Role of Central Leptin Signaling in the Starvation-Induced Alteration of B-Cell Development

Department of Molecular Medicine and Metabolism, Medial Research Institute and Global Center of Excellence Program, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2011; 31(23):8373-80. DOI: 10.1523/JNEUROSCI.6562-10.2011
Source: PubMed


Nutritional deprivation or malnutrition suppresses immune function in humans and animals, thereby conferring higher susceptibility to infectious diseases. Indeed, nutritional deprivation induces atrophy of lymphoid tissues such as thymus and spleen and decreases the number of circulating lymphocytes. Leptin, a major adipocytokine, is exclusively produced in the adipose tissue in response to the nutritional status and acts on the hypothalamus, thereby regulating energy homeostasis. Although leptin plays a critical role in the starvation-induced T-cell-mediated immunosuppression, little is known about its role in B-cell homeostasis under starvation conditions. Here we show the alteration of B-cell development in the bone marrow of fasted mice, characterized by decrease in pro-B, pre-B, and immature B cells and increase in mature B cells. Interestingly, intracerebroventricular leptin injection was sufficient to prevent the alteration of B-cell development of fasted mice. The alteration of B lineage cells in the bone marrow of fasted mice was markedly prevented by oral administration of glucocorticoid receptor antagonist RU486 (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one). It was also effectively prevented by intracerebroventricular injection of neuropeptide Y Y(1) receptor antagonist BIBP3226 [(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(4-hydroxyphenyl)methyl]pentanamide], along with suppression of the otherwise increased serum corticosterone concentrations. This study provides the first in vivo evidence for the role of central leptin signaling in the starvation-induced alteration of B-cell development. The data of this study suggest that the CNS, which is inherent to integrate information from throughout the organism, is able to control immune function.

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    • "In addition, intracerebroventricular leptin injection was sufficient to prevent the alteration of B-cell development in the bone marrow of fasted mice (characterized by altered balance between immature and mature B-cells), thus providing again the in vivo evidence for the role of central leptin signaling in B-cell development (144). Other studies have shown that leptin-deficient mice showed an increased susceptibility to sepsis and mortality, due to an impaired recruitment and function of neutrophils. "
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    ABSTRACT: The nervous and immune systems have long been considered as compartments that perform separate and different functions. However, recent clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders, such as multiple sclerosis (MS), might involve factors, hormones, and neural mediators that link the immune and nervous system. These molecules are members of the same superfamily, which allow the mutual and bi-directional neural-immune interaction. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones that control food intake and metabolism, has suggested that nutritional/metabolic status, acting at central level, can control immune self-tolerance, since it promotes experimental autoimmune encephalomyelitis, an animal model of MS. Here, we summarize the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. Understanding this coordinated interaction may pave the way for novel therapeutic approaches to increase host defense and suppress immune-mediated disorders.
    Frontiers in Immunology 04/2014; 5:143. DOI:10.3389/fimmu.2014.00143
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    • "In the T cell compartment, double positive CD4 + CD8 + immature thymocytes are most affected, as these cells require leptin as a survival, antiapoptotic factor ( Howard et al. , 1999 ). Leptin administration profoundly restores these defects ( Howard et al. , 1999 ; Claycombe et al. , 2008 ; Tanaka et al. , 2011 ), but the cellular targets of leptin in restoring this thymic cellularity and whether the lack of leptin or its receptor specifically affects subpopulations of T lymphocytes in the periphery remains unclear. At least in vitro , several studies point to direct effects of leptin on T cells. "
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    Biological Chemistry 02/2014; 395(5). DOI:10.1515/hsz-2013-0283 · 3.27 Impact Factor
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    • "The major factors responsible for these changes in B and T lymphocyte population are likely hormones such as corticosterone, for which serum levels are high in DR and significantly higher after FA [28]. Leptin, which has all the characteristics of a pro-inflammatory cytokine, has been shown to link nutritional status with immune responses and has been demonstrated to play a major role in altering the B cell development during FA [27], [29]. A recent study by Fujita et al., also report the role played by leptin in B cell homeostasis by inhibiting apoptosis. "
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