Metabolic syndrome is an umbrella term for a large network of interdependent biochemical, metabolic and physiological factors that are associated with a higher risk of cardiovascular disease, and type 2 diabetes mellitus. Physiological risk factors such as insulin resistance, elevated blood pressure, visceral adiposity, and chronic inflammation are often rooted in alterations and dysfunction of the underlying metabolic tissues of the body, such as the adipose tissue and skeletal muscle. This work focuses on elucidating molecular mechanisms of gene regulation that impact the differentiation and function of both adipose tissue and skeletal muscle using well established in vitro models as well as genetic mouse models.
The first two chapters describe the transcriptional profiling of GPS2-Adiponectin-Cre specific knockout (GPS2-