Regulation of Visceral Adipose Tissue Development and Remodeling in Obesity

Date

2018-08-31

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Abstract

Mammals possess functionally and anatomically distinct types of adipose tissues that differentially impact metabolic health. Pathologic expansion of visceral white adipose tissue (WAT) in obesity confers significant risk for the development of diabetes, whereas thermogenic brown and beige adipose tissues are protective against insulin resistance. My research focuses on understanding 1) the mechanisms driving the development and maintenance of adipocytes, and 2) factors controlling adipose tissue remodeling in obesity. My early work in the Gupta lab contributed to the identification of PDGFRβ+ perivascular (mural) cells that give rise to visceral white adipocytes in association with diet-induced obesity. Furthermore, I contributed to a number of studies that determined that the transcription factor, Zfp423, acts to maintain white adipocyte function by suppressing the gene program of brown/beige adipocytes. My independent thesis work centers on defining the degree of functional heterogeneity within adipose PDGFRβ+ precursors. Through single cell RNA-sequencing and FACS, I identified functionally distinct subpopulations of perivascular cells in visceral WAT: LY6C- CD9- PDGFRβ+ cells represent highly adipogenic visceral adipocyte precursor cells ("APCs"), whereas LY6C+ PDGFRβ+ cells represent fibro-inflammatory progenitors ("FIPs"). FIPs lack adipogenic capacity, display pro-fibrogenic/pro-inflammatory phenotypes, and can exert an anti-adipogenic effect on APCs. These results are significant as they provide a novel prospective approach to purifying adipocyte precursors, and identify a novel niche cell population that may influence adipose tissue inflammation and remodeling. Through the use of inducible tissue-specific gene targeting in mice, I found that Zfp423 regulates the fate and function of PDGFRβ+ mural cells in visceral WAT. The genetic deletion of Zfp423 in the PDGFRβ+ cells leads to the suppression of PDGFRβ cell inflammation and a decrease in WAT inflammation. Furthermore, the deletion of Zfp423 in the visceral adipocyte lineage leads to the formation of thermogenic beige-like visceral adipocytes that can prevent and reverse insulin resistance in obesity. Altogether, my studies provide insight into the regulation of visceral WAT adipogenesis, fibrosis, and remodeling, and provide improved strategies to isolate stromal cell populations from visceral WAT.

General Notes

Page xiiii is misnumbered as page xiv.

Table of Contents

Subjects

Adipocytes, White, Adipogenesis, Obesity

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