LEPTIN: FROM APPETITE SUPPRESSION TO AUTOIMMUNITY

Milica Ranđelović, Tatjana M. Jevtović-Stoimenov

DOI Number
http://doi.org/10.22190/FUMB191004017R
First page
34
Last page
38

Abstract


The hormone leptin is released by adipocytes accordingly to current energy stores to suppress appetite. Apart from this, leptin acts as a proinflammatory cytokine and strongly stimulates  inflammation. Immune-modulating properties are partly achieved by affecting T-cell maturation, polarization, and viability. Leptin rises inflammatory cells count, increases proinflammatory cytokine secretion, and impairs regulatory T-lymphocytes differentiation. Leptin secretion and signalization disturbances have recently started to be observed in the context of autoimmunity.  In this review, we discuss signaling pathways affected by the satiety hormone, its effect on T-lymphocyte maturation, differentiation and polarization, and relation to other immune-modulating agents. In the end, we highlight the rising evidence connecting hyperleptinemia state which is almost always related to obesity, with autoimmune disorders and take a brief overview of possible mechanisms behind leptin’s potency to induce self-reactivity.


Keywords

leptin, leptin resistance, leptin receptor, autoimmunity

Full Text:

PDF

References


Denver RJ, Bonett RM, Boorse GC. Evolution of Leptin Structure and Function. Neuroendocrinology 2011; 94(1):21–38.

Münzberg H, Morrison CD. Structure, production and signaling of leptin. Metabolism 2015; 64(1):13–23.

Allison MB, Myers MG. 20 Years of Leptin: Connecting leptin signaling to biological function. J Endocrinol 2014; 223(1):T25–35.

Flier JS, Maratos-Flier E. Leptin’s Physiologic Role: Does the Emperor of Energy Balance Have No Clothes? Cell Metab 2017; 26(1):24–26.

Liu J, Yang X, Yu S, Zheng R. The Leptin Resistance. In: Wu Q, Zheng R, editors. Neural Regulation of Metabolism. Singapore: Springer Singapore; 2018; p. 145–163.

Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med 2013; 7(2):207–222.

Caron E, Sachot C, Prevot V, Bouret SG. Distribution of leptin-sensitive cells in the postnatal and adult mouse brain. J Comp Neurol 2010; 518(4):459–476.

Tartaglia LA. The Leptin Receptor. J Biol Chem 1997; 272(10):6093–6096.

Wada N, Hirako S, Takenoya F, Kageyama H, Okabe M, Shioda S. Leptin and its receptors. J Chem Neuroanat 2014;61–62: 191–199.

Schaab M, Kratzsch J. The soluble leptin receptor. Best Pract Res Clin Endocrinol Metab 2015; 29(5):661–670.

Wauman J, Zabeau L, Tavernier J. The Leptin Receptor Complex: Heavier Than Expected? Front Endocrinol 2017; 8.

Engin A. Diet-Induced Obesity and the Mechanism of Leptin Resistance. In: Engin AB, Engin A, editors. Obesity and Lipotoxicity. Cham: Springer International Publishing; 2017: p. 381–397.

Kwon O, Kim KW, Kim M-S. Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci 2016; 73:1457–1477.

La Cava A. Leptin in inflammation and autoimmunity. Cytokine 2017; 98:51–58.

Procaccini C, La Rocca C, Carbone F, De Rosa V, Galgani M, Matarese G. Leptin as immune mediator: Interaction between neuroendocrine and immune system. Dev Comp Immunol 2017; 66:120–129.

Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, MacIver NJ. Leptin Metabolically Licenses T Cells for Activation To Link Nutrition and Immunity. J Immunol 2014; 192:136–144.

de Heredia FP, Gómez-Martínez S, Marcos A. Obesity, inflammation and the immune system. Proc Nutr Soc 2012; 71:332–338.

Abella V, Scotece M, Conde J, Pino J, Gonzalez-Gay MA, Gómez-Reino JJ, et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 2017; 13:100–109.

Sreenivasan J, Schlenner S, Franckaert D, Dooley J, Liston A. The thymoprotective function of leptin is indirectly mediated via suppression of obesity. Immunology 2015; 146:122–129.

Gruver AL, Ventevogel MS, Sempowski GD. Leptin receptor is expressed in thymus medulla and leptin protects against thymic remodeling during endotoxemia-induced thymus involution. J Endocrinol 2009; 203:75–85.

Hsu H-C, Mountz JD. Metabolic syndrome, hormones, and maintenance of T cells during aging. CurrOpin Immunol 2010; 22:541–548.

