulatory, locomotor and central nervous system). Thus these symptoms lead to multi-organ dysfunctions, including the heart, liver, kidneys, brain and joints. An in-depth summary of the roles of adipokines in the regulation of other tissues and organs can help to provide more effective therapeutic strategies for obesity-related diseases and explore potential therapeutic targets. Therefore, this review has retrospected the endocrine function of adipose tissue under obesity and the role of dysregulated adipokine secretion in related diseases and the underlying mechanisms, in order to provide a theoretical basis for targeting adipokine-mediated systemic dysregulation.
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Affiliation(s)
- Feiyi Duan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiaoyan Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Jiayi Chang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Haoyuan Peng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zitao Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengfei Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Xu Han
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Tiantian Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Dandan Shang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yutian Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Zhihao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Pengkun Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yixuan Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yonghao Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Yunzhi Lv
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; School of Stomatology, Henan University, Kaifeng, 475004, China
| | - Xiumei Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Ying Zhao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China
| | - Yang An
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Henan University, Kaifeng, 475004, China; Henan Provincial Engineering Center for Tumor Molecular Medicine, Kaifeng Key Laboratory of Cell Signal Transduction, Henan University, Kaifeng, 475004, China.
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Ansarin A, Mahdavi AM, Javadivala Z, Shanehbandi D, Zarredar H, Ansarin K. The cross-talk between leptin and circadian rhythm signaling proteins in physiological processes: a systematic review. Mol Biol Rep 2023; 50:10427-10443. [PMID: 37874505 DOI: 10.1007/s11033-023-08887-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 10/04/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND Today, modern lifestyles and disrupted sleep patterns cause circadian clock rhythm impairments that are associated with altered leptin levels, which subsequently affect a wide range of physiological processes and have significant health burdens on societies. Nevertheless, there has been no systematic review of circadian clock genes and proteins, leptin, and related signaling pathways. METHODS Accordingly, we systematically reviewed circadian clock proteins, leptin, and molecular mechanisms between them by searching Pubmed, Scopus, ProQuest, Web of Sciences, and Google Scholar until September 2022. After considering the inclusion and exclusion criteria, 20 animal studies were selected. The risk of bias was assessed in each study. RESULTS The results clarified the reciprocal interconnected relationship between circadian clock genes and leptin. Circadian clock genes regulate leptin expression and signaling via different mechanisms, such as CLOCK-BMAL1 heterodimers, which increase the expression of PPARs. PPARs induce the expression of C/EBPα, a key factor in upregulating leptin expression. CLOCK-BMAL1 also induces the expression of Per1 and Rev-erb genes. PER1 activates mTORC1 and mTORC1 enhances the expression of C/EBPα. In addition, REV-ERBs activate the leptin signaling pathway. Also, leptin controls the expression of circadian clock genes by triggering the AMPK and ERK/MAPK signaling pathways, which regulate the activity of PPARs. Moreover, the roles of these molecular mechanisms are elucidated in different physiological processes and organs. CONCLUSIONS Crosstalk between circadian clock genes and leptin and their affecting elements should be considered in the selection of new therapeutic targets for related disorders, especially obesity and metabolic impairments.
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Affiliation(s)
- Atefeh Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran
| | - Aida Malek Mahdavi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Javadivala
- Department of Health Education & Promotion, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran
| | - Khalil Ansarin
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Pashmineh Research Complex, Daneshgah Street, P.O. Box: 5448151429, Tabriz, Iran.
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Schilloks MC, Giese IM, Hinrichs A, Korbonits L, Hauck SM, Wolf E, Deeg CA. Effects of GHR Deficiency and Juvenile Hypoglycemia on Immune Cells of a Porcine Model for Laron Syndrome. Biomolecules 2023; 13:biom13040597. [PMID: 37189345 DOI: 10.3390/biom13040597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/16/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023] Open
Abstract
Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (GHR). A GHR-knockout (GHR-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in GHR-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4− and CD4+ lymphocytes and IFN-α serum levels between wild-type (WT) controls and GHR-KO pigs, which revealed significant differences in the relative proportion of the CD4+CD8α− subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4+ and CD4− lymphocyte populations revealed multiple significant protein abundance differences between GHR-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of GHR-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.
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Estienne A, Brossaud A, Reverchon M, Ramé C, Froment P, Dupont J. Adipokines Expression and Effects in Oocyte Maturation, Fertilization and Early Embryo Development: Lessons from Mammals and Birds. Int J Mol Sci 2020; 21:E3581. [PMID: 32438614 PMCID: PMC7279299 DOI: 10.3390/ijms21103581] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 12/28/2022] Open
Abstract
Some evidence shows that body mass index in humans and extreme weights in animal models, including avian species, are associated with low in vitro fertilization, bad oocyte quality, and embryo development failures. Adipokines are hormones mainly produced and released by white adipose tissue. They play a key role in the regulation of energy metabolism. However, they are also involved in many other physiological processes including reproductive functions. Indeed, leptin and adiponectin, the most studied adipokines, but also novel adipokines including visfatin and chemerin, are expressed within the reproductive tract and modulate female fertility. Much of the literature has focused on the physiological and pathological roles of these adipokines in ovary, placenta, and uterine functions. The purpose of this review is to summarize the current knowledge regarding the involvement of leptin, adiponectin, visfatin, and chemerin in the oocyte maturation, fertilization, and embryo development in both mammals and birds.
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Affiliation(s)
- Anthony Estienne
- INRAE UMR 85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France; (A.E.); (A.B.); (C.R.); (P.F.)
- CNRS UMR 7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France
- Université François Rabelais de Tours, F-37041 Tours, France
- Institut Français du Cheval et de l’Equitation, Centre INRAE Val de Loire, F-37380 Nouzilly, France
| | - Adeline Brossaud
- INRAE UMR 85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France; (A.E.); (A.B.); (C.R.); (P.F.)
- CNRS UMR 7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France
- Université François Rabelais de Tours, F-37041 Tours, France
- Institut Français du Cheval et de l’Equitation, Centre INRAE Val de Loire, F-37380 Nouzilly, France
| | - Maxime Reverchon
- SYSAAF-Syndicat des Sélectionneurs Avicoles et Aquacoles Français, Centre INRAE Val de Loire, F-37380 Nouzilly, France;
| | - Christelle Ramé
- INRAE UMR 85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France; (A.E.); (A.B.); (C.R.); (P.F.)
- CNRS UMR 7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France
- Université François Rabelais de Tours, F-37041 Tours, France
- Institut Français du Cheval et de l’Equitation, Centre INRAE Val de Loire, F-37380 Nouzilly, France
| | - Pascal Froment
- INRAE UMR 85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France; (A.E.); (A.B.); (C.R.); (P.F.)
- CNRS UMR 7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France
- Université François Rabelais de Tours, F-37041 Tours, France
- Institut Français du Cheval et de l’Equitation, Centre INRAE Val de Loire, F-37380 Nouzilly, France
| | - Joëlle Dupont
- INRAE UMR 85 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France; (A.E.); (A.B.); (C.R.); (P.F.)
- CNRS UMR 7247 Physiologie de la Reproduction et des Comportements, F-37380 Nouzilly, France
- Université François Rabelais de Tours, F-37041 Tours, France
- Institut Français du Cheval et de l’Equitation, Centre INRAE Val de Loire, F-37380 Nouzilly, France
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Leung YB, Cave NJ, Heiser A, Edwards PJB, Godfrey AJR, Wester T. Metabolic and Immunological Effects of Intermittent Fasting on a Ketogenic Diet Containing Medium-Chain Triglycerides in Healthy Dogs. Front Vet Sci 2020; 6:480. [PMID: 31998762 PMCID: PMC6961514 DOI: 10.3389/fvets.2019.00480] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022] Open
Abstract
In several species, intermittent fasting (IF) has been shown to have beneficial effects, including delayed aging, increased lifespan, increased insulin sensitivity, reduced ischemic tissue damage, delayed onset of neurodegenerative disease and improved neuronal repair following injury. However, the metabolic and immunological effects of IF have not been well-established in dogs. The aim of this study was to examine the effects of a 48 h IF regimen using a low fat and a high fat diet in healthy dogs by quantifying the metabolic, hormonal, and immunological changes. We hypothesized that IF dogs would have higher blood ketone and ghrelin concentrations, lower blood leptin, insulin and glucose concentrations, and signs of immunosuppression compared to dogs eating daily. Ten healthy adult dogs were randomized into three group and underwent three feeding regimes in a 3 × 3 Latin square design: twice a day feeding on a low fat (23% energy from fat; LF) diet, 48 h fasting on a low fat diet, and 48 h fasting on a high fat enriched with medium-chain triglycerides (68% energy from fat; HF) diet. Body weight, food intake, activity, blood glucose, β-hydroxybutyrate, leptin, ghrelin, and insulin were measured. Lymphocyte proliferation and neutrophil/macrophage phagocytosis and respiratory burst were measured as markers of immune function. Nuclear magnetic resonance spectroscopy was used to relatively quantify plasma metabolites. When the dogs were IF on a HF diet, they had the highest concentration of blood ketones (mean 0.061 mmol/L, SD 0.024), whereas they had the lowest concentration (mean 0.018 mmol/L, SD 0.004) when fed daily. Blood glucose and insulin concentrations were lower in IF dogs on a HF diet compared to daily feeding or IF on a LF diet. There was an increase in plasma β-hydroxybutyrate concentrations, and a reduction in glucose and insulin concentrations when dogs were IF on a HF diet. There was only a decline in the immune parameters studied when the dogs were IF on a LF diet, which was not seen when on the HF diet. The results of this study indicate the potential of IF to be further investigated as a potential beneficial feeding regime for dogs.
