The worldwide epidemic of obesity and global incidence of cancer are both rising. Obesity is linked to an increased risk of certain types of cancer including postmenopausal breast, renal, ovarian, esophagus, pancreas, prostate, hepatobiliary, colorectal, and melanoma. Our recent research on environmental enrichment (EE), a housing condition boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, white to brown adipocyte phenotypic switch, enhanced insulin sensitivity, resistance to diet-induced obesity (DIO), lower leptin level, higher adiponectin level and marked inhibition in melanoma and colon cancer growth. One key underlying mechanism is the activation of the hypothalamic- sympathoneural-adipocyte (HSA) axis with brain-derived neurotrophic factor (BDNF) as the upstream mediator in the brain and leptin as the key peripheral component mediating the anticancer phenotype. These data support the link between adipose remodeling and cancer progression. However obesity is not always linked to insulin resistance or adverse metabolic profile. There is considerable interest in the role of the healthy expansion of adipose tissue in improving insulin sensitivity. Human adenovirus type 36 (Ad-36) can serve as a novel model dissociating adipose expansion from the common adverse health consequences of obesity including diabetes and cancer. Ad-36 has been causatively and correlatively linked with obesity in animals and humans, respectively. However Ad-36 infection paradoxically improves glycemic control, increases adiponectin level, and decreases leptin level. These are the features resemble those closely related to the anticancer phenotype induced by the activation of the HSA axis, although HSA axis activation causes leanness. The goal of this project is to study the effects of healthy expansion of adipose tissue on cancer growth. Specifically we propose to use the adipogenic Ad-36 as a model of a subset of obesity that is derived from metabolically favorable remodeling of adipose tissue and is insulin sensitive. We plan to comprehensively characterize the effects of Ad-36 infection on adipose remodeling, metabolism, hypothalamic gene expression, and cancer progression in both normal weight animals and conventional DIO model. Accomplishing the proposed studies may help to better understand the role of adiposity in cancer progression, clarify the contribution of altered adipokine profiles (specifically the adiponectin/leptin ratio) versus expansion of adipose tissue per se to cancer risk, and stimulate studies to harness certain properties of microbes for beneficial purposes.

Public Health Relevance

Human adenovirus type 36 (Ad-36) promotes obesity in experimentally infected animals and is widely present in humans with most cross-sectional studies showing a significant association of Ad-36 infection with obesity in adults and children. However Ad-36 infection paradoxically improves glycemic control and metabolic profile, and shares certain characteristics with the activation of a brain-fat axis that induces anticancer phenotype. The purpose of this project is to study the subset of obesity (Ad-36 infection) that is insulin sensitive and metabolically healthy, and to explore the possibility of creatively using viruses for beneficial purposes in the treatment of metabolic syndromes and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA178227-02
Application #
8691755
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Perloff, Marjorie
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
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
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
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
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
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
Huang, Wei; McMurphy, Travis; Liu, Xianglan et al. (2016) Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector. Mol Ther 24:1062-1069
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:
Xiao, Run; Bergin, Stephen M; Huang, Wei et al. (2016) Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype. Cancer Immunol Res 4:488-497
Foglesong, Grant D; Huang, Wei; Liu, Xianglan et al. (2016) Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice. Endocrinology 157:983-96

Showing the most recent 10 out of 14 publications