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, they have a strong reduction in the numbers of circulating immune cells, including T and NK cells[187]. Exogenous administration of leptin was shown to restore T and B cell numbers in starved mice and humans and increase production of pro-inflammatory Th1 cytokines168169170171188]. In addition, exogenous administration of leptin reversed the effects of starvation on the innate immune system and promoted migration of neutrophils and their secretion of H 2 O 2 . "
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    ABSTRACT: Adipose tissue provides the body with a storage depot of nutrients that is drained during times of starvation and replenished when food sources are abundant. As such, it is the primary sensor for nutrient availability in the milieu of an organism, which it communicates to the body through the excretion of hormones. Adipose tissue regulates a multitude of body functions associated with metabolism, such as gluconeogenesis, feeding and nutrient uptake. The immune system forms a vital layer of protection against micro-organisms that try to gain access to the nutrients contained in the body. Because infections need to be resolved as quickly as possible, speed is favored over energy-efficiency in an immune response. Especially when immune cells are activated, they switch to fast, but energy-inefficient anaerobic respiration to fulfill their energetic needs. Despite the necessity for an effective immune system, it is not given free rein in its energy expenditure. Signals derived from adipose tissue limit immune cell numbers and activity under conditions of nutrient shortage, whereas they allow proper immune cell activity when food sources are sufficiently available. When excessive fat accumulation occurs, such as in diet-induced obesity, adipose tissue becomes the site of pathological immune cell activation, causing chronic low-grade systemic inflammation. Obesity is therefore associated with a number of disorders in which the immune system plays a central role, such as atherosclerosis and non-alcoholic steatohepatitis. In this review, we will discuss the way in which adipose tissue regulates activity of the immune system under healthy and pathological conditions.
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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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    • "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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