Cancer prevention and treatment by activation of a brain-adipocyte axis

通过激活脑-脂肪细胞轴来预防和治疗癌症

• 批准号: 10317047
• 负责人: Lei Cao
• 金额: $ 36.31万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317047
• 关键词: Adipocytes; Adipose tissue; Adrenergic beta-Agonists; Affinity; Agonist; Brain; Brain-Derived Neurotrophic Factor; Breast Cancer Model; Brown Fat; Cancer Patient; Cancer Prevention Intervention; Cells; Clinical; Cognitive; Colon Carcinoma; Data; Development; Diet; Distal; Environment; Environmental Risk Factor; Equilibrium; Exercise; Fatty acid glycerol esters; Female; Funding; Gene Transfer; Genetic; Glioma; Goals; Growth; Health; High Fat Diet; Homeostasis; Housing; Hypothalamic structure; Immune; Immunity; Individual; Insulin-Like Growth Factor I; Interleukin-15; Intervention; Knowledge; Leptin; Life Style; Link; Lymphoid Tissue; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Mediating; Mediator of activation protein; Mental Health; Metabolic; Modeling; Mouse Mammary Tumor Virus; Mus; Natural Increases; Natural Killer Cells; Neurosecretory Systems; Obesity; Outcome; Palpable; Pharmacology; Phenotype; Physical environment; Preventive; Psychological Stress; Recombinants; Regulation; Resistance; Risk; Role; Serum; Signal Transduction; Social Environment; Social isolation; Social support; Solid Neoplasm; Sympathetic Nervous System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Thinness; Transplantation; Visceral fat; Well in self; Work; adeno-associated viral vector; adiponectin; antagonist; anti-cancer; antitumor effect; beta-adrenergic receptor; biobehavior; cancer prevention; cancer therapy; cell killing; clinically relevant; cytotoxic CD8 T cells; diet-induced obesity; energy balance; environmental enrichment for laboratory animals; epidemiology study; glycemic control; hypothalamic-pituitary-adrenal axis; hypothalamic-sympathoneural-adipocyte axis; immune function; immunoregulation; improved; insight; insulin sensitivity; knock-down; lifestyle factors; malignant breast neoplasm; mammary; melanoma; mortality; novel; overexpression; pre-clinical; prospective; receptor; response; social; social influence; transplant model; tumor progression; tumor-immune system interactions

Project Summary 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 (β-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.

项目总结

项目成果

Induction of adipose and hepatic SWELL1 expression is required for maintaining systemic insulin-sensitivity in obesity.

诱导脂肪和肝脏 SWELL1 表达是维持肥胖患者全身胰岛素敏感性所必需的。

• DOI: 10.1080/19336950.2017.1373225
• 发表时间: 2017
• 期刊: Channels (Austin, Tex.)
• 作者: Xie,Litao;Zhang,Yanhui;Gunasekar,SusheelK;Mishra,Anil;Cao,Lei;Sah,Rajan
• 通讯作者: Sah,Rajan

Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis.

• DOI: 10.21037/tcr.2020.02.39
• 发表时间: 2020-09
• 期刊: Translational cancer research
• 影响因子: 0.9
• 作者: Hassan QN 2nd;Queen NJ;Cao L
• 通讯作者: Cao L

Implementation of environmental enrichment after middle age promotes healthy aging.

• DOI: 10.18632/aging.101502
• 发表时间: 2018-07-20
• 期刊: Aging
• 作者: McMurphy T;Huang W;Queen NJ;Ali S;Widstrom KJ;Liu X;Xiao R;Siu JJ;Cao L
• 通讯作者: Cao L

LMO3 reprograms visceral adipocyte metabolism during obesity.

• DOI: 10.1007/s00109-021-02089-9
• 发表时间: 2021-08
• 期刊: Journal of molecular medicine (Berlin, Germany)
• 作者: Wagner G;Fenzl A;Lindroos-Christensen J;Einwallner E;Husa J;Witzeneder N;Rauscher S;Gröger M;Derdak S;Mohr T;Sutterlüty H;Klinglmüller F;Wolkerstorfer S;Fondi M;Hoermann G;Cao L;Wagner O;Kiefer FW;Esterbauer H;Bilban M
• 通讯作者: Bilban M

Visceral adipose tissue-directed FGF21 gene therapy improves metabolic and immune health in BTBR mice.

• DOI: 10.1016/j.omtm.2020.12.011
• 发表时间: 2021-03-12
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Queen NJ;Bates R;Huang W;Xiao R;Appana B;Cao L
• 通讯作者: Cao L