DOI
https://doi.org/10.25772/HEF8-A345
Defense Date
2018
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Andrew C. Larner, MD, PhD
Abstract
Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK-STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1. We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. Without STAT3, the brown preadipocytes have increased apoptosis early in the terminal differentiation phase. We also show that the block in differentiation is caused by an inability of STAT3 knockouts to down regulate β-catenin by the end of the induction phase. Application of Wnt/β-catenin inhibitors or knockdown of β-catenin during the induction phase is sufficient to fully rescue differentiation of brown adipocytes from the Myf5+ lineage, including reduction in apoptosis, restoration of histone acetylation in the UCP1 promoter and enhancer regions, and full restoration of the expression of brown fat genes. Finally, we show that in the beige lineage, STAT3 is also necessary during the induction phase and can be rescued by Wnt/β-catenin inhibitors, although the rescue is not as robust as it is in the Myf5+ lineage.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
3-30-2018