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

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $370,500

## Abstract

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.

## Key facts

- **NIH application ID:** 9853738
- **Project number:** 5R01CA166590-08
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Lei Cao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,500
- **Award type:** 5
- **Project period:** 2013-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853738

## Citation

> US National Institutes of Health, RePORTER application 9853738, Cancer prevention and treatment by activation of a brain-adipocyte axis (5R01CA166590-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9853738. Licensed CC0.

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