Date of Award

2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Patrick Seale

Abstract

Obesity is a major driver of medical morbidity worldwide by promoting the pathogenesis of diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease. Obesity is fundamentally a disorder of energy balance with energy intake chronically exceeding energy expenditure. There exists an urgent need to understand pathways in vivo that can be coopted to increase energy expenditure in a specific manner. One organ in small mammals and humans that expends large amounts of energy is thermogenic adipose tissue. Genetic models in rodents and environmental perturbations in humans have identified an important role for this tissue in controlling insulin sensitivity and energy expenditure. Thermogenic adipocytes develop during stereotyped periods during embryogenesis are their activity is controlled postnatally by environmental factors such as cold exposure. This thesis work is comprised of two studies that sought to determine how transcription factors that control thermogenic adipocyte development to facilitate environmental responsiveness and what specific cells develop into thermogenic adipocytes in vivo. In the first study we used in vivo genetic loss of function studies, metabolic phenotyping, and transcription factor reporter assays to identify that activity of Early B Cell Factors are required for the basal and cold-stimulated thermogenic program in brown adipose tissue by controlling the activity and expression of cold-induced transcription factors. This study linked regulators that had traditionally been studied in the development of thermogenic adipocytes to the factors that control the cold-induced thermogenic program. In the second study, we determined the developmental and maintenance structure of perivascular adipose tissue, a thermogenic adipose depot present in small mammals and humans. We discovered that this lineage initially develops from a fibroblastic lineage and identified a novel adipogenic adventitial smooth muscle cell present in adulthood that has the capacity to generate adipocytes in vitro and in vivo. Taken together, these two studies have identified the key factors required for controlling thermogenic gene transcription in brown adipocytes and the precise progenitor cells for making thermogenic adipocytes in vivo.

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