Honors Theses

Advisor

Joel D. Schilling, M.D., Ph.D. and Anne Crecelius, Ph.D.

Department

Health and Sports Science

Publication Date

4-2018

Document Type

Honors Thesis

Abstract

Metabolic disorders such as type two diabetes mellitus (T2DM) and obesity are known to have a chronic low grade inflammatory tissue environment as well as an increase in excess lipids. Current research suggests that a tightly regulated oligoprotein complex known as the NLRP3 inflammasome is highly activated in T2DM and obesity. However, it is not well understood the interplay between excess lipids, which was previously shown in our lab to cause lysosome damage, and inflammation. A key transcription factor that is known to have both an inflammatory effect as well as an effect on lipid metabolism is PPARγ. For this reason, we attempted to determine if PPARγ had an effect on the degree of pro-inflammatory cytokine release such as IL-1β in the presence of excess lipids. A myeloid specific knock-out of PPARγ (mPPARγ KO) showed significantly less IL-1β and IL-1α levels when stimulated with palmitate-LPS. The selective suppression of the IL-1 family occurred via transcriptional changes. RNA sequencing data showed that the mPPARγ KO had a heightened type 1 IFN signature, with both increases in IFNβ and IFN-regulated genes. The type-1 interferon receptor antibody (IFNAR1 ab) raised IL-1 levels to wild type levels, confirming the PPARγ phenotype was due to the heightened IFNβ levels. When WT macrophages were stimulated with palm-LPS and recombinant IFNβ (rIFNβ), it phenocopied the mPPARγ KO macrophages, confirming IFNβ was sufficient to decrease IL-1 levels. These findings suggest crosstalk between lipid metabolism and inflammation in macrophages, adding to the understanding of the complex pathology seen in T2DM and obesity.

Permission Statement

This item is protected by copyright law (Title 17, U.S. Code) and may only be used for noncommercial, educational, and scholarly purposes

Keywords

Undergraduate research

Disciplines

Medicine and Health Sciences | Sports Sciences

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