Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, lower leptin level, higher adiponectin level, enhanced immune functions, and marked inhibition in melanoma, breast, and colon cancer growth. Mechanistically, the physical, social and cognitive stimulations provided in EE stimulate hypothalamic brain-derived neurotrophic factor (BDNF) expression and thereby activates a specific neuroendocrine axis, hypothalamic-sympathoneural-adipocyte (HSA) axis leading to inhibition of leptin expression and release, as well as white fat browning. EE also enhances T cell immunity via both sympathetic nervous system (SNS) and the hypothalamic-pituitary- adrenal (HPA) axis. Both of the metabolic and immune modulations contribute to the antitumor effects of EE, and are orchestrated by the hypothalamic BDNF. Furthermore, our preliminary data suggest that EE induces adipose-resident natural killer (NK) cells likely also mediated by the HSA axis. The long-term goal of this project is to investigate how lifestyle and environmental factors regulate the development and function of adipose immune cells, and their implications in cancer prevention and treatment. We propose to test our hypothesis that environmental and genetic activation of the HSA axis induces adipose-resident NK cell through adipocyte-derived interleukin 15, which may have preventive and therapeutic significance of cancer. We plan to characterize the EE-induced regulation of adipose NK cells and elucidate the mechanisms in Aim 1. Specifically, the role of HSA axis will be investigated by both genetic (antagonizing hypothalamic BDNF signaling) and pharmacological approaches (?-adrenergic receptor agonist or antagonist). To assess whether adipocyte IL-15 is the key downstream mediator of the proposed brain-adipocyte-NK axis, we will use our novel adipose-specific recombinant adeno- associated viral vector to overexpress or knockdown IL-15 specifically in adipocytes. Moreover, we will study the preventive and therapeutic effects of EE-induced adipose NK cells on mammary tumor in the MMTV-PyMT spontaneous model as well as orthotopic and metastatic transplantation models of breast cancer in Aim 2. These studies will further characterize the brain-mediated anticancer effects, identify a novel brain-adipocyte-immune axis linking the beneficial adaptive responses to physical and social environments, and provide the preclinical data to assess the potential for ultimate clinical intervention.

Public Health Relevance

Our recent work demonstrates that the environmental or genetic activation of a brain-adipocyte axis, leads to an anti-obesity and anti-cancer phenotype. The purpose of this project is to characterize this brain-adipocyte axis-induced immunomodulation in fat, to study the preventive and therapeutic effects of adipose-resident natural kill cell activation in several clinical relevant models, and to further elucidate the underlying mechanisms with the ultimate goal of utilizing this knowledge to develop interventions for cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166590-07
Application #
9617220
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Malone, Winfred F
Project Start
2013-01-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Ohio State University
Department
Genetics
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
McMurphy, Travis; Huang, Wei; Queen, Nicholas J et al. (2018) Implementation of environmental enrichment after middle age promotes healthy aging. Aging (Albany NY) 10:1698-1721
Ng, Raymond; Hussain, Nurul Attiqah; Zhang, Qiongyi et al. (2017) miRNA-32 Drives Brown Fat Thermogenesis and Trans-activates Subcutaneous White Fat Browning in Mice. Cell Rep 19:1229-1246
Siu, J J; Queen, N J; Huang, W et al. (2017) Improved gene delivery to adult mouse spinal cord through the use of engineered hybrid adeno-associated viral serotypes. Gene Ther 24:361-369
Barth, Rolf F; Maximilian Buja, L; Cao, Lei et al. (2017) An Obesity Paradox: Increased Body Mass Index Is Associated with Decreased Aortic Atherosclerosis. Curr Hypertens Rep 19:55
Huang, Wei; Liu, Xianglan; Queen, Nicholas J et al. (2017) Targeting Visceral Fat by Intraperitoneal Delivery of Novel AAV Serotype Vector Restricting Off-Target Transduction in Liver. Mol Ther Methods Clin Dev 6:68-78
Siu, Jason J; Queen, Nicholas J; Liu, Xianglan et al. (2017) Molecular Therapy of Melanocortin-4-Receptor Obesity by an Autoregulatory BDNF Vector. Mol Ther Methods Clin Dev 7:83-95
McMurphy, Travis B; Huang, Wei; Xiao, Run et al. (2017) Hepatic Expression of Adenovirus 36 E4ORF1 Improves Glycemic Control and Promotes Glucose Metabolism Through AKT Activation. Diabetes 66:358-371
Zhang, Yanhui; Xie, Litao; Gunasekar, Susheel K et al. (2017) SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. Nat Cell Biol 19:504-517
Xie, Litao; Zhang, Yanhui; Gunasekar, Susheel K et al. (2017) Induction of adipose and hepatic SWELL1 expression is required for maintaining systemic insulin-sensitivity in obesity. Channels (Austin) 11:673-677
Xiao, Run; Bergin, Stephen M; Zhang, Manchao et al. (2016) Anticancer Molecules in Brain: Implication for Novel Strategy for Cancer Immunotherapy. Immunotherapy (Los Angel) 2:

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