Date of Award

Spring 2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular, Cellular, and Developmental Biology

First Advisor

Rodeheffer, Matthew

Abstract

Obesity, defined as the excessive accumulation of white adipose tissue (WAT), is a global pandemic and increases risk of many other pathologies. However, in vivo molecular mechanisms of adipocyte formation, or adipogenesis, during obesity and high-fat diet (HFD) consumption are still being understood. WAT can expand either through the proliferation of adipocyte precursors (APs) and their differentiation to form new adipocytes (adipogenesis) or through the increased size of adipocytes (hypertrophy). To study how dietary fats impact adipose expansion, mice were fed custom HFDs, each containing a different fat source, and adipogenesis and hypertrophy were quantified. This screen illustrated how dietary fats may bias the WAT toward expanding primarily through increased adipocyte size or number. This dietary fat screen was also instrumental in identifying oleic acid as a molecular signal inducing adipocyte precursor (AP) activation and proliferation. Oleic acid increased adipogenesis in vitro through Akt2 signaling and induction of lipogenesis. Using RNA sequencing of APs from mice fed HFD, downregulation of LXRα signaling was consistently identified in adipose tissue depots that demonstrate an adipogenic response to HFD. LXRα phosphorylation was identified as a modulator in the proliferative response to HFD, with dephosphorylation of LXRα resulting in enhanced diet-induced AP proliferation. This dietary fat screen also provided an effective tool to investigate how expression of the adipokines, adiponectin and leptin, related to mechanisms of adipose expansion. Interestingly, VWAT expression of leptin correlated with several measures of adipocyte formation, contrasting with its typical association with hypertrophy. Finally, while studies using a lard-based HFD found increased expression of inflammatory and fibrotic markers with obesity, this screen also identified several diets that induce obesity but do not result in increased expression of these markers. This work identifies a novel mechanism to regulate diet-induced AP proliferation and highlights the need to study obesity within physiologically relevant contexts.

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