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Affiliation(s)
- Y. Becca Leung
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Nick J. Cave
- School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Axel Heiser
- AgResearch, Grasslands Research Centre, Hopkirk Research Institute, Palmerston North, New Zealand
| | | | | | - Tim Wester
- School of Agriculture and Environment, Massey University, Palmerston North, New Zealand
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Becerril S, Rodríguez A, Catalán V, Ramírez B, Unamuno X, Portincasa P, Gómez-Ambrosi J, Frühbeck G. Functional Relationship between Leptin and Nitric Oxide in Metabolism. Nutrients 2019; 11:2129. [PMID: 31500090 PMCID: PMC6769456 DOI: 10.3390/nu11092129] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/23/2019] [Accepted: 09/02/2019] [Indexed: 12/28/2022] Open
Abstract
Leptin, the product of the ob gene, was originally described as a satiety factor, playing a crucial role in the control of body weight. Nevertheless, the wide distribution of leptin receptors in peripheral tissues supports that leptin exerts pleiotropic biological effects, consisting of the modulation of numerous processes including thermogenesis, reproduction, angiogenesis, hematopoiesis, osteogenesis, neuroendocrine, and immune functions as well as arterial pressure control. Nitric oxide (NO) is a free radical synthesized from L-arginine by the action of the NO synthase (NOS) enzyme. Three NOS isoforms have been identified: the neuronal NOS (nNOS) and endothelial NOS (eNOS) constitutive isoforms, and the inducible NOS (iNOS). NO mediates multiple biological effects in a variety of physiological systems such as energy balance, blood pressure, reproduction, immune response, or reproduction. Leptin and NO on their own participate in multiple common physiological processes, with a functional relationship between both factors having been identified. The present review describes the functional relationship between leptin and NO in different physiological processes.
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Affiliation(s)
- Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Xabier Unamuno
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Medical Engineering Laboratory, University of Navarra, 31008 Pamplona, Spain.
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Policlinico Hospital, 70124 Bari, Italy.
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 31008 Pamplona, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain.
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
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8
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Becerril S, Rodríguez A, Catalán V, Ramírez B, Unamuno X, Gómez-Ambrosi J, Frühbeck G. iNOS Gene Ablation Prevents Liver Fibrosis in Leptin-Deficient ob/ob Mice. Genes (Basel) 2019; 10:genes10030184. [PMID: 30818874 PMCID: PMC6470935 DOI: 10.3390/genes10030184] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/14/2019] [Accepted: 02/22/2019] [Indexed: 12/30/2022] Open
Abstract
The role of extracellular matrix (ECM) remodeling in fibrosis progression in nonalcoholic fatty liver disease (NAFLD) is complex and dynamic, involving the synthesis and degradation of different ECM components, including tenascin C (TNC). The aim was to analyze the influence of inducible nitric oxide synthase (iNOS) deletion on inflammation and ECM remodeling in the liver of ob/ob mice, since a functional relationship between leptin and iNOS has been described. The expression of molecules involved in inflammation and ECM remodeling was analyzed in the liver of double knockout (DBKO) mice simultaneously lacking the ob and the iNOS genes. Moreover, the effect of leptin was studied in the livers of ob/ob mice and compared to wild-type rodents. Liver inflammation and fibrosis were increased in leptin-deficient mice. As expected, leptin treatment reverted the obesity phenotype. iNOS deletion in ob/ob mice improved insulin sensitivity, inflammation, and fibrogenesis, as evidenced by lower macrophage infiltration and collagen deposition as well as downregulation of the proinflammatory and profibrogenic genes including Tnc. Circulating TNC levels were also decreased. Furthermore, leptin upregulated TNC expression and release via NO-dependent mechanisms in AML12 hepatic cells. iNOS deficiency in ob/ob mice improved liver inflammation and ECM remodeling-related genes, decreasing fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in hepatocytes, suggesting an important role of this alarmin in the development of NAFLD.
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Affiliation(s)
- Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
| | - Amaia Rodríguez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
| | - Victoria Catalán
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
| | - Beatriz Ramírez
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
| | - Xabier Unamuno
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Medical Engineering Laboratory, University of Navarra, Pamplona, Spain.
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain.
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Spain.
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
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9
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Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA, Gómez R, Gualillo O. Obesity, Fat Mass and Immune System: Role for Leptin. Front Physiol 2018; 9:640. [PMID: 29910742 PMCID: PMC5992476 DOI: 10.3389/fphys.2018.00640] [Citation(s) in RCA: 269] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 05/11/2018] [Indexed: 12/13/2022] Open
Abstract
Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.
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Affiliation(s)
- Vera Francisco
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Jesús Pino
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Victor Campos-Cabaleiro
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Clara Ruiz-Fernández
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Antonio Mera
- Servizo Galego de Saude, Division of Rheumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Miguel A Gonzalez-Gay
- Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria and IDIVAL, Santander, Spain
| | - Rodolfo Gómez
- Musculoskeletal Pathology Group, Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
| | - Oreste Gualillo
- The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain
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10
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Growth Hormone Secretion Patterns in German Landrace (DL) Fetuses and Piglets Compared to DL Piglets with Inherited 1,25-Dihydroxyvitamin D3 Deficiency. Nutrients 2018; 10:nu10050617. [PMID: 29762475 PMCID: PMC5986497 DOI: 10.3390/nu10050617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 05/07/2018] [Accepted: 05/09/2018] [Indexed: 11/24/2022] Open
Abstract
The regulation of growth hormone (GH) release during prenatal development and during early postnatal life is not entirely clarified. In this study plasma GH concentrations in pigs with inherited pseudo vitamin D deficiency type I (PDDR-I), which regularly show growth retardation, were compared during ontogeny with unaffected pigs of the same breed (German Landrace, DL) as control. Plasma GH concentrations were measured in plasma of chronically catheterized fetuses (beginning on day 101 after mating or after artificial insemination) and in piglets (day 37 postpartum (p.p.)—day 42 p.p.) of both lines. A growth curve beginning at day 7 p.p. was recorded for both lines. The relative amount of GH receptor (GHR) mRNA in liver was quantified by competitive reverse transcription polymerase chain reaction in piglets at day 42 p.p. A trend for higher GH concentrations was observed in PDDR-I fetuses (p < 0.1). In PDDR-I piglets compared to DL piglets higher plasma GH values (p < 0.01), were observed despite lower body weight. The relative quantity of GHR mRNA in liver was not significantly different between the two lines. Piglets with an inherited defect of vitamin D synthesis showed higher GH concentrations. A hormonal imprinting by low 1,25(OH)2D3 could be one reason for our observations and should be analysed in detail in future.
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11
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Targeted disruption of the iNOS gene improves adipose tissue inflammation and fibrosis in leptin-deficient ob/ob mice: role of tenascin C. Int J Obes (Lond) 2018; 42:1458-1470. [PMID: 29449623 DOI: 10.1038/s41366-018-0005-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 12/12/2017] [Accepted: 12/21/2017] [Indexed: 01/14/2023]
Abstract
BACKGROUND/OBJECTIVES Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. SUBJECTS/METHODS The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg-1 day-1) and pair-fed]. RESULTS Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. CONCLUSIONS Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.
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12
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Pérez-Pérez A, Vilariño-García T, Fernández-Riejos P, Martín-González J, Segura-Egea JJ, Sánchez-Margalet V. Role of leptin as a link between metabolism and the immune system. Cytokine Growth Factor Rev 2017; 35:71-84. [PMID: 28285098 DOI: 10.1016/j.cytogfr.2017.03.001] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Revised: 03/01/2017] [Accepted: 03/02/2017] [Indexed: 12/24/2022]
Abstract
Leptin is an adipocyte-derived hormone not only with an important role in the central control of energy metabolism, but also with many pleiotropic effects in different physiological systems. One of these peripheral functions of leptin is a regulatory role in the interplay between energy metabolism and the immune system, being a cornerstone of the new field of immunometabolism. Leptin receptor is expressed throughout the immune system and the regulatory effects of leptin include cells from both the innate and adaptive immune system. Leptin is one of the adipokines responsible for the inflammatory state found in obesity that predisposes not only to type 2 diabetes, metabolic syndrome and cardiovascular disease, but also to autoimmune and allergic diseases. Leptin is an important mediator of the immunosuppressive state in undernutrition status. Placenta is the second source of leptin and it may play a role in the immunomodulation during pregnancy. Finally, recent work has pointed to the participation of leptin and leptin receptor in the pathophysiology of inflammation in oral biology. Therefore, leptin and leptin receptor should be considered for investigation as a marker of inflammation and immune activation in the frontier of innate-adaptive system, and as possible targets for intervention in the immunometabolic mediated pathophysiology.
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Affiliation(s)
- Antonio Pérez-Pérez
- Department of Medical Biochemistry and Molecular Biology and Immunology, Medical School and Department of Clinical Biochemistry, Virgen Macarena University Hospital, University of Seville, Spain
| | - Teresa Vilariño-García
- Department of Medical Biochemistry and Molecular Biology and Immunology, Medical School and Department of Clinical Biochemistry, Virgen Macarena University Hospital, University of Seville, Spain
| | - Patricia Fernández-Riejos
- Department of Medical Biochemistry and Molecular Biology and Immunology, Medical School and Department of Clinical Biochemistry, Virgen Macarena University Hospital, University of Seville, Spain
| | - Jenifer Martín-González
- Department of Stomatology (Endodontics Section), School of Dentistry, University of Seville, Seville, Spain
| | - Juan José Segura-Egea
- Department of Stomatology (Endodontics Section), School of Dentistry, University of Seville, Seville, Spain
| | - Víctor Sánchez-Margalet
- Department of Medical Biochemistry and Molecular Biology and Immunology, Medical School and Department of Clinical Biochemistry, Virgen Macarena University Hospital, University of Seville, Spain.
