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.
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.
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|Liu, Xianglan; McMurphy, Travis; Xiao, Run et al. (2014) Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice. Mol Ther 22:1275-84|
|Liu, Xianglan; Magee, Daniel; Wang, Chuansong et al. (2014) Adipose tissue insulin receptor knockdown via a new primate-derived hybrid recombinant AAV serotype. Mol Ther Methods Clin Dev 1:|