Thursday, November 21, 2024
11/21/2024
Metabolic syndrome and diabetes are pandemic in modern society. Humans with increased an 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). Results under the previous award 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, in a sex-specific manner. 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 alleviate AhR-induced metabolic dysfunction using a treatment that involves bolstering circadian clock function. Previous findings also demonstrate that AhR regulation of adipose tissue is more important in females, and that female adipose tissue has significant impact in regulating systemic glucose metabolism. We hypothesize that restricted feeding can regulate can restore depleted rhythms in adipose tissue function and rescue metabolism from the detrimental effects of chronic AhR activation. Further we hypothesize that estrogen/AhR interactions underlie adipose regulation of systemic metabolism in females. The proposal combines approaches that examine systemic metabolic parameters and behavioral circadian rhythms and molecular studies that focus on mechanisms of AhR/estrogen interactions. Specific aim I explores restricted feeding as a mechanism to reset clock function after its ablation by chronic AhR activation. Aim II explores molecular mechanisms of AhR interactions with estrogen signaling specifically in female adipose tissue. The project provides a framework for training undergraduate, graduate and medical students in preparation for careers in the biomedical sciences. The proposal highlights a novel mechanism for xenobiotic action in the development of metabolic syndrome, explores a biological basis for sex-specific therapeutics, and provides insight into the potential for chronotherapy as a treatment for diabetes and metabolic syndrome.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
