Research Project
9890473
Metabolic syndrome and diabetes are pandemic in modern society. Humans with increased and elevated body burden of certain lipophilic xenobiotics such as dioxins are at increased risk for type 2 diabetes and metabolic syndrome. These anthropogenic substances exert their effects through activation of aryl hydrocarbon receptor (AhR). Preliminary data present a compelling argument that disruption of circadian rhythmicity, particularly desynchronization of the central clock from those in metabolically important organs, 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. Chronic AhR activation causes a similar disruption in rhythms in liver and adipose tissue. This proposal thus seeks to link the development of metabolic syndrome in response to long-term AhR activation to circadian clock disruption. Because many AhR agonists accumulate in fat, this proposal focuses on rhythm disruption in adipose tissue as a precipitating factor in the development of metabolic disease. We hypothesize that AhR activation directly disrupts the molecular circadian clock in adipose tissue and creates desynchrony between the clock in the brain and adipose tissue; metabolic syndrome develops subsequent to clock disruption. Finally, we hypothesize that protection 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 metabolic genes that are regulated by the circadian clock. Specific aim I explores effects of AhR activation state on SCN and adipose tissue rhythms, and establishes fundamental differences in the effects of AhR activation on these two oscillator systems. Aim I explores behavioral circadian rhythms and 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 an AhR agonist. Aim II explores molecular mechanisms of AhR-mediated disruption of rhythms in lipolysis genes, which are known targets of the circadian clock transcription factors, Clock and Bmal1, with an emphasis on interactions between AhR and E-box- mediated transcription. The project provides a framework for training both undergraduate and graduate students in preparation for careers in the biomedical sciences. 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.