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13
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Ubags NDJ, Stapleton RD, Vernooy JHJ, Burg E, Bement J, Hayes CM, Ventrone S, Zabeau L, Tavernier J, Poynter ME, Parsons PE, Dixon AE, Wargo MJ, Littenberg B, Wouters EFM, Suratt BT. Hyperleptinemia is associated with impaired pulmonary host defense. JCI Insight 2016; 1. [PMID: 27347561 DOI: 10.1172/jci.insight.82101] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.
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Affiliation(s)
- Niki D J Ubags
- Department of Respiratory Medicine, Maastricht University Medical Centre+, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands; Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Renee D Stapleton
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Juanita H J Vernooy
- Department of Respiratory Medicine, Maastricht University Medical Centre+, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
| | - Elianne Burg
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Jenna Bement
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Catherine M Hayes
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Sebastian Ventrone
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Lennart Zabeau
- Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Ghent University, Ghent, Belgium
| | - Jan Tavernier
- Flanders Institute for Biotechnology (VIB), Department of Medical Protein Research, Ghent University, Ghent, Belgium
| | - Matthew E Poynter
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Polly E Parsons
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Anne E Dixon
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Matthew J Wargo
- Department of Microbiology & Molecular Genetics, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Benjamin Littenberg
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
| | - Emiel F M Wouters
- Department of Respiratory Medicine, Maastricht University Medical Centre+, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
| | - Benjamin T Suratt
- Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont, USA
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14
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Wensveen FM, Valentić S, Šestan M, Wensveen TT, Polić B. Interactions between adipose tissue and the immune system in health and malnutrition. Semin Immunol 2015; 27:322-33. [PMID: 26603491 DOI: 10.1016/j.smim.2015.10.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 10/26/2015] [Accepted: 10/27/2015] [Indexed: 02/07/2023]
Abstract
Adipose tissue provides the body with a storage depot of nutrients that is drained during times of starvation and replenished when food sources are abundant. As such, it is the primary sensor for nutrient availability in the milieu of an organism, which it communicates to the body through the excretion of hormones. Adipose tissue regulates a multitude of body functions associated with metabolism, such as gluconeogenesis, feeding and nutrient uptake. The immune system forms a vital layer of protection against micro-organisms that try to gain access to the nutrients contained in the body. Because infections need to be resolved as quickly as possible, speed is favored over energy-efficiency in an immune response. Especially when immune cells are activated, they switch to fast, but energy-inefficient anaerobic respiration to fulfill their energetic needs. Despite the necessity for an effective immune system, it is not given free rein in its energy expenditure. Signals derived from adipose tissue limit immune cell numbers and activity under conditions of nutrient shortage, whereas they allow proper immune cell activity when food sources are sufficiently available. When excessive fat accumulation occurs, such as in diet-induced obesity, adipose tissue becomes the site of pathological immune cell activation, causing chronic low-grade systemic inflammation. Obesity is therefore associated with a number of disorders in which the immune system plays a central role, such as atherosclerosis and non-alcoholic steatohepatitis. In this review, we will discuss the way in which adipose tissue regulates activity of the immune system under healthy and pathological conditions.
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Affiliation(s)
- Felix M Wensveen
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia; Department of Experimental Immunology, Amsterdam Medical Centre, Amsterdam, The Netherlands
| | - Sonja Valentić
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Marko Šestan
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | | | - Bojan Polić
- Department of Histology & Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
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15
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Abstract
PURPOSE OF REVIEW This review summarizes current knowledge on the contribution of mesenteric adipose tissue in intestinal inflammation. We will describe the cellular and humoral characteristics of creeping fat, their potential impact for Crohn's disease and propose a working model for the critical interplay between the creeping fat and the inflamed intestine. RECENT FINDINGS Creeping fat can be distinguished from healthy adipose tissue by its distinctively small adipocytes, by a specific microenvironment defined by high levels of adipokines and by a dominant immune cell infiltration. In Crohn's disease transmural inflammation facilitates increased bacterial translocation into the creeping fat. Translocalizing antigens can directly activate (pre)adipocytes via innate receptors. Adipocyte-derived mediators modulate phenotype and function of innate and adaptive immune cells. Activated (pre)adipocytes and adipokine-modulated immune cells might support a degree of inflammatory activation within the creeping fat that allows competent immune defense against exogenous factors while preventing systemic inflammation. SUMMARY Fat tissue as an active organ in health and disease has been ignored for too long. The last few years of research provided evidence for the complex metabolic and immunological functions of adipose tissue. On the basis of the available data, creeping fat in Crohn's disease exerts a protective function by a localized anti-inflammatory effect, thus preventing a systemic inflammatory response.
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16
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Csaba G. Hormones in the immune system and their possible role. A critical review. Acta Microbiol Immunol Hung 2014; 61:241-60. [PMID: 25261940 DOI: 10.1556/amicr.61.2014.3.1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Immune cells synthesize, store and secrete hormones, which are identical with the hormones of the endocrine glands. These are: the POMC hormones (ACTH, endorphin), the thyroid system hormones (TRH, TSH, T3), growth hormone (GH), prolactin, melatonin, histamine, serotonin, catecholamines, GnRH, LHRH, hCG, renin, VIP, ANG II. This means that the immune cells contain all of the hormones, which were searched at all and they also have receptors for these hormones. From this point of view the immune cells are similar to the unicells (Tetrahymena), so it can be supposed that these cells retained the properties characteristic at a low level of phylogeny while other cells during the evolution accumulated to form endocrine glands. In contrast to the glandular endocrine cells, immune cells are polyproducers and polyreceivers. As they are mobile cells, they are able to transport the stored hormone to different places (packed transport) or attracted by local factors, accumulate in the neighborhood of the target, synthesizing and secreting hormones locally. This is taking place, e.g. in the case of endorphin, where the accumulating immune cells calms pain caused by the inflammation. The targeted packed transport is more economical than the hormone-pouring to the blood circulation of glandular endocrines and the targeting also cares the other receptor-bearing cells timely not needed the effect. Mostly the immune-effects of immune-cell derived hormones were studied (except endorphin), however, it is not exactly cleared, while the system could have scarcely studied important roles in other cases. The evolutionary aspects and the known as well, as possible roles of immune-endocrine system and their hormones are listed and discussed.
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Affiliation(s)
- György Csaba
- 1 Semmelweis University Department of Genetics, Cell and Immunobiology Budapest Hungary
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17
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The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury. Crit Care Med 2014; 42:e143-51. [PMID: 24231757 DOI: 10.1097/ccm.0000000000000048] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES One of the hallmarks of severe pneumonia and associated acute lung injury is neutrophil recruitment to the lung. Leptin is thought to be up-regulated in the lung following injury and to exert diverse effects on leukocytes, influencing both chemotaxis and survival. We hypothesized that pulmonary leptin contributes directly to the development of pulmonary neutrophilia during pneumonia and acute lung injury. DESIGN Controlled human and murine in vivo and ex vivo experimental studies. SETTING Research laboratory of a university hospital. SUBJECTS Healthy human volunteers and subjects hospitalized with bacterial and H1N1 pneumonia. C57Bl/6 and db/db mice were also used. INTERVENTIONS Lung samples from patients and mice with either bacterial or H1N1 pneumonia and associated acute lung injury were immunostained for leptin. Human bronchoalveolar lavage samples obtained after lipopolysaccharide-induced lung injury were assayed for leptin. C57Bl/6 mice were examined after oropharyngeal aspiration of recombinant leptin alone or in combination with Escherichia coli- or Klebsiella pneumoniae-induced pneumonia. Leptin-resistant (db/db) mice were also examined using the E. coli model. Bronchoalveolar lavage neutrophilia and cytokine levels were measured. Leptin-induced chemotaxis was examined in human blood- and murine marrow-derived neutrophils in vitro. MEASUREMENTS AND MAIN RESULTS Injured human and murine lung tissue showed leptin induction compared to normal lung, as did human bronchoalveolar lavage following lipopolysaccharide instillation. Bronchoalveolar lavage neutrophilia in uninjured and infected mice was increased and lung bacterial load decreased by airway leptin administration, whereas bronchoalveolar lavage neutrophilia in infected leptin-resistant mice was decreased. In sterile lung injury by lipopolysaccharide, leptin also appeared to decrease airspace neutrophil apoptosis. Both human and murine neutrophils migrated toward leptin in vitro, and this required intact signaling through the Janus Kinase 2/phosphatidylinositol-4,5-bisphosphate 3-kinase pathway. CONCLUSIONS We demonstrate that pulmonary leptin is induced in injured human and murine lungs and that this cytokine is effective in driving alveolar airspace neutrophilia. This action appears to be caused by direct effects of leptin on neutrophils.
