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

Tanaka, Miyako; Suganami, Takayoshi; Kim-Saijo, Misa; Toda, Chitoku; Tsuiji, Makoto; Ochi, Kenji; Kamei, Yasutomi; Minokoshi, Yasuhiko; Ogawa, Yoshihiro

doi:10.1523/jneurosci.6562-10.2011

Cited by 56 publications

(48 citation statements)

References 46 publications

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“…In summary, our observations provide a unique role for hypothalamic AgRP neurons in integrative physiology. Our data support the notion that the CNS can affect immune functions (40,41), which can supersede the predicted effects of circulating metabolic hormones, such as leptin. These results, together with our recent demonstration of specific behavioral and metabolic phenotypes of AgRP-Sirt1 KO animals (3,4), suggest that traits of altered motivated behaviors and basic metabolic parameters can be predictors of adaptive immune system phenotypes.…”

Section: Discussionsupporting

confidence: 84%

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Matarese

Procaccini

Menale

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Whole-body energy metabolism is regulated by the hypothalamus and has an impact on diverse tissue functions. Here we show that selective knockdown of Sirtuin 1 Sirt1 in hypothalamic Agouti-related peptide-expressing neurons, which renders these cells less responsive to cues of low energy availability, significantly promotes CD4 + T-cell activation by increasing production of T helper 1 and 17 proinflammatory cytokines via mediation of the sympathetic nervous system. These phenomena were associated with an impaired thymic generation of forkhead box P3 (FoxP3 + ) naturally occurring regulatory T cells and their reduced suppressive capacity in the periphery, which resulted in increased delayed-type hypersensitivity responses and autoimmune disease susceptibility in mice. These observations unmask a previously unsuspected role of hypothalamic feeding circuits in the regulation of adaptive immune response.immune system | sirtuins H ypothalamic Agouti-related peptide-expressing (AgRP) neurons are mandatory for feeding and survival (1, 2) and they mediate effects of the hystone deacetylase Sirtuin 1 (Sirt1) on energy metabolism (3, 4). Behavioral and metabolic adaptations to low energy availability are enabled by AgRP neurons, but it is unknown whether these neurons are involved in the regulation of other tissue functions key to survival, such as adaptive immune responses. Sirtuins are NAD + -dependent class-III deacetylases that are highly conserved across species (5). Nutrient deprivation up-regulates Sirt1 in several tissues (6, 7), which is important for the metabolic shift that occurs during negative energy balance (8), a metabolic state in which energy expenditure is higher than energy intake. Evidence suggests that the effects of sirtuins may mediate the beneficial effects of calorie restriction, the only known physiological intervention that promotes a longer, healthier lifespan across species (9-14). However, the site of action of sirtuins in these physiological processes remains ill-defined.The CNS was previously recognized as an immune-privileged site with lack of immunosurveillance. However, accumulating evidence has shown that a mutual interaction between the immune system and CNS exists both in physiological and pathological situations (15). The CNS influences and controls the immune system at least partly through the autonomic nervous system (15). Lymphocytes express the receptors for different neurotransmitters, which enable the brain to properly coordinate the immune system and to maintain the homeostasis of the whole body by responding to environmental changes, such as infections, in an appropriate manner. In this context, we and others have shown that nutritional status can affect T helper 1 (Th1) proinflammatory immune responses through a series of adipose-tissue-derived hormones including leptin, which mediates its effects on immune cells either directly by activating leptin receptors on T cells or indirectly by its effect on autonomic nervous system.

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Section: Discussionsupporting

confidence: 84%

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Matarese

Procaccini

Menale

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Flow cytometric analyses of SVF were performed as described 43,44 . In brief, the epididymal fat tissue was collected and cut into small pieces and incubated for 20 min in collagenase solution (2 mg ml À 1 of collagenase type 2 (Worthington, Lakewood, NJ)) with gentle shaking.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

et al. 2014

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“…Acute hypolep tinemia caused by starvation is associated with reduced development of B cells in the bone marrow, and decre ased T lymphocyte subpopulation with impairment of delayed type hypersensitivity responses and thymic atro phy. These effects are more pronounced in patient sub mitted to chronic exposure to hypoleptinemia, and are prevented by replacement with exogenous leptin (44).…”

Section: Hypoleptinemic Statesmentioning

confidence: 99%

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

Paz-Filho

Mastronardi

Franco

et al. 2012

Arq Bras Endocrinol Metab

179

148

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SUMMARYLeptin, the adipokine produced mainly by the white adipose tissue, plays important roles not only in the regulation of food intake, but also in controlling immunity and inflammation. It has been widely demonstrated that the absence of leptin leads to immune defects in animal and human models, ultimately increasing mortality. Leptin also regulates inflammation by means of actions on its receptor, that is widely spread across different immune cell populations. The molecular mechanisms by which leptin determines its biological actions have also been recently elucidated, and three intracellular pathways have been implicated in leptin actions: JAK-STAT, PI3K, and ERK 1/2. These pathways are closely regulated by intracellular proteins that decrease leptin biological activity. In this review, we discuss the molecular mechanisms by which leptin regulates immunity and inflammation, and associate those mechanisms with chronic inflammatory disorders. Arq Bras Endocrinol Metab. 2012;56(9):597-607 Keywords Leptin; immunity; inflammation; cytokines SUMÁRIO A leptina, uma adipocina produzida principalmente pelo tecido adiposo branco, tem um papel importante não somente na regulação da ingestão alimentar, mas também no controle da imunidade e da inflamação. Já foi amplamente demonstrado que a ausência de leptina causa deficiências imunológicas em modelos animais e em humanos, levando ao aumento da mortalidade. A leptina também regula a inflamação por meio da ação em seu receptor, amplamente distribuído em diversos tipos de células do sistema imunológico. Os mecanismos moleculares pelos quais a leptina determina suas ações biológicas foram recentemente elucidados, e três cascatas intracelulares são ativadas pela leptina: JAK-STAT, PI3K e ERK 1/2. Essas cascatas são reguladas por proteínas intracelulares, reduzindo as ações da leptina. Nesta revisão, são discutidos os mecanismos moleculares pelos quais a leptina regula a imunidade e a inflamação, associando-os a enfermidades inflamatórias crônicas. Arq Bras Endocrinol Metab. 2012;56(9):597-607 Descritores

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

Cited by 56 publications

References 46 publications

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications

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