Leptin Receptor Expression and Signaling in Lymphocytes: Kinetics During Lymphocyte Activation, Role in Lymphocyte Survival, and Response to High Fat Diet in Mice

Papathanassoglou, Elizabeth; El-Haschimi, Karim; Li, Xian Chang; Matarese, Giuseppe; Strom, Terry B.; Mantzoros, Christos S.

doi:10.4049/jimmunol.176.12.7745

Cited by 220 publications

(204 citation statements)

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“…The very recent description of a reduced intracellular leptin signaling in splenic T lymphocytes isolated from diet-induced obese mice (57) is perfectly in line with our proposal of a model of leptin resistance affecting immune cells (T cells (Ref. 57) and DCs (our present work)). Thus, we propose that our demonstration of a functional deficiency of DCs and of an alteration of their steady-state number in ob/ob mice could be generalized to more frequent forms of obesity and could partly explain the immune deficiency commonly associated with the obese state.…”

Section: Figuresupporting

confidence: 74%

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Impairment of Dendritic Cell Functionality and Steady-State Number in Obese Mice

Macia

Delacre

Abboud

et al. 2006

The Journal of Immunology

123

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There is a finely tuned interplay between immune and neuroendocrine systems. Metabolic disturbances like obesity will have serious consequences on immunity both at the cellular and at the cytokine expression levels. Our in vivo results confirm the immune deficiency of ob/ob mice, leptin deficient and massively obese, characterized by a reduced Ag-specific T cell proliferation after keyhole limpet hemocyanin immunization. In this report, we show that dendritic cells (DCs), major APCs involved in T lymphocyte priming, are affected in obese mice. Both their function and their steady-state number are disturbed. We demonstrate that DCs from ob/ob mice are less potent in stimulation of allogenic T cells in vitro. This impaired functionality is not associated with altered expression of phenotypic markers but with the secretion of immunosuppressive cytokines such as TGF-β. Moreover, we show increased in vivo steady-state number of epidermal DCs in ob/ob mice, which is not due to a migratory defect. The ob/ob mice are characterized by the absence of functional leptin, a key adipokine linking nutrition, metabolism, and immune functions. Interestingly, intradermal injection of leptin is able to restore epidermal DC number in obese mice. Thus, DCs might be directly sensitive to metabolic disturbances, providing a partial explanation of the immunodeficiency associated with obesity.

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Section: Figuresupporting

confidence: 74%

“…In obesity, this balance is disturbed; the immune response is impaired and a state of leptin resistance gradually developed. We propose that, in addition to T cells (57), leptin resistance also affects DCs, partly explaining the immune deficiency occurring in obesity.…”

Section: Figurementioning

confidence: 99%

Impairment of Dendritic Cell Functionality and Steady-State Number in Obese Mice

Macia

Delacre

Abboud

et al. 2006

The Journal of Immunology

123

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“…18,48 Among the various STAT proteins activated by OB-Rb, STAT3 has been shown to mediate the leptin signal in activated macrophages and in promoting the survival and activation of lymphocytes and peripheral blood mononuclear cells (PBMCs). 18,45,49,50 In NK cells, leptin is involved in all processes of cell development, differentiation, proliferation, activation and cytotoxicity, and this effect is mediated by STAT3 activation. 51 Based on the complex activation network of the STAT proteins, further analyses of their regulation by leptin signaling in immune cells will merit a better understanding of leptin-mediated immune modulation.…”

Section: Leptin and Autoimmunity M Vadacca Et Al 204mentioning

confidence: 99%

“…24,36 In fact, leptin receptors can also be found in different tissues and immune cell types, including various subpopulations of T and B lymphocytes, dendritic cells, monocytes, neutrophils, macrophages and natural killer (NK) cells. 18,[37][38][39][40][41] The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. This concept is discussed in detail in the present review.…”

Section: Introductionmentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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“…Attempts to use fasting to acutely reduce leptin below a putative "threshold" that would be necessary to maintain trophic effects on immune and endocrine organs, as well as experiments using administration of recombinant leptin, have generated inconsistent results [18,19]. Thirdly, obesity, a state associated with high leptin levels, is characterized by leptin resistance, which appears to involve alterations in leptin receptor signaling abilities and to extend to receptors expressed by lymphocytes [20].…”

mentioning

confidence: 99%

Leptin: Nourishment for the immune system

Fantuzzi

2006

Eur J Immunol

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Leptin, a protein produced by adipocytes, exerts several functions, including modulation of the immune response. A report in this issue of the European Journal of Immunology describes for the first time the effect of either leptin receptor deficiency or blockade on murine dendritic cell (DC) maturation, survival and function. The study describes how leptin receptor deficiency/blockade delays DC maturation and promotes apoptosis, shifts the balance between pro-and anti-inflammatory cytokine production, and reduces the ability of DC to stimulate CD4 + lymphocytes. These exciting novel data add an important piece of evidence to the picture of the role of leptin in immunity and inflammation and generate the possibility that many of the effects of leptin on T lymphocytes might be mediated through DC. Leptin, a protein produced by adipocytes and released into the systemic circulation, acts as a master hormone, controlling most of the body's functions involved in energy acquisition and utilization. Although leptin is best known for its role in regulating food intake, this adipokine controls several other critical systems, including modulation of various endocrine axes, bone metabolism, as well as the immune/inflammatory response [1].The observation that an absence of leptin or its receptor results in alterations of the cellularity and function of the immune system was made several years before the term leptin had been coined and the genes for leptin and its receptor identified. In fact, the finding of thymic atrophy and reduced lymphocyte function in ob/ob (leptin-deficient) and db/db (leptin receptordeficient) mice dates to the late 1970s and early 1980s [2][3][4][5]. Cloning of leptin in 1994 and the subsequent rapid identification of its receptor lead to a renewed interest and reevaluation of those discoveries of the late 1970s/early 1980s. In agreement with the early observations of lymphocyte abnormalities in ob/ob and db/db mice, most of the studies on the role of leptin in regulating immune responses focused on the effect of this adipokine on the lymphoid compartment, particularly maturation, function and survival of T lymphocytes. A critical finding of the majority of these studies was the demonstration that leptin skews the immune response towards a Th1 phenotype and protects T lymphocytes from apoptosis [6,7], possibly accounting for the protective effect of leptin-and leptin receptor-deficiency in models of autoimmune/inflammatory conditions [8][9][10]. Studies on the role of leptin in the modulation of monocytes/macrophages, neutrophils, basophils, eosinophils and natural killer cells soon followed (see [11,12] for reviews).However, it was not until 2005 that the first report on the effect of leptin on dendritic cells (DC) was published

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Leptin Receptor Expression and Signaling in Lymphocytes: Kinetics During Lymphocyte Activation, Role in Lymphocyte Survival, and Response to High Fat Diet in Mice

Cited by 220 publications

References 39 publications

Impairment of Dendritic Cell Functionality and Steady-State Number in Obese Mice

Impairment of Dendritic Cell Functionality and Steady-State Number in Obese Mice

Leptin in immuno-rheumatological diseases

Leptin: Nourishment for the immune system

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