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18
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The correlation of serum levels of leptin, leptin receptor and NO x (NO 2 (-) and NO 3 (-)) in patients with obstructive sleep apnea syndrome. Eur Arch Otorhinolaryngol 2014; 271:2943-8. [PMID: 24609643 DOI: 10.1007/s00405-014-2946-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Accepted: 02/07/2014] [Indexed: 10/25/2022]
Abstract
The aim of this study was to investigate the relations between nitric oxide (NO) and leptin levels in a cohort of untreated adult Obstructive sleep apnea syndrome (OSAS) patients. Between June 1, 2012, and January 1, 2013, we evaluated a total of 58 subjects including 36 OSAS patients and 22 healthy controls, both polysomnographically confirmed. Following the completion of polysomnographic evaluation, serum samples were taken at 08:00. Leptin, leptin receptor, NO2 (-) and NO3 (-) levels were analyzed by commercial ELISA kits. Data analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 16.0 (SPSS Inc., Chicago, IL, USA). There was no statistically significant difference between the OSAS patients and control groups with relation to the demographic parameters and body mass index (p > 0.05). Significantly higher serum leptin and plasma NO levels were found in OSAS patients compared to the controls (p < 0.001). In this study, higher leptin levels which were positively correlated with NO levels in OSAS group may indicate a possible link with increased incidence of airway pathologies in these patients.
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Paz-Filho G, Mastronardi C, Franco CB, Wang KB, Wong ML, Licinio J. Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications. ACTA ACUST UNITED AC 2013; 56:597-607. [PMID: 23329181 DOI: 10.1590/s0004-27302012000900001] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2012] [Accepted: 10/24/2012] [Indexed: 12/13/2022]
Abstract
Leptin, the adipokine produced mainly by the white adipose tissue, plays important roles not only in the regulation of food intake, but also in controlling immunity and inflammation. It has been widely demonstrated that the absence of leptin leads to immune defects in animal and human models, ultimately increasing mortality. Leptin also regulates inflammation by means of actions on its receptor, that is widely spread across different immune cell populations. The molecular mechanisms by which leptin determines its biological actions have also been recently elucidated, and three intracellular pathways have been implicated in leptin actions: JAK-STAT, PI3K, and ERK 1/2. These pathways are closely regulated by intracellular proteins that decrease leptin biological activity. In this review, we discuss the molecular mechanisms by which leptin regulates immunity and inflammation, and associate those mechanisms with chronic inflammatory disorders.
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20
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Ghrelin-leptin network influences serum chitinase 3-like protein 1 (YKL-40) levels in obese prepubertal children. ACTA ACUST UNITED AC 2013; 183:69-73. [PMID: 23501042 DOI: 10.1016/j.regpep.2013.03.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Revised: 12/27/2012] [Accepted: 03/03/2013] [Indexed: 11/21/2022]
Abstract
OBJECTIVE This study aimed to investigate any possible interactions between hormonal regulators of weight gain and markers of subclinical inflammation in childhood obesity. Forty-one obese prepubertal children and 41 age- and gender-matched lean controls were included. Children were classified as obese or non-obese according to international age- and gender-specific body mass index (BMI) cutoff points defined by the International Obesity Task Force to define childhood obesity. Anthropometric measurements, serum insulin, chitinase 3-like protein (YKL-40), ghrelin and leptin levels as well as plasma glucose in the fasting state were determined. RESULTS Obese children as compared with controls had higher YKL-40 (50.7±15.2 vs 41.0±10.5 ng/ml, p=0.003), higher leptin (33.8±16.0 vs 9.7±7.5 ng/ml, p<0.001) and lower ghrelin serum levels (871.4±368.0 vs 1417.6±387.3 pg/ml, p<0.001). The obese children with ghrelin levels above median (43.8±10.2 ng/ml) as compared to those with ghrelin below median (57.2±16.6 ng/ml) presented lower serum YKL-40 levels (p=0.009), indicating more severe inflammation with lower levels of ghrelin. By contrast, although the obese children with leptin levels above median (49.7±16.3 ng/ml) presented lower serum YKL-40 levels as compared to those with leptin levels below median (51.6±14.6 ng/ml), this difference did not reach the level of statistical significance (p=0.726). Moreover, serum YKL-40 levels were significantly correlated with ghrelin (r=-0.359, p=0.014) but not with leptin levels (r=0.169, p=0.261). A significant negative correlation between ghrelin and leptin levels was also found (r=-0.276, p=0.041). These findings remained unchanged for obese, when analyses were done separately, whereas the significance of correlations was lost for non-obese subjects. CONCLUSIONS Ghrelin-leptin network had an impact on serum YKL-40 levels in obese prepubertal children; upregulation of YKL-40 secretion seems to be a consequence of reduced ghrelin rather than elevated leptin concentrations.
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Odiere MR, Scott ME, Leroux LP, Dzierszinski FS, Koski KG. Maternal protein deficiency during a gastrointestinal nematode infection alters developmental profile of lymphocyte populations and selected cytokines in neonatal mice. J Nutr 2013; 143:100-7. [PMID: 23190758 DOI: 10.3945/jn.112.160457] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Neonatal immune development begins in pregnancy and continues into lactation and may be affected by maternal diet. We investigated the possibility that maternal protein deficiency (PD) during a chronic gastrointestinal (GI) nematode infection could impair neonatal immune development. Beginning on d 14 of pregnancy, mice were fed protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isoenergetic diets and were infected weekly with either 0 (sham) or 100 Heligmosomoides bakeri larvae. Pups were killed on d 2, 7, 14, and d 21 and dams on d 20 of lactation. Lymphoid organs were weighed. Cytokine concentration in maternal and pup serum and in milk from pup stomachs and lymphoid cell populations in pup spleen and thymus were determined using luminex and flow cytometry, respectively. GI nematode infection increased Th2 cytokines (IL-4, IL-5, IL-13), IL-2, IL-10, and eotaxin in serum of dams whereas PD reduced IL-4 and IL-13. The lower IL-13 in PD dams was associated with increased fecal egg output and worm burdens. Maternal PD increased vascular endothelial growth factor in pup milk and eotaxin in pup serum. Maternal infection increased eotaxin in pup serum. Evidence of impaired neonatal immune development included reduced lymphoid organ mass in pups associated with both maternal infection and PD and increased percentage of T cells and T:B cell ratio in the spleen associated with maternal PD. Findings suggest that increases in specific proinflammatory cytokines as a result of the combination of infection and dietary PD in dams can impair splenic immune development in offspring.
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Affiliation(s)
- Maurice R Odiere
- Institute of Parasitology, McGill University (Macdonald Campus), Ste-Anne de Bellevue, Quebec, Canada
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Amelio PD, Panico A, Spertino E, Isaia GC. Energy metabolism and the skeleton: Reciprocal interplay. World J Orthop 2012; 3:190-8. [PMID: 23330074 PMCID: PMC3547113 DOI: 10.5312/wjo.v3.i11.190] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Revised: 07/31/2012] [Accepted: 10/20/2012] [Indexed: 02/06/2023] Open
Abstract
The relation between bone remodelling and energy expenditure is an intriguing, and yet unexplained, challenge of the past ten years. In fact, it was only in the last few years that the skeleton was found to function, not only in its obvious roles of body support and protection, but also as an important part of the endocrine system. In particular, bone produces different hormones, like osteocalcin (OC), which influences energy expenditure in humans. The undercarboxylated form of OC has a reduced affinity for hydroxyapatite; hence it enters the systemic circulation more easily and exerts its metabolic functions for the proliferation of pancreatic β-cells, insulin secretion, sensitivity, and glucose tolerance. Leptin, a hormone synthesized by adipocytes, also has an effect on both bone remodelling and energy expenditure; in fact it inhibits appetite through hypothalamic influence and, in bone, stimulates osteoblastic differentiation and inhibits apoptosis. Leptin and serotonin exert opposite influences on bone mass accrual, but several features suggest that they might operate in the same pathway through a sympathetic tone. Serotonin, in fact, acts via two opposite pathways in controlling bone remodelling: central and peripheral. Serotonin product by the gastrointestinal tract (95%) augments bone formation by osteoblast, whereas brain-derived serotonin influences low bone mineral density and its decrease leads to an increase in bone resorption parameters. Finally, amylin (AMY) acts as a hormone that alters physiological responses related to feeding, and plays a role as a growth factor in bone. In vitro AMY stimulates the proliferation of osteoblasts, and osteoclast differentiation. Here we summarize the evidence that links energy expenditure and bone remodelling, with particular regard to humans.
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Becerril S, Rodríguez A, Catalán V, Sáinz N, Ramírez B, Gómez-Ambrosi J, Frühbeck G. Transcriptional analysis of brown adipose tissue in leptin-deficient mice lacking inducible nitric oxide synthase: evidence of the role of Med1 in energy balance. Physiol Genomics 2012; 44:678-88. [PMID: 22570438 DOI: 10.1152/physiolgenomics.00039.2012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Leptin and nitric oxide (NO) are implicated in the control of energy homeostasis. The aim of the present study was to examine the impact of the absence of the inducible NO synthase (iNOS) gene on the regulation of energy balance in ob/ob mice analyzing the changes in gene expression levels in brown adipose tissue (BAT). Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated and the expression of genes involved in energy balance including fatty acid and glucose metabolism as well as mitochondrial genes were analyzed by microarrays. DBKO mice exhibited an improvement in energy balance with a decrease in body weight (P < 0.001), total fat pads (P < 0.05), and food intake (P < 0.05), as well as an enhancement in BAT function compared with ob/ob mice. To better understand the molecular events associated with this improvement, BAT gene expression was analyzed. Of particular interest, gene expression levels of the key subunit of the Mediator complex Med1 was upregulated (P < 0.05) in DBKO mice. Real-time PCR and immunohistochemistry further confirmed this data. Med1 is implicated in adipogenesis, lipid metabolic and biosynthetic processes, glucose metabolism, and mitochondrial metabolic pathways. Med1 plays an important role in the transcriptional control of genes implicated in energy homeostasis, suggesting that the improvement in energy balance and BAT function of the DBKO mice is mediated, at least in part, through the transcription coactivator Med1.
