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1.
Brain Behav Immun ; 95: 477-488, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33989745

RESUMO

Physical and social environments influence immune homeostasis within adipose tissue, yet the mechanisms remain poorly defined. We report that an enriched environment (EE) housing modulates the immune cell population in white adipose tissue of mice including an increase in the abundance of natural killer (NK) cells. EE upregulates the expression of IL-15 and its receptor IL-15Rα specifically within mature adipocytes. Mechanistically, we show that hypothalamic brain-derived neurotrophic factor (BDNF) upregulates IL-15 production in adipocytes via sympathetic ß-adrenergic signaling. Overexpressing BDNF mediated by recombinant adeno-associated virus (rAAV) vector in the hypothalamus expands adipose NK cells. Conversely, inhibition of hypothalamic BDNF signaling via gene transfer of a dominant negative TrkB receptor suppresses adipose NK cells. In white adipose tissue, overexpression of IL-15 using an adipocyte-specific rAAV vector stimulates adipose NK cells and inhibits the progression of subcutaneous melanoma, whereas local IL-15 knockdown blocks the EE effect. These results suggest that bio-behavioral factors regulate adipose NK cells via a hypothalamic BDNF-sympathoneural-adipocyte IL-15 axis. Targeting this pathway may have therapeutic significance for cancer.


Assuntos
Adipócitos , Fator Neurotrófico Derivado do Encéfalo , Interleucina-15 , Células Matadoras Naturais , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipotálamo/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
2.
Brain Behav Immun ; 75: 137-148, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30287389

RESUMO

Environmental and social factors have profound impacts on immune homeostasis. Our work on environmental enrichment (EE) has revealed a novel anti-obesity and anticancer phenotype associated with enhanced activity of CD8+ cytotoxic T lymphocytes in secondary lymphoid tissues. Here we investigated how an EE modulated thymus and thymocyte development. EE decreased thymus mass and cellularity, decreased the double positive thymocyte population, increased the proportion of CD8+ T cells, reduced the CD4:CD8 ratio, and downregulated CD69 expression in T cells. In a model of multiple sclerosis: experimental autoimmune encephalomyelitis (EAE), EE alleviated symptoms, inhibited spinal cord inflammation through regulation of type 1 T-helper cells mediated by glucocorticoid receptor signaling, and prevented EAE-induced thymic disturbance. Our mechanistic studies demonstrated that hypothalamic BDNF activated a hypothalamic-pituitary-adrenal axis mediating the EE's thymic effects. Our results indicate that a lifestyle intervention links the nervous, endocrine, and adaptive immune system, allowing the body to adapt to internal and external environments.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Meio Ambiente , Timócitos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linfócitos T CD8-Positivos/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/terapia , Feminino , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Células Th1/metabolismo
3.
Endocr Relat Cancer ; 26(5): 483-495, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30856610

RESUMO

Obesity is becoming a global epidemic and is a risk factor for breast cancer. Environmental enrichment (EE), a model recapitulating an active lifestyle, leads to leanness, resistance to diet-induced obesity (DIO) and cancer. One mechanism is the activation of the hypothalamic-sympathoneural-adipocyte (HSA) axis. This results in the release of norepinephrine onto adipose tissue inducing a drop of leptin. This study aimed to test the effects of EE on breast cancer onset and progression while considering the effect of leptin by utilizing the transgenic MMTV-PyMT model as well as several models of varied leptin signaling. EE was highly effective at reducing weight gain, regardless of the presence of leptin. However, the effects of EE on tumor progression were dependent on leptin signaling. EE decreased leptin and reduced mammary tumor growth rate in MMTV-PyMT spontaneous and DIO transplantation models; in contrast, the absence of leptin in ob/ob mice resulted in increased tumor growth likely due to elevated norepinephrine levels. Our results suggest that the microenvironment is critical in breast tumorigenesis and that the drop in leptin is an important peripheral mediator of the EE anti-breast cancer effects, offsetting the potential pro-tumorigenic effects of norepinephrine responding to a complex environment.


Assuntos
Leptina/metabolismo , Neoplasias Mamárias Experimentais/prevenção & controle , Obesidade/complicações , Microambiente Tumoral , Animais , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Feminino , Humanos , Neoplasias Mamárias Experimentais/etiologia , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Transdução de Sinais , Aumento de Peso
4.
Aging (Albany NY) ; 10(7): 1698-1721, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-30036185

RESUMO

With increases in life expectancy, it is vital to understand the dynamics of aging, their interaction with lifestyle factors, and the connections to age-related disease processes. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel anticancer and anti-obesity phenotype mediated by a brain-fat axis: the hypothalamic-sympathoneural-adipocyte (HSA) axis in young animals. Here we investigated EE effects on healthspan and lifespan when initiated after middle age. Short-term EE for six weeks activated the HSA axis in 10-month-old mice. Long-term EE for twelve months reduced adiposity, improved glucose tolerance, decreased leptin levels, enhanced motor abilities, and inhibited anxiety. In addition to adipose remodeling, EE decreased age-related liver steatosis, reduced hepatic glucose production, and increased glucose uptake by liver and adipose tissue contributing to the improved glycemic control. The EE-induced liver modulation was associated with a suppression of protein kinase Cε. Moreover, EE down-regulated the expression of inflammatory genes in the brain, adipose, and liver. EE initiated at 18-month of age significantly improved glycemic control and showed a trend of positive impact on mean lifespan. These data suggest that EE induces metabolic and behavioral adaptations that are shared by factors known to increase healthspan and lifespan.


Assuntos
Envelhecimento/fisiologia , Envelhecimento Saudável , Abrigo para Animais , Tecido Adiposo/metabolismo , Animais , Comportamento Animal , Temperatura Corporal , DNA Mitocondrial , Feminino , Intolerância à Glucose , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ácido Pirúvico/metabolismo , Baço/citologia
5.
Cancer Immunol Res ; 4(6): 488-497, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27045020

RESUMO

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488-97. ©2016 AACR.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Interação Gene-Ambiente , Hipotálamo/metabolismo , Melanoma Experimental/imunologia , Subpopulações de Linfócitos T/imunologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/deficiência , Linfócitos T CD8-Positivos/imunologia , Abrigo para Animais , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/genética , Imunidade Celular/imunologia , Imunofenotipagem , Masculino , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Propranolol/farmacologia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia
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