Role of Central Leptin Signaling in the Starvation-Induced Alteration of B-Cell Development
ABSTRACT 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.
- SourceAvailable from: Claudio Procaccini
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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. "
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. "
ABSTRACT: Abstract The adipocyte-derived hormone/cytokine leptin acts as a metabolic switch, connecting the body's nutritional status to high energy consuming processes such as reproduction and immune responses. Inappropriate leptin responses can promote autoimmune diseases and tumorigenesis. In this review we discuss the current strategies to modulate leptin signaling and the possibilities for their use in research and therapy.Biological Chemistry 02/2014; 395(5). DOI:10.1515/hsz-2013-0283 · 2.69 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 . 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 , . A recent study by Fujita et al., also report the role played by leptin in B cell homeostasis by inhibiting apoptosis. "
ABSTRACT: Dietary restriction (DR) delays ageing and extends life span. Both long- and short-term DR, as well as short-term fasting provide robust protection against many "neuronal and surgery related damaging phenomena" such as Parkinson's disease and ischemia-reperfusion injury. The exact mechanism behind this phenomenon has not yet been elucidated. Its anti-inflammatory actions prompted us to thoroughly investigate the consequences of DR and fasting on B and T cell compartments in primary and secondary lymphoid organs of male C57Bl/6 mice. In BM we found that DR and fasting cause a decrease in the total B cell population and arrest early B cell development, while increasing the number of recirculating mature B cells. In the fasting group, a significant reduction in peripheral B cell counts was observed in both spleen and mesenteric lymph nodes (mLN). Thymopoiesis was arrested significantly at double negative DN2 stage due to fasting, whereas DR resulted in a partial arrest of thymocyte development at the DN4 stage. Mature CD3(+) T cell populations were increased in BM and decreased in both spleen and mLN. Thus, DR arrests B cell development in the BM but increases the number of recirculating mature B cells. DR also arrests maturation of T cells in thymus, resulting in depletion of mature T cells from spleen and mLN while recruiting them to the BM. The functional relevance in relation to protection against organ damage needs to be determined.PLoS ONE 02/2014; 9(2):e87772. DOI:10.1371/journal.pone.0087772 · 3.23 Impact Factor