Metabolic syndrome and diabetes are pandemic in modern society. Epidemiological studies indicate increased incidence of insulin resistance and type 2 diabetes in humans with elevated body burden of certain lipophilic xenobiotics such as dioxins. These anthropogenic substances exert their effects through activation of aryl hyrdrocarbon receptor (AhR). Preliminary data present a compelling argument that disruption of circadian rhythmicity, particularly desynchronization of clocks located in the brain and liver, occurs subsequent to long-term AhR activation. Metabolic syndrome develops in mice that have a disrupted circadian clock, and diabetic mice display marked alterations in circadian rhythms. This proposal thus seeks to link the development of metabolic syndrome in response to long term AhR activation to circadian clock disruption. We hypothesize that AhR activation directly disrupts the molecular circadian clock in the liver and creates desynchrony between clocks in the brain and the liver;metabolic syndrome develops subsequent to clock disruption. Finally, we hypothesize that restoration of rhythmicity will alleviate the detrimental effects of AhR activation on metabolic parameters. The proposal combines approaches that examine systemic metabolic parameters and behavioral circadian rhythms and molecular studies that focus on mechanisms of AhR-mediated repression of circadian clock gene expression.
Specific aims I and II explore effects of AhR activation state on SCN and liver rhythms, respectively, and establishes fundamental differences in the effects of AhR activation on these two oscillator systems.
Aim I explores behavioral circadian rhythms and SCN responses to differences in AhR activation state using aryl hydrocarbon receptor-deficient mice (AhRKO), mice with constitutive activation of AhR (CA-AhR), and wild-type mice treated with long-acting or short-acting AhR agonists.
Aim II uses mPer2luc mice and real time bioluminescence to determine effects of AhR activation on the liver clock.
Aim III explores molecular mechanisms of AhR-mediated disruption of clock gene function, with an emphasis on interactions between AhR and E-box-mediated transcription driven by the clock genes, Clock and Bmal1.
Aim I V explores metabolic changes associated with clock gene disruption after AhR activation and the effects of reversing these disruptions. The proposal highlights a novel mechanism for xenobiotic action in the development of metabolic syndrome and provides insight into the potential for chronotherapy as a treatment for diabetes and metabolic syndrome.

Public Health Relevance

Human and animal populations are increasingly exposed to toxic environmental chemicals as a result of living in a heavily industrialized world. Human exposure to dioxins causes both sleep and metabolic disturbances, including increased risk of type II diabetes and metabolic syndrome. This proposal examines the novel hypothesis that dioxins exert their action through aryl hydrocarbon receptor-mediated uncoupling of homeostatic regulation of organismic circadian rhythms.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
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Heindel, Jerrold
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Southern Illinois University School of Medicine
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Xu, Can-Xin; Wang, Chun; Zhang, Zhi-Ming et al. (2015) Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure. Int J Obes (Lond) 39:1300-1309
Wang, Chun; Zhang, Zhi-Ming; Xu, Can-Xin et al. (2014) Interplay between Dioxin-mediated signaling and circadian clock: a possible determinant in metabolic homeostasis. Int J Mol Sci 15:11700-12
Wang, Chun; Xu, Can-Xin; Bu, Yiwen et al. (2014) Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling. Carcinogenesis 35:703-13
Xu, Can-Xin; Wang, Chun; Krager, Stacey L et al. (2013) Aryl hydrocarbon receptor activation attenuates Per1 gene induction and influences circadian clock resetting. Toxicol Sci 132:368-78
Tischkau, Shelley A; Jaeger, Cassie D; Krager, Stacey L (2011) Circadian clock disruption in the mouse ovary in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett 201:116-22
Wang, Chun; Xu, Can-Xin; Krager, Stacey L et al. (2011) Aryl hydrocarbon receptor deficiency enhances insulin sensitivity and reduces PPAR-? pathway activity in mice. Environ Health Perspect 119:1739-44
Xu, Can-Xin; Krager, Stacey L; Liao, Duan-Fang et al. (2010) Disruption of CLOCK-BMAL1 transcriptional activity is responsible for aryl hydrocarbon receptor-mediated regulation of Period1 gene. Toxicol Sci 115:98-108