Maciolek JA, Alex Pasternak J, Wilson HL. Metabolism of activated T lymphocytes. CurrOpin Immunol 2014; 27:60–74.

Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12:21–35.

Gerriets VA, Danzaki K, Kishton RJ, Eisner W, Nichols AG, Saucillo DC, et al. Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity. Eur J Immunol 2016; 46:1970–1983.

Vadacca M, Margiotta DP, Navarini L, Afeltra A. Leptin in immuno-rheumatological diseases. Cell Mol Immunol 2011; 8:203–212.

Ali N, Rosenblum MD. Regulatory T cells in skin. Immunology 2017; 152:372–381.

Pacella I, Piconese S. Immunometabolic Checkpoints of Treg Dynamics: Adaptation to Microenvironmental Opportunities and Challenges. Front Immunol 2019; 10.

Yang J, Yang X, Zou H, Li M. Oxidative Stress and Treg and Th17 Dysfunction in Systemic Lupus Erythematosus. Oxid Med Cell Longev 2016; 2016:1–9.

Park H-K, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 2015; 64:24–34.

Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 2015; 16:188–196.

Cassano S, Pucino V, La Rocca C, Procaccini C, De Rosa V, Marone G, et al. Leptin modulates autophagy in human CD4+CD25− conventional T cells. Metabolism 2014; 63:1272–1279.

Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 2014; 14:585–600.

Isailovic N, Daigo K, Mantovani A, Selmi C. Interleukin-17 and innate immunity in infections and chronic inflammation. J Autoimmun 2015; 60:1–11.

Beringer A, Noack M, Miossec P. IL-17 in Chronic Inflammation: From Discovery to Targeting. Trends Mol Med 2016; 22:230–241.

Naylor C, Petri WA. Leptin Regulation of Immune Responses. Trends Mol Med 2016; 22:88–98.

Pucino V, De Rosa V, Procaccini C, Matarese G. Regulatory T Cells, Leptin and Angiogenesis. In: Marone G, Granata F, editors. Chemical Immunology and Allergy. Basel: S. KARGER AG; 2013: p. 155–169.

Francisco V, Pino J, Campos-Cabaleiro V, Ruiz-Fernández C, Mera A, Gonzalez-Gay MA, et al. Obesity, Fat Mass and Immune System: Role for Leptin. Front Physiol 2018; 9.

Dar L, Tiosano S, Watad A, Bragazzi NL, Zisman D, Comaneshter D, et al. Are obesity and rheumatoid arthritis interrelated? Int J Clin Pract 2018; 72:e13045.

Lago F, Gomez R, Conde J, Scotece M, Dieguez C, Gualillo O. Functions of Adipose Tissue and Adipokines in Health and Disease. In: Aimaretti G, editor. Update on Mechanisms of Hormone Action - Focus on Metabolism, Growth and Reproduction. InTech; 2011.

Tian G, Liang J-N, Wang Z-Y, Zhou D. Emerging role of leptin in rheumatoid arthritis: Emerging role of leptin in RA. Clin Exp Immunol. 2014; 177:557–570.

Carrión M, Frommer KW, Pérez-García S, Müller-Ladner U, Gomariz RP, Neumann E. The Adipokine Network in Rheumatic Joint Diseases. Int J Mol Sci 2019; 20:4091.

Lee YH, Bae S ‑C. Circulating leptin level in rheumatoid arthritis and its correlation with disease activity: a meta-analysis. Z FürRheumatol 2016; 75:1021–1027.

Guerrero-García J de J, Carrera-Quintanar L, López-Roa RI, Márquez-Aguirre AL, Rojas-Mayorquín AE, Ortuño-Sahagún D. Multiple Sclerosis and Obesity: Possible Roles of Adipokines. Mediators Inflamm 2016; 2016:1–24.

Umano GR, Pistone C, Tondina E, Moiraghi A, Lauretta D, Miraglia del Giudice E, et al. Pediatric Obesity and the Immune System. Front Pediatr 2019; 7.

Munger KL, Bentzen J, Laursen B, Stenager E, Koch-Henriksen N, Sørensen TI, et al. Childhood body mass index and multiple sclerosis risk: a long-term cohort study. MultScler J 2013; 19(10):1323–1329.

Matarese G, Sanna V, Lechler RI, Sarvetnick N, Fontana S, Zappacosta S, et al. Leptin Accelerates Autoimmune Diabetes in Female NOD Mice. Diabetes 2002; 51:1356–1361.

