# Aryl hydrocarbon receptor regulation of energy metabolism

> **NIH NIH R15** · SOUTHERN ILLINOIS UNIVERSITY SCH OF MED · 2020 · $442,500

## Abstract

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.

## Key facts

- **NIH application ID:** 9890473
- **Project number:** 1R15ES030556-01A1
- **Recipient organization:** SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
- **Principal Investigator:** Shelley A Tischkau
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890473

## Citation

> US National Institutes of Health, RePORTER application 9890473, Aryl hydrocarbon receptor regulation of energy metabolism (1R15ES030556-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9890473. Licensed CC0.

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