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Affiliation(s)
- Sara Becerril
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain
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Klein S, Parvizi N. Visualization of immunoreactive growth hormone in cultured peripheral bovine lymphocytes. Growth Horm IGF Res 2012; 22:59-63. [PMID: 22341304 DOI: 10.1016/j.ghir.2012.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 01/10/2012] [Accepted: 01/20/2012] [Indexed: 11/19/2022]
Abstract
Growth hormone (GH) has been shown to be released by immune cells in vitro. Thus, the intracellular confinement of GH immunoreactivity was investigated in cultured bovine lymphocytes using con-focal microscopy. Peripheral blood lymphocytes from cows in early pregnancy (10-20 days post insemination; pi) or during mid-pregnancy (day 110-140 pi) were harvested and cultured for 48 h in presence of phytohemagglutinin-M (PHA-M) or served as controls. Thereafter, immunocytochemistry was conducted using a homologous GH-antibody. Double staining (GH-antibody and directly DYE 549 labeled CD3-antibody) was performed to classify the cells. Con-focal laser scanning was applied verifying the immunofluorescence labeling. Interestingly, the presence of GH immunoreactivity in the cytoplasm, which indicates GH synthesis, was restricted to small cells. Whereas, few T-like cells revealed surface bound GH. Lowest immunoreactivity, concerning the number of the total labeled cells as well as the intensity of labeling was recorded in early pregnancy. Stimulation with PHA-M enhanced total labeled cells in early pregnancy. In contrast, PHA-M had no such effects in mid-pregnancy. The results confirm the specific regulation of synthesis of lymphocytic GH during pregnancy in the cow. The identification of cells producing GH and the elucidation of the mechanisms underlying the expression of GH in larger number of cells during mid-pregnancy than in the early pregnancy need further investigations.
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Affiliation(s)
- Sabine Klein
- Department of Functional Genomics and Bioregulation, Institute of Farm Animal Genetics Mariensee, FLI, Höltystr. 10, 31535 Neustadt, Germany
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Gutierrez DA, Hasty AH. Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity. J Endocrinol 2012; 212:343-51. [PMID: 22194312 PMCID: PMC3381898 DOI: 10.1530/joe-11-0338] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The adipokine leptin is primarily produced by white adipose tissue (AT) and is a potent monocyte/macrophage chemoattractant in vitro. The long form of the leptin receptor (LepR) is required for monocyte/macrophage chemotaxis towards leptin. In this study, we examined the effects of haematopoietic LepR as well as LepR with C-C chemokine receptor 2 (CCR2) deficiency (double knockout (DKO)) on macrophage recruitment to AT after two different periods of high fat diet (HFD) feeding. Briefly, 8-week-old C57BL/6 mice were transplanted with bone marrow (BM) from Lepr(+/+), Lepr(-/-) or DKO donors (groups named BM-Lepr(+/+), BM-Lepr(-/-) and BM-DKO respectively), and were placed on an HFD for 6 or 12 weeks. At the end of the study, macrophage infiltration and the inflammatory state of AT were evaluated by real-time RT-PCR, histology and flow cytometry. In addition, glucose and insulin tolerance were assessed at both time points. Our results showed no differences in macrophage accumulation or AT inflammatory state between the BM-Lepr(+/+) and BM-Lepr(-/-) mice after 6 or 12 weeks of HFD feeding; any effects observed in the BM-DKO were attributed to the haematopoietic deficiency of CCR2. In addition, no changes in glucose or insulin tolerance were observed between groups after either period of HFD feeding. Our findings suggest that although leptin is a potent chemoattractant in vitro, haematopoietic LepR deficiency does not affect macrophage accumulation in AT in early to moderate stages of diet-induced obesity.
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Affiliation(s)
| | - Alyssa H. Hasty
- Corresponding Author Alyssa H. Hasty Room 702 Light Hall, Nashville, TN 37232-0615 Phone: 615-322-5177 Fax: 615-322-8973
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Begriche K, Sutton GM, Butler AA. Homeostastic and non-homeostatic functions of melanocortin-3 receptors in the control of energy balance and metabolism. Physiol Behav 2011; 104:546-54. [PMID: 21497617 DOI: 10.1016/j.physbeh.2011.04.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Revised: 04/04/2011] [Accepted: 04/08/2011] [Indexed: 01/05/2023]
Abstract
The central nervous melanocortin system is a neural network linking nutrient-sensing systems with hypothalamic, limbic and hindbrain neurons regulating behavior and metabolic homeostasis. Primary melanocortin neurons releasing melanocortin receptor ligands residing in the hypothalamic arcuate nucleus are regulated by nutrient-sensing and metabolic signals. A smaller group of primary neurons releasing melanocortin agonists in the nucleus tractus solitarius in the brainstem are also regulated by signals of metabolic state. Two melanocortin receptors regulate energy homeostasis. Melanocortin-4 receptors regulate satiety and autonomic outputs controlling peripheral metabolism. The functions of melanocortin-3 receptors (MC3R) expressed in hypothalamic and limbic structures are less clear. Here we discuss published data and preliminary observations from our laboratory suggesting that neural MC3R regulate inputs into systems governing the synchronization of rhythms in behavior and metabolism with nutrient intake. Mice subjected to a restricted feeding protocol, where a limited number of calories are presented at a 24h interval, rapidly exhibit bouts of increased wakefulness and activity which anticipate food presentation. The full expression of these responses is dependent on MC3R. Moreover, MC3R knockout mice are unique in exhibiting a dissociation of weight loss from improved glucose homeostasis when subject to a restricted feeding protocol. While mice lacking MC3R fed ad libitum exhibit normal to moderate hyperinsulinemia, when subjected to a restricted protocol they develop hyperglycemia, glucose intolerance, and dyslipidemia. Collectively, our data suggest that the central nervous melanocortin system is a point convergence in the control of energy balance and the expression of rhythms anticipating nutrient intake.
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Affiliation(s)
- Karima Begriche
- Department of Metabolism and Aging, The Scripps Research Institute-Florida, Jupiter, FL 33458, USA
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Rose MK, Parvizi N. Up-regulation of lymphocytic growth hormone secretion during the luteal phase of cycle and early pregnancy. ACTA ACUST UNITED AC 2011; 167:1-4. [DOI: 10.1016/j.regpep.2010.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Revised: 10/12/2010] [Accepted: 11/10/2010] [Indexed: 10/18/2022]
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Odiere MR, Scott ME, Weiler HA, Koski KG. Protein deficiency and nematode infection during pregnancy and lactation reduce maternal bone mineralization and neonatal linear growth in mice. J Nutr 2010; 140:1638-45. [PMID: 20660285 DOI: 10.3945/jn.110.125013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Using a 2 x 2 factorial design, we investigated the combined impact of protein deficiency (PD) and gastrointestinal nematode infection during late pregnancy and lactation on resting metabolic rate (RMR), body composition and bone mineralization, neonatal growth, and the regulatory hormones [corticosterone, leptin, and insulin-like growth factor-1 (IGF-1)] and proinflammatory cytokines [interleukin (IL)-1 beta and IL-6] that may drive these processes. Pregnant CD1 mice, fed either a protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isocaloric diet, were infected 4 times with either 0 (sham) or 100 Heligmosomoides bakeri larvae beginning on d 14 of pregnancy. Dams were killed on d 20 postpartum and pups on d 2, 7, 14, and 21. Diet and infection had largely independent effects. The PD diet elevated corticosterone and upregulated leptin concentration in maternal serum, which was associated with reduced food intake leading to lower body mass, RMR, and body temperature. Infection reduced food intake but elevated maternal serum IL-1 beta and IL-6 and did not affect corticosterone, leptin, RMR, or body temperature. The PD diet decreased maternal bone area and bone mineral content. Infection lowered maternal bone mineral density, consistent with elevated IL-1 beta and IL-6. The elevated serum IL-1 beta and lower IGF-1 in pups of PD dams and lower serum leptin and IGF-1 in pups of infected dams were both consistent with the lower pup body mass and shorter crown-rump length. This mouse model provides a novel framework to study the impact of diet and nematode infection on bone.
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Affiliation(s)
- Maurice R Odiere
- Institute of Parasitology, McGill University, Ste-Anne de Bellevue, QC, Canada
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Deletion of inducible nitric-oxide synthase in leptin-deficient mice improves brown adipose tissue function. PLoS One 2010; 5:e10962. [PMID: 20532036 PMCID: PMC2881035 DOI: 10.1371/journal.pone.0010962] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 05/16/2010] [Indexed: 01/22/2023] Open
Abstract
Background Leptin and nitric oxide (NO) on their own participate in the control of non-shivering thermogenesis. However, the functional interplay between both factors in this process has not been explored so far. Therefore, the aim of the present study was to analyze the impact of the absence of the inducible NO synthase (iNOS) gene in the regulation of energy balance in ob/ob mice. Methods and Findings Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated, and the expression of molecules involved in the control of brown fat cell function was analyzed by real-time PCR, western-blot and immunohistochemistry. Twelve week-old DBKO mice exhibited reduced body weight (p<0.05), decreased amounts of total fat pads (p<0.05), lower food efficiency rates (p<0.05) and higher rectal temperature (p<0.05) than ob/ob mice. Ablation of iNOS also improved the carbohydrate and lipid metabolism of ob/ob mice. DBKO showed a marked reduction in the size of brown adipocytes compared to ob/ob mutants. In this sense, in comparison to ob/ob mice, DBKO rodents showed an increase in the expression of PR domain containing 16 (Prdm16), a transcriptional regulator of brown adipogenesis. Moreover, iNOS deletion enhanced the expression of mitochondria-related proteins, such as peroxisome proliferator-activated receptor γ coactivator-1 α (Pgc-1α), sirtuin-1 (Sirt-1) and sirtuin-3 (Sirt-3). Accordingly, mitochondrial uncoupling proteins 1 and 3 (Ucp-1 and Ucp-3) were upregulated in brown adipose tissue (BAT) of DBKO mice as compared to ob/ob rodents. Conclusion Ablation of iNOS improved the energy balance of ob/ob mice by decreasing food efficiency through an increase in thermogenesis. These effects may be mediated, in part, through the recovery of the BAT phenotype and brown fat cell function improvement.
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Abstract
As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin-Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin-Sca1+CD117(lo)CD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-beta TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.
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Yang H, Youm YH, Dixit VD. Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. THE JOURNAL OF IMMUNOLOGY 2009; 183:3040-52. [PMID: 19648267 DOI: 10.4049/jimmunol.0900562] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures. Interestingly, CR prevented the age-related increase in epithelial-mesenchymal transition (EMT) regulators, FoxC2, and fibroblast-specific protein-1 (FSP-1), together with reduction in lipid-laden thymic fibroblasts. Additionally, CR specifically blocked the age-related elevation of thymic proadipogenic master regulator, peroxisome proliferator activated receptor gamma (PPARgamma), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPARgamma in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPARgamma-driven adipogenesis in OP9-DL1 stromal cells compromised their ability to support T cell development. Conversely, CR-induced reduction in EMT and thymic adipogenesis were coupled with elevated thymic output. Compared with 26-mo-old ad libitum fed mice, the T cells derived from age-matched CR animals displayed greater proliferation and higher IL-2 expression. Furthermore, CR prevented the deterioration of the peripheral TCR repertoire diversity in older animals. Collectively, our findings demonstrate that reducing proadipogenic signaling in thymus via CR may promote thymopoiesis during aging.
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Affiliation(s)
- Hyunwon Yang
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA
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Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood 2009; 113:5202-5. [PMID: 19324904 DOI: 10.1182/blood-2008-09-181255] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Ghrelin (Grln) is a peptide hormone that is predominantly produced in the stomach and stimulates appetite and induces growth hormone (GH) release. We have previously reported that ghrelin is also expressed in T cells and exerts prothymic and anti-inflammatory effects. However, the biologic relevance of T cell-derived ghrelin remains to be determined. Here, we report that acylated-bioactive ghrelin is expressed in human T cells and preferentially segregates within the lipid raft domains upon TCR ligation. The RNA interference (RNAi)-mediated down-regulation of ghrelin in primary human T cells activates IkB, and increases Th1 cytokines and IL-17 secretion. Ghrelin expression declines with increasing age in spleen and T cells and exogenous ghrelin administration in old mice reduces proinflammatory cytokines. These findings demonstrate that ghrelin functions in an autocrine and paracrine capacity to regulate proinflammatory cytokine expression in human and murine T cells and may contribute in regulating "inflamm-aging."
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Ruth MR, Taylor CG, Zahradka P, Field CJ. Abnormal immune responses in fa/fa Zucker rats and effects of feeding conjugated linoleic acid. Obesity (Silver Spring) 2008; 16:1770-9. [PMID: 18483478 DOI: 10.1038/oby.2008.266] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE The objective of this study was to characterize immune function in the fa/fa Zucker rat, and to determine the effects of feeding conjugated linoleic acid (CLA) isomers on immune function. METHODS AND PROCEDURES Lean and fa/fa Zucker rats were fed for 8 weeks nutritionally complete diets with different CLA isomers (%wt/wt): control (0%), c9t11 (0.4%), t10c12 (0.4%), or MIX (0.4% c9t11 + 0.4% t10c12). Isolated splenocytes were used to determine phospholipid (PL) fatty acid composition and cell phenotypes, or stimulated with mitogen to determine their ability to produce cytokines, immunoglobulins (Ig), and nitric oxide (NO). RESULTS Splenocyte PL of fa/fa rats had a higher proportion of total monounsaturated fatty acids and n -3 polyunsaturated fatty acids (PUFA), and lower n -6 PUFA and n -6-to-n -3 PUFA ratio (P < 0.05). Feeding CLA increased the content of CLA isomers into PL, but there were lower proportions of each CLA isomer in fa/fa rats. Splenocytes of fa/fa rats produced more amounts of IgA, IgG, and IgM, NO, and interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) (P < 0.05). Obese rats fed the t10c12 diet produced less TNF-alpha and IL-1beta (lippopolysaccharide (LPS), P < 0.05). Splenocytes of fa/fa rats produced less concanavalin A (ConA)-stimulated IL-2 (P < 0.0001) than lean rats, except fa/fa rats fed the c9t11 diet (P < 0.05). DISCUSSION The c9t11 and t10c12 CLA isomers were incorporated into the membrane PL of the fa/fa Zucker rat, but to a lesser extent than lean rats. Splenocytes of obese rats responded in a proinflammatory manner and had reduced T-cell function and feeding the t10c12 and c9t11 CLA isomers may improve some of these abnormalities by distinct methods.
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Affiliation(s)
- Megan R Ruth
- Department of Agricultural Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
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Matarese G, Procaccini C, De Rosa V. The intricate interface between immune and metabolic regulation: a role for leptin in the pathogenesis of multiple sclerosis? J Leukoc Biol 2008; 84:893-9. [PMID: 18552206 DOI: 10.1189/jlb.0108022] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Over the last few years, a series of molecules known to play a function in metabolism has also been shown to play an important role in the regulation of the immune response. In this context, the adipocyte-derived hormone leptin has been shown to regulate the immune response in normal as well as in pathological conditions. More specifically, it has been shown that conditions of reduced leptin production (i.e., genetic leptin deficiency, anorexia nervosa, malnutrition) are associated with increased susceptibility to infections. Conversely, immune-mediated disorders such as autoimmune disorders are associated with increased secretion of leptin and production of proinflammatory, pathogenic cytokines. Leptin could represent the "missing link" among immune response, metabolic function, and nutritional status. Indeed, more recently, leptin-deficient mice have been shown to be resistant to a series of experimentally induced autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Normal wild-type mice show increased secretion of leptin in serum upon EAE induction, and brain inflammatory infiltrates stain positive for leptin. Finally, leptin neutralization with leptin antagonists improves the EAE course by profoundly altering intracellular signaling of myelin-reactive T cells and increasing the number of regulatory forkhead/winged helix transcription factor 3(+)CD4(+) T cells. These data suggest that leptin can be considered as a link among immune tolerance, metabolic state, and autoimmunity and that strategies aimed at interfering with the leptin axis could represent innovative, therapeutic tools for autoimmune disorders.
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Affiliation(s)
- Giuseppe Matarese
- Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche, via S. Pansini 5, 80131, Napoli, Italy.
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Alexandraki K, Piperi C, Kalofoutis C, Singh J, Alaveras A, Kalofoutis A. Inflammatory process in type 2 diabetes: The role of cytokines. Ann N Y Acad Sci 2007; 1084:89-117. [PMID: 17151295 DOI: 10.1196/annals.1372.039] [Citation(s) in RCA: 211] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Population-based studies have shown strong relationship between inflammatory markers and metabolic disturbances, obesity, and atherosclerosis, whereas inflammation has been considered as a "common soil" between these clinical entities and type 2 diabetes (T2D). The accumulation of macrophages in adipose tissue (AT), the common origin of macrophages and adipocytes, the prevalent presence of peripheral mononuclear cells, and apoptotic beta cells by themselves seem to be the sources of inflammation present in T2D, since they generate the mediators of the inflammatory processes, namely cytokines. The main cytokines involved in the pathogenesis of T2D are interleukin-1beta (IL-1beta), with an action similar to the one present in type 1 diabetes, tumor necrosis factor-alpha (TNF-alpha), and IL-6, considered as the main regulators of inflammation, leptin, more recently introduced, and several others, such as monocyte chemoattractant protein-1, resistin, adiponectin, with either deleterious or beneficial effects in diabetic pathogenesis. The characterization of these molecules targeted diabetes treatment beyond the classical interventions with lifestyle changes and pharmaceutical agents, and toward the determination of specific molecular pathways that lead to low grade chronic inflammatory state mainly due to an immune system's unbalance.
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Affiliation(s)
- Krystallenia Alexandraki
- Laboratory of Biological Chemistry, University of Athens Medical School, M. Asias 75, Goudi 11527, Athens, Greece
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Rodríguez A, Fortuño A, Gómez-Ambrosi J, Zalba G, Díez J, Frühbeck G. The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism. Endocrinology 2007; 148:324-31. [PMID: 17038553 DOI: 10.1210/en.2006-0940] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Leptin inhibits the contractile response induced by angiotensin (Ang) II in vascular smooth muscle cells (VSMCs) of the aorta. We studied in vitro and ex vivo the role of nitric oxide (NO) in the effect of leptin on the Ang II-induced vasoconstriction of the aorta of 10-wk-old Wistar rats. NO and nitric oxide synthase (NOS) activity were assessed by the Griess and (3)H-arginine/citrulline conversion assays, respectively. Stimulation of inducible NOS (iNOS) as well as Janus kinases/signal transducers and activators of transcription (JAK/STAT) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were determined by Western blot. The contractile responses to Ang II were evaluated in endothelium-denuded aortic rings using the organ bath system. Changes in intracellular Ca(2+) were measured in VSMCs using fura-2 fluorescence. Leptin significantly (P < or = 0.01) stimulated NO release and NOS activity in VSMCs. Leptin's effect on NO was abolished by the NOS inhibitor, N(G)-monomethyl l-arginine, or the iNOS selective inhibitor L-N(6)-(1-iminoethyl)-lysine. Accordingly, leptin increased iNOS protein expression, with a comparable time course with that of NO production and NOS activity. Leptin also significantly increased STAT3 (P < or = 0.01) and Akt (P < or = 0.001) phosphorylation. Moreover, either the JAK2 inhibitor, AG490, or the PI3K inhibitor, wortmannin, significantly (P < or = 0.05) abrogated the leptin-induced increase in iNOS protein. Finally, both N(G)-monomethyl L-arginine and L-N(6)-(1-iminoethyl)-lysine inhibitors completely blunted (P < or = 0.001) the leptin-mediated inhibition of the Ang II-induced VSMC activation and vasoconstriction. These findings suggest that the endothelium-independent depressor action of leptin is mediated by an increase of NO bioavailability in VSMCs. This process requires the up-regulation of iNOS through mechanisms involving JAK2/STAT3 and PI3K/Akt pathways.
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Affiliation(s)
- Amaia Rodríguez
- Department of Endocrinology, Clínica Universitaria de Navarra, Avda. Pío XII, 36, 31008 Pamplona, Spain
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Taub DD. Novel connections between the neuroendocrine and immune systems: the ghrelin immunoregulatory network. VITAMINS AND HORMONES 2007; 77:325-46. [PMID: 17983863 DOI: 10.1016/s0083-6729(06)77014-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
There appears to be bidirectional communication between the neuroendocrine and immune systems. This communication is mediated by way of an array of cytokines, hormones, and neuropeptides. Inflammatory cytokines released by immune cells have been shown to act on the central nervous system to control food intake and energy homeostasis. Decrease in food intake or anorexia is one of the most common symptoms of illness, injury, or inflammation. The adipocyte-derived hormone, leptin, is considered a critical sensory anorexigenic mediator that signals to the brain changes in stored energy, determined by an altered balance between food intake and energy expenditure and has been shown to exert certain proinflammatory effects on immune cells. In contrast, ghrelin, the endogenous ligand for growth hormone secretagogue receptors (GHSRs), is produced primarily from stomach serving as a potent circulating orexigen controlling energy expenditure, adiposity, and GH secretion. However, the functional role of ghrelin and GHS in immune cell function remains unclear. Here, we review the current literature supporting a role for ghrelin in controlling inflammation and immunity and the potential therapeutic use of ghrelin and GHSR agonists in the management of inflammation and in restoration of thymic function in immunocompromised individuals.
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Affiliation(s)
- Dennis D Taub
- Laboratory of Immunology, National Institute on Aging (NIH), Baltimore, MD 21224., USA
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Greenstein J, Guest S, Tan JC, Tummala P, Busque S, Rabkin R. Circulating growth hormone binding protein levels and mononuclear cell growth hormone receptor expression in uremia. J Ren Nutr 2006; 16:141-9. [PMID: 16567271 DOI: 10.1053/j.jrn.2006.01.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2005] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND Resistance to growth hormone (GH) in end-stage renal disease (ESRD) causes growth retardation and muscle wasting. In humans, circulating GH binding protein (GHBP), the extracellular domain of the GH receptor that is shed into the circulation and is believed to reflect tissue GH receptor levels, is reduced in uremia and suggests that cellular GH receptor levels are correspondingly reduced. If true, this could be a cause of GH resistance. We set out to establish whether serum GHBP levels reflect cellular GH receptor levels and whether changes in serum GHBP levels are related to nutritional or inflammatory status. METHODS GH receptor protein expression in peripheral blood mononuclear cells (PBMC) from 21 ESRD and 14 normal subjects were analyzed by fluorochrome flow cytometry. RESULTS The GH receptor density and percent total PBMCs expressing the GH receptor were similar in the 2 groups, and there was no difference in percent GH receptor positive T or B cells or monocytes. In contrast, serum GHBP levels were 80% lower in ESRD. GHBP levels did not correlate with serum albumin, body mass index, or muscle mass but seemed to be partly related to the log serum C-reactive protein levels. CONCLUSIONS Serum GHBP levels are markedly reduced in ESRD; this seems to occur independent of nutritional status and may in part be caused by inflammation. Because GH receptor expression on PBMC of ESRD and control subjects was similar, our findings argue against a reduction in GH receptor as a cause of GH resistance and the use of serum GHBP levels as a reliable marker of specific tissue GH receptor levels.
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Otero M, Lago R, Gomez R, Dieguez C, Lago F, Gómez-Reino J, Gualillo O. Towards a pro-inflammatory and immunomodulatory emerging role of leptin. Rheumatology (Oxford) 2006; 45:944-50. [PMID: 16720637 DOI: 10.1093/rheumatology/kel157] [Citation(s) in RCA: 172] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Leptin is a 16 kDa adipocyte-secreted hormone that regulates weight centrally and links nutritional status with neuroendocrine and immune function. Since its cloning in 1994, leptin's role in regulating immune and inflammatory response has become increasingly evident. Actually, the increase of leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokines loop which governs the inflammatory-immune response and the host defence mechanism. Indeed, leptin stimulates the production of pro-inflammatory cytokines from cultured monocytes and enhances the production of Th1 type cytokines from stimulated lymphocytes. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as type 1 diabetes, rheumatoid arthritis and chronic bowel disease. Obesity is characterized by elevated circulating leptin levels which might contribute significantly to the so called low-grade systemic inflammation, making obese individuals more susceptible to the increased risk of developing cardiovascular diseases, type II diabetes or inflammatory articular degenerative disease such as osteorathritis (OA). As a matter of fact, a key role for leptin in OA has been recently demonstrated since leptin exhibits, in synergy with other pro-inflammatory cytokines, a detrimental effect on articular cartilage cells by promoting nitric oxide synthesis. This review will focus prevalently on the complex relationships existing among leptin, inflammatory response and immunity, trying to provide surprising insights into leptin's role and to discuss challenges and prospects for the future.
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Affiliation(s)
- M Otero
- Santiago University Clinical Hospital, Research Laboratory 4 (NEIRID LAB, Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago de Compostela, Spain
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Karmiris K, Koutroubakis IE, Xidakis C, Polychronaki M, Voudouri T, Kouroumalis EA. Circulating levels of leptin, adiponectin, resistin, and ghrelin in inflammatory bowel disease. Mol Nutr Food Res 2006; 52:855-66. [PMID: 16432373 DOI: 10.1002/mnfr.200700050] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND There is evidence that adipocytokines play an important role in metabolism and in inflammation. Because human metabolism dramatically changes in inflammatory bowel disease (IBD) and chronic inflammation is the hallmark of the disease, we studied serum levels of leptin, adiponectin, resistin, and ghrelin in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with healthy controls (HC). METHODS Leptin, adiponectin, resistin, and active ghrelin serum levels were measured in 100 IBD patients (46 UC and 54 CD) and in 60 matched HC using commercially available enzyme-linked immunosorbent assays. Leptin, adiponectin, resistin, and ghrelin levels were correlated with disease activity, type, localization, and treatment. RESULTS Mean serum leptin levels were 10.6+/-2.0 ng/mL in UC patients, 12.5+/-2.6 ng/mL in CD patients, and 15.0+/-1.8 ng/mL in HC (P=.01). Mean serum adiponectin levels were 9514.8+/-787.8 ng/mL in UC patients, 7651.1+/-613 ng/mL in CD patients, and 7270.6+/-559.4 ng/mL in HC (P=.05). Mean serum resistin levels were 21.2+/-2.2 ng/mL in UC patients, 18.7+/-1.6 ng/mL in CD patients and 11.8+/-0.6 ng/mL in HC (P=.0002). Mean serum ghrelin levels were 48.2+/-4.2 pg/mL in UC patients, 49.4+/-4.6 pg/mL in CD patients and 14.8+/-3.0 pg/mL in HC (P<.0001). Serum levels of these adipocytokines were not correlated with either C-reactive protein levels or the clinical indices of activity. No association between serum adipocytokines levels and disease localization in both UC and CD patients was found. Only serum ghrelin was significantly higher in ileal compared with colonic CD (P=.04). CONCLUSIONS Serum levels of adiponectin, resistin, and active ghrelin are increased whereas serum levels of leptin are decreased in patients with IBD. Further studies are needed to elucidate the role of adipocytokines in IBD.
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Dixit VD, Taub DD. Ghrelin and immunity: a young player in an old field. Exp Gerontol 2005; 40:900-10. [PMID: 16233968 DOI: 10.1016/j.exger.2005.09.003] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2005] [Revised: 09/01/2005] [Accepted: 09/06/2005] [Indexed: 01/16/2023]
Abstract
There is increasing evidence of the coupling of immune status to the metabolic system. The communication between the state of systemic and cellular energy balance to immune compartment is mediated via a complex array of cytokines, hormones and neuropeptides. Ghrelin, a recently described orexigenic peptide hormone, is predominantly produced by the stomach and functions as a positive regulator of the somatotropic axis and a peripheral signal of negative energy balance. Apart from its well-studied metabolic effects, ghrelin also exerts multiple regulatory effects on several other organ systems including the cardiovascular, central nervous and immune systems. Here, we summarize the growing evidence of ghrelin as a significant player in the regulation of inflammation and the immune function and the potential therapeutic targeting of ghrelin or its receptor, the growth hormone secretagogue receptor (GHS-R), in various inflammatory and cachexic disease states.
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Affiliation(s)
- Vishwa Deep Dixit
- Laboratory of Immunology, National Institute on Aging, Intramural Research Program, National Institutes of Health, Gerontology Research Centre, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825, USA.
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Karmiris K, Koutroubakis IE, Kouroumalis EA. The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel disease. Inflamm Bowel Dis 2005; 11:847-55. [PMID: 16116320 DOI: 10.1097/01.mib.0000178915.54264.8f] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD.
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Shirshev SV, Orlova EG. Molecular Mechanisms of Regulation of Functional Activity of Mononuclear Phagocytes by Leptin. BIOCHEMISTRY (MOSCOW) 2005; 70:841-7. [PMID: 16212539 DOI: 10.1007/s10541-005-0193-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Leptin is a peptide hormone synthesized by adipocytes. The main function of leptin is associated with regulation of the body energetic balance and restriction of excess accumulation of fat. This review considers in detail the involvement of leptin in regulation of fundamental effector functions of mononuclear phagocytes, which express receptors for this hormone. Possible molecular mechanisms of modulation by leptin of phagocytic activity, oxygen-dependent microbicidity, and nitric oxide generation by mononuclear phagocytes are analyzed, as well as the role of leptin in the formation of the produced cytokine pattern. The data presented suggest that the regulation of mononuclear phagocytes by leptin is associated with activation of the JAK/STAT signaling pathway, which leads to stimulation of phagocytosis, production of oxygen and nitrogen reactive species, and also to increase in secretion of pro-inflammatory cytokines.
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Affiliation(s)
- S V Shirshev
- Institute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, Perm, 614081, Russia
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Lulu Strat A, Kokta TA, Dodson MV, Gertler A, Wu Z, Hill RA. Early signaling interactions between the insulin and leptin pathways in bovine myogenic cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2005; 1744:164-75. [PMID: 15950750 DOI: 10.1016/j.bbamcr.2005.03.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2005] [Revised: 02/18/2005] [Accepted: 03/16/2005] [Indexed: 11/25/2022]
Abstract
Cross-talk between hormone signaling pathways provides mechanisms to facilitate flexibility in the cellular response to extracellular conditions. One function of insulin is to signal high extracellular glucose, while leptin may signal the abundance of extracellular lipid, both energy sources being readily utilized by muscle. The present study reports early signaling events in the insulin and leptin cascades in primary bovine myogenic cells (BMC). BMC were treated with insulin, or leptin for 1, 10, 30 and 120 min, or pretreated with leptin for 10 min followed by insulin for 1, 10, 30 and 120 min. BMC were insulin resistant, showing a significant inhibition of IRS-1 association with the insulin receptor (IR) following insulin stimulation, a corresponding increase in PI 3-kinase association with the IR, and a slow and modest increase in GLUT4 recruitment to the plasma membrane. Pretreatment of BMC for 10 min leptin, followed by insulin time-course, caused IRS-1 recruitment to be unresponsive, but evoked a rapid, phasic response of PI 3-kinase recruitment to the IR and abrogated the response of GLUT4 translocation to the plasma membrane evoked by insulin alone. The lack of insulin response was independent of IR abundance or affinity. JAK-2 association with the ObR and JAK-2 tyrosine phosphorylation were responsive to all three treatments. Insulin alone down-regulated the leptin signaling pathway, JAK-2 association with ObR decreased at all time-points, and JAK-2 phosphorylation decreased similarly. Leptin alone also appeared to down-regulate JAK-2 association with the ObR, but stimulated the down-regulated pathway to signal, JAK-2 tyrosine phosphorylation being increased at later time-points. Pretreatment with leptin followed by insulin time-course showed marked up-regulation of the early leptin signaling pathway, JAK-2 association with the ObR being increased by insulin while JAK-2 tyrosine phosphorylation was also increased. The contrasting responses of BMC to insulin alone, leptin alone and the sequential leptin-insulin treatment may point to the ability of these cells to respond to energy substrate availability, as bovine muscle has evolved to utilize lipids and fatty acids in response to a metabolism which provides only limited glucose. This cross-talk between insulin and leptin signaling pathways points to a better understanding of the mechanisms driving energy substrate utilization in ruminant muscle and may provide a useful model for greater understanding of the molecular mechanisms underlying the development of insulin resistance and Type 2 diabetes in man.
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Affiliation(s)
- A Lulu Strat
- Department of Animal and Veterinary Science, University of Idaho, Moscow, 8344, USA
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Mehebik N, Jaubert AM, Sabourault D, Giudicelli Y, Ribière C. Leptin-induced nitric oxide production in white adipocytes is mediated through PKA and MAP kinase activation. Am J Physiol Cell Physiol 2005; 289:C379-87. [PMID: 15772123 DOI: 10.1152/ajpcell.00320.2004] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Leptin injection increases plasma levels of nitrites and/or nitrates, an index of nitric oxide (NO) production. Because plasma levels of NO are correlated with fat mass and because adipose tissue is the main source of leptin, it seems that adipose tissue plays a major role in NO release induced by leptin. Adipocytes express both leptin receptors and nitric oxide synthase (NOS; including the endothelial isoform, NOS III, and the inducible isoform, NOS II). In this study, we have demonstrated that physiological concentrations of leptin stimulate NOS activity in adipocytes. This effect of leptin is abolished by 1) AG490, an inhibitor of Janus tyrosine kinase 2/signal transducer and activator of transcription 3; 2) U0126, an inhibitor of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (p42/p44 MAPK); and 3) N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89) or Rp diastereomer of adenosine 3',5'-cyclic phosphorothioate, two inhibitors of protein kinase A, but not by wortmannin, an inhibitor of phosphatidylinositol 3-kinase. Immunoblotting studies have shown that leptin fails to activate Akt but increases p42/p44 MAPK phosphorylation, an effect that is prevented by U0126 but not by H-89. Furthermore, leptin induces NOS III phosphorylation at Ser(1179) and Thr(497), but not when adipocytes are pretreated with H-89 or U0126. Finally, stimulation of adipocyte NOS activity by leptin is either unaltered when protein phosphatase 2A is inhibited by 1 nM okadaic acid or completely abolished when protein phosphatase 1 (PP1) activity is inhibited by 3 nM tautomycin, which supports a crucial role for PP1 in mediating this effect of leptin. On the whole, these experiments demonstrate that NOS activity is a novel target for leptin in adipocytes and that the leptin-induced NOS activity is at least in part the result of NOS III phosphorylations via both protein kinase A and p42/p44 MAPK activation. More generally, this study also leads to the hypothesis of NO as a potentially important factor for leptin signaling in adipocytes.
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Affiliation(s)
- Nadia Mehebik
- Department of Biochemistry and Molecular Biology (UPRES EA-2493), Faculty of Médecine Paris-Ile de France-Ouest, University of Versailles Saint-Quentin en Yvelines, Paris, France
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Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gómez-Reino JJ, Gualillo O. Leptin, from fat to inflammation: old questions and new insights. FEBS Lett 2005; 579:295-301. [PMID: 15642335 DOI: 10.1016/j.febslet.2004.11.024] [Citation(s) in RCA: 240] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2004] [Revised: 10/09/2004] [Accepted: 11/04/2004] [Indexed: 10/26/2022]
Abstract
Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.
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Affiliation(s)
- Miguel Otero
- Santiago University Clinical Hospital, Research Laboratory 4 (Laboratory of Neuro Endocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago de Compostela, Spain
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Cervero A, Horcajadas JA, Domínguez F, Pellicer A, Simón C. Leptin system in embryo development and implantation: a protein in search of a function. Reprod Biomed Online 2005; 10:217-23. [PMID: 15823226 DOI: 10.1016/s1472-6483(10)60943-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Implantation is a crucial moment in the reproduction process that requires perfect synchronization between the embryo and the maternal endometrium. The embryo must reach the blastocyst stage and the endometrium must be prepared to receive it. An appropriate and specific molecular dialogue must also take place between them. There is ample evidence to show that the leptin system is implicated in this cross-talk. Examples are described. Although there is some controversy surrounding the data, they are supported by the presence of leptin receptor mRNA in mouse and human oocytes and embryos throughout preimplantation development. Otherwise, the leptin mRNA is only detected at the blastocyst stage in both human and mouse. Furthermore, leptin is found at higher concentrations in the conditioned media from competent human blastocysts than in those from arrested embryos, suggesting that this molecule is a marker for blastocyst viability. Given that expression of the leptin receptor increases in the human endometrium during the luteal phase, the secreted leptin could trigger its activation. Finally, leptin and the leptin receptor have been detected in implantation sites. All these findings point to the involvement of the leptin system in the molecular mechanism of the implantation process and embryo development.
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Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW, Taub DD. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 2004; 114:57-66. [PMID: 15232612 PMCID: PMC437970 DOI: 10.1172/jci21134] [Citation(s) in RCA: 253] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2004] [Accepted: 04/27/2004] [Indexed: 12/17/2022] Open
Abstract
Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1beta, IL-6, and TNF-alpha. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.
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Affiliation(s)
- Vishwa Deep Dixit
- Laboratory of Immunology, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA
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