Luna R, Garcia-Mayor RV, Lage M, Andrade MA, Barreiro J, Pombo M, et al. High serum leptin levels in children with type 1 diabetes mellitus: contribution of age, BMI, pubertal development and metabolic status. Clin Endocrinol (Oxf) 1999; 51:603–610.

Drobniak A, Kanecki K, Grymowicz M, Radowicki S. Serum leptin concentration in women of reproductive age with euthyroid autoimmune thyroiditis. Gynecol Endocrinol 2016; 32:128–131.

Wang S, Baidoo SE, Liu Y, Zhu C, Tian J, Ma J, et al. T cell-derived leptin contributes to increased frequency of T helper type 17 cells in female patients with Hashimoto’s thyroiditis: Leptin and Th17 cells in HT patients. Clin Exp Immunol 2013; 171:63–68.

Huitema MJD, Schenk GJ. Insights into the Mechanisms That May Clarify Obesity as a Risk Factor for Multiple Sclerosis. Curr Neurol Neurosci Rep 2018; 18.

Yu Y, Liu Y, Shi F-D, Zou H, Matarese G, La Cava A. Cutting Edge: Leptin-Induced RORγt Expression in CD4 + T Cells Promotes Th17 Responses in Systemic Lupus Erythematosus. J Immunol 2013; 190:3054–3058.

Lourenço EV, Liu A, Matarese G, La Cava A. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci 2016; 113:10637–10642.

Tabarkiewicz J, Pogoda K, Karczmarczyk A, Pozarowski P, Giannopoulos K. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Arch Immunol Ther Exp 2015; 63:435–449.

Lee YH, Song GG. Association between circulating leptin levels and systemic lupus erythematosus: an updated meta-analysis. Lupus 2018; 27:428–435.

Chougule D, Nadkar M, Venkataraman K, Rajadhyaksha A, Hase N, Jamale T, et al. Adipokine interactions promote the pathogenesis of systemic lupus erythematosus. Cytokine 2018; 111:20–27.

Liu Y, Yu Y, Matarese G, La Cava A. Cutting edge: fasting-induced hypoleptinemia expands functional regulatory T cells in systemic lupus erythematosus. J Immunol Baltim Md 1950: 2012;188:2070–2073. doi: 10.4049/jimmunol.1102835

Ouyang S, Hsuchou H, Kastin AJ, Mishra PK, Wang Y, Pan W. Leukocyte infiltration into spinal cord of EAE mice is attenuated by removal of endothelial leptin signaling. Brain Behav Immun 2014; 40:61–73.

Fujita Y, Fujii T, Mimori T, Sato T, Nakamura T, Iwao H, et al. Deficient Leptin Signaling Ameliorates Systemic Lupus Erythematosus Lesions in MRL/Mp- Faslpr Mice. J Immunol 2014; 192:979–984.

Tarzi RM, Cook HT, Jackson I, Pusey CD, Lord GM. Leptin-Deficient Mice Are Protected from Accelerated Nephrotoxic Nephritis. Am J Pathol 2004; 164:385–390.

Zhou Y, Yu X, Chen H, Sjöberg S, Roux J, Zhang L, et al. Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages. Cell Metab 2015; 22:1045–1058.

Frühbeck G, Catalán V, Rodríguez A, Ramírez B, Becerril S, Portincasa P, et al. Normalization of adiponectin concentrations by leptin replacement in ob/ob mice is accompanied by reductions in systemic oxidative stress and inflammation. Sci Rep 2017; 7:2752.

Katsiki N, Mikhailidis DP, Banach M. Leptin, cardiovascular diseases and type 2 diabetes mellitus. Acta Pharmacol Sin 2018; 39:1176–1188. doi: 10.1038/aps.2018.40

Park HK, Kwak MK, Kim HJ, Ahima RS. Linking resistin, inflammation, and cardiometabolic diseases. Korean J Intern Med 2017; 32:239–247.

Forsbladd’Elia H, Pullerits R, Carlsten H, Bokarewa M. Resistin in serum is associated with higher levels of IL-1Ra in post-menopausal women with rheumatoid arthritis. Rheumatology 2008; 47:1082–1087.

ArunkumarAchari, Sushil Jain. Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction. Int J Mol Sci 2017; 18:1321.




DOI: https://doi.org/10.22190/FUMB191004017R

Refbacks

  • There are currently no refbacks.


© University of Niš, Serbia
Creative Commons licence CC BY-NC-ND
ISSN 0354-4699 (Print)
ISSN 2406-050X (Online)