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Leptin in the interplay of inflammation, metabolism and immune system disorders

Key Points

  • Leptin is an adipokine produced predominantly by adipose tissue, but also expressed in the articulation by chondrocytes and synoviocytes, and by immune cells

  • As a consequence of its dual role as an anorexigenic and a proinflammatory factor, leptin is now considered a link between the neuroendocrine and immune systems

  • Leptin participates in innate immunity by inhibiting natural killer cells and by inducing proliferation and activation of monocytes

  • Leptin signalling can also regulate adaptive immunity by activating T-cell proliferation and responsiveness, and by stimulating B-cell proliferation and cytokine production

  • Leptin can exert its proinflammatory and pro-catabolic actions on cartilage, leading to articular degeneration characteristic of osteoarthritis

Abstract

Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.

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Figure 1: Schematic representation of leptin receptors and its signal transduction pathway.
Figure 2: Leptin effects on innate and adaptive immunity.
Figure 3: Schematic representation of the effects of adipose tissue-derived leptin on osteoarthritis (OA) and rheumatoid arthritis (RA).

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Acknowledgements

O.G. and F.L. are Staff Personnel of Xunta de Galicia (SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS). R.G. is a 'Miguel Servet' Researcher funded by Instituto de Salud Carlos III (ISCIII). O.G. is a member of RETICS (Redes Temáticas de Investigación Cooperativa en Salud) Programme, RD16/0012/0014, RIER (Red de Investigación en Inflamación y Enfermedades Reumáticas) via Instituto de Salud Carlos III and FEDER (Fondo Europeo de Desarrollo Regional). The work of O.G. (PIE 13/00024, PI14/00016), F.L. and R.G. is funded by Instituto de Salud Carlos III and FEDER. J.C. is a recipient of Sara Borrell Program funding by Instituto de Salud Carlos III (ISCIII). F.L. is a member of CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardio¬vasculares), funded by ISCIII and FEDER. The funders had no role in study design, data collection and analy¬sis, decision to publish, or preparation of the manuscript.

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O.G., V.A., M.S., J.C., M-A.G-G., J-J.G-R., A.M., and F.L. researched data for the article. J.P., M.-A.G.-G.,J.-J.G.-R., A.M., F.L., R.G contributed substantially to the discussion of the content, and O.G. and V.A. wrote the article. M.S., J.P., F.L., R.G., and O.G. reviewed and edited the article before submission.

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Correspondence to Oreste Gualillo.

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Glossary

Anorexigenic factors

Mediators that reduce food intake by acting on hypothalamic receptors

Orexigenic factors

Mediators that induce appetite and stimulate food intake

Type 1 T helper cells

(TH1 cells). Subset of helper-inducer T-lymphocytes that synthesize and secrete IL-2, IFNγ and IL-12. Owing to their ability to kill antigen-presenting cells, TH1 cells are associated with vigorous delayed-type hypersensitivity reactions

TH2 cells

Subset of helper-inducer T-lymphocytes that synthesize and secrete IL-4, IL-5, IL-6 and IL-10. These cytokines influence B-cell development and antibody production as well as augmenting humoral responses.

Superoxides

Highly reactive compounds produced when oxygen is reduced by a single electron.

Toll-like receptors

A family of pattern-recognition receptors characterized by an extracellular leucine-rich domain and a cytoplasmic domain that share homology with the IL-1 receptor and the drosophila toll protein. Following pathogen recognition, Toll-like receptors recruit and activate a variety of signal-transducing adaptor proteins.

Hyperleptinaemia

Presence of a higher than normal amount of leptin in the bloodstream.

Lymphopenia

Reduction in the number of lymphocytes

Lipodystrophy

A collection of heterogenous conditions resulting from defective lipid metabolism and characterized by adipose tissue atrophy

Hypothalamic amenorrhea

Hypogonadotropic hypogonadism related to an aberration of the pulsatile release of gonadotropin-releasing hormone from the hypothalamus

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Abella, V., Scotece, M., Conde, J. et al. Leptin in the interplay of inflammation, metabolism and immune system disorders. Nat Rev Rheumatol 13, 100–109 (2017). https://doi.org/10.1038/nrrheum.2016.209

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