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The weight of leptin in immunity

Key Points

  • Leptin is a hormone that mainly regulates body weight by stimulating energy expenditure through increased thermogenesis and by suppressing intake of food.

  • Leptin is also a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6 (IL-6), IL-12, IL-15, granulocyte colony-stimulating factor (G-CSF), oncostatin M (OSM), prolactin and growth hormone. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine system to the immune system.

  • The leptin receptor, OBR, is a member of the class I cytokine receptor family (which includes receptors for IL-6, IL-12, OSM and prolactin) and exists in at least six alternatively spliced forms. The short forms seem to mediate the transport and degradation of leptin. The long form, known as OBRb, is expressed by the hypothalamus in areas that are responsible for the secretion of neuropeptides and neurotransmitters that regulate appetite. OBRb is also expressed by the ovary, pancreatic β-cells, endothelial cells, CD34+ haematopoietic bone-marrow precursors, monocytes/macrophages, and T and B cells.

  • Leptin influences innate immune responses by promoting the activation of monocytes/macrophages, chemotaxis and activation of neutrophils, and the development and activation of natural killer cells.

  • Leptin influences adaptive immunity by increasing the expression of adhesion molecules by CD4+ T cells, promoting proliferation and secretion of IL-2 by naive CD4+ T cells and promoting a bias towards T helper 1-cell responses on memory CD4+ T cells.

  • Leptin-deficient (ob/ob) mice and humans with congenital deficiency of leptin have both metabolic disturbances and immune abnormalities, including abnormal cytokine secretion and thymic hypotrophy. These immune disturbances are corrected by administration of recombinant leptin in both mice and humans.

  • A possible role of leptin in autoimmunity is suggested by the observation that ob/ob mice are protected from several experimental autoimmune diseases and that administration of exogenous leptin to mice that are genetically susceptible to develop autoimmune disease anticipates onset and accelerates the progression of autoimmune responses.

Abstract

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. As a hormone, leptin regulates food intake and basal metabolism, and is sexually dimorphic — that is, its serum concentration is higher in females than in males with a similar body fat mass. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 and tumour-necrosis factor. Similar to other pro-inflammatory cytokines, leptin promotes T helper 1 (TH1)-cell differentiation and can modulate the onset and progression of autoimmune responses in several animal models of disease. Here, we review the advances and controversy for a role of leptin in the pathophysiology of immune responses.

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Figure 1: Central and peripheral neuroendocrine effects of leptin.
Figure 2: Effects of leptin on innate and adaptive immune responses.
Figure 3: Three-dimensional structure of leptin.
Figure 4: Signalling pathways activated by the leptin receptor.
Figure 5: Schematic model for a role of leptin in autoimmunity.

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Acknowledgements

This work was supported by the Fondazione Italiana Sclerosi Multipla (FISM) and Comitato Trenta Ore per la Vita (Mediaset), and the Arthritis National Research and Lupus Foundations. This work is dedicated to the memory of A. Di Tuoro.

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DATABASES

LocusLink

ACTH

CCL3

CD49B

COX2

CRH

CRP

CXCL2

G-CSF

GLUT1

GLUT4

ICAM1

IFN-γ

IL-1

IL-6

IL-18

ob

OBR

OSM

STAT3

TNF

Glossary

HYPOTHALAMO–PITUITARY–ADRENAL (HPA) AXIS

The neuroendocrine and immune systems communicate bidirectionally through shared ligands and receptors. Factors secreted by the hypothalamus, the pituitary and adrenal glands, such as corticotrophin-releasing hormone, adrenocorticotropic hormone and glucocorticoids, can influence both immune and neuroendocrine responses. Cytokines secreted by immune cells, such as interleukin-1 (IL-1), IL-6, tumour-necrosis factor and interferon-γ, also influence the HPA axis.

GLUCOCORTICOIDS

A series of steroids that influence glucose metabolism, lipolysis and protein synthesis. In humans, the most abundant glucocorticoid is cortisol (also known as hydrocortisone). Secreted with circadian rhythm by the adrenal-gland cortex, glucocorticoids mediate their effects by binding to specific cytosolic receptors. Immunologically, glucocorticoids inhibit the mobilization and function of T and B cells, as well as the secretion of inflammatory mediators. Also, glucocorticoids can induce the apoptosis of developing thymocytes. Natural and synthetic glucocorticoids (that is, prednisolone and dexamethasone) are often used in therapy as anti-inflammatory and immunosuppressive agents.

C-REACTIVE PROTEIN

(CRP). An important acute-phase reactant secreted during inflammation and sepsis. It is part of the collectin family — a group of soluble proteins with an amino terminus similar to collagen. CRP can activate both the classical and alternative pathways of complement activation after binding one of its ligands — Fc-γ receptor I on immune cells or carbohydrates of Streptococcus pneumoniae.

OMENTUM

A fold of the peritoneum that extends downwards from the greater curvature of the stomach to lie anteriorly in the peritoneal cavity. It folds back on itself and is adherent to the transverse colon as it crosses the pancreas. The anterior and posterior leaves usually fuse. It often contains an abundant accumulation of adipose tissue and lymph nodes in strict anatomical contiguity.

MIXED LYMPHOCYTE REACTION

(MLR). When lymphocytes from two unrelated individuals are cultured together, the T cells of one donor proliferate in response to the allogeneic MHC molecules on the cells of the other donor. The MLR is used to test for histocompatibility.

DELAYED-TYPE HYPERSENSITIVITY

(DTH). A form of cell-mediated immunity elicited by antigen in the skin and mediated by CD4+ T helper 1 cells. It is called 'delayed-type' because the reaction appears hours to days after antigen is injected.

ANTIGEN-INDUCED ARTHRITIS

(AIA). An inflammatory disease of the joints that develops in susceptible mice immunized with methylated bovine serum albumin into the knees in immunogenic adjuvant. It is considered to be a model of inflammatory arthritis.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

(EAE). An inflammatory disease of the central nervous system that develops in susceptible mice immunized with neural antigens in immunogenic adjuvant. It is considered to be a model of human multiple sclerosis.

HYPERPHAGIA

A condition of excessive eating beyond normal hunger.

HYPOTHALAMIC HYPOGONADISM

A condition of decreased functional activity of the gonads, resulting in retardation of puberty and/or reproductive insufficiency. It is due to disorders of the hypothalamus or of the pituitary gland.

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Cava, A., Matarese, G. The weight of leptin in immunity. Nat Rev Immunol 4, 371–379 (2004). https://doi.org/10.1038/nri1350

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