RESUMO
Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneural-adipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF up-regulation or decrease of adiposity indicating a minor role of VGF in the hypothalamic-sympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF.
Assuntos
Adaptação Fisiológica/genética , Adipócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Metabolismo Energético/genética , Meio Ambiente , Hipotálamo/metabolismo , Neuropeptídeos/genética , Obesidade/genética , Sistema Nervoso Simpático/metabolismo , Adaptação Fisiológica/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adiposidade , Animais , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Metabolismo Energético/efeitos dos fármacos , Privação de Alimentos , Hipotálamo/efeitos dos fármacos , Leptina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Crescimento Neural , Neuropeptídeos/efeitos dos fármacos , Receptores de Melanocortina/agonistas , Meio Social , Sistema Nervoso Simpático/efeitos dos fármacos , Regulação para CimaRESUMO
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/imunologiaRESUMO
Environmental enrichment (EE) is a housing environment for mice that boosts mental and physical health compared to standard laboratory housing. Our recent studies demonstrate that environmental enrichment decreases adiposity, increases energy expenditure, resists diet induced obesity, and causes cancer remission and inhibition in mice. EE typically consists of larger living space, a variety of 'toys' to interact with, running wheels, and can include a number of other novel environmental changes. All of this fosters a more complex social engagement, cognitive and physical stimulations. Importantly, the toy location and type of toy is changed regularly, which encourages the mice to adapt to a frequently changing and novel environment. Many variables can be manipulated in EE to promote health effects in mice. Thus these approaches are difficult to control and must be properly managed to successfully replicate the associated phenotypes. Therefore, the goal of this video is to demonstrate how EE is properly set up and maintained to assure a complex, challenging, and controlled environment so that other researchers can easily reproduce the protective effects of EE against obesity and cancer.