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Aryl hydrocarbon receptor regulation of energy metabolism

芳烃受体对能量代谢的调节

基本信息

批准号：
9890473
负责人：
Shelley A Tischkau
金额：
$ 44.25万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890473
关键词：
ARNTL gene Adipocytes Adipose tissue Affect Agonist Animals Aryl Hydrocarbon Receptor Behavior Blood Glucose Body Burden Body Composition Chromatin Chronic Chronic Disease Chronically Ill Chronotherapy Circadian Dysregulation Circadian Rhythms Curcumin Data Detection Development Diabetes Mellitus Diabetic mouse Diet Dioxins Dyslipidemias Eating Elements Energy Metabolism Exposure to Fasting Fatty acid glycerol esters Flavonoids Foundations Genes Genetic Transcription Goals Growth Healthcare Hepatic High Fat Diet Homeostasis Human Hypertension In Vitro Industrialization Insulin Insulin Resistance Life Expectancy Ligands Link Lipase Lipolysis Liver Luciferases Malignant Neoplasms Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Modernization Molecular Mus Mutagenesis Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity associated disease Organ Organism Periodicity Pharmaceutical Preparations Phase Population Precipitating Factors Receptor Activation Regulation Reporting Repression Response Elements Rest Risk Science Signal Transduction Sleep Societies Stains Structure System Testing Time Tissues Toxic Environmental Substances Training Transcription Coactivator Transcription Process Triglycerides Weight Gain Wild Type Mouse Xenobiotics adipokines anthropogenesis aryl hydrocarbon receptor ligand base brain tissue career preparation circadian circadian behavioral rhythms circadian pacemaker combat cytokine dimer environmental chemical exposed human population feeding food surveillance glucose tolerance graduate student improved in vivo innovation insight insulin sensitivity insulin tolerance lipid biosynthesis lipophilicity metabolic rate mutant new therapeutic target novel novel therapeutics pandemic disease promoter response sterol esterase targeted treatment transcription factor translational study uncoupling protein 1 undergraduate student

项目摘要

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.

代谢综合征和糖尿病在现代社会普遍存在。人的身体负担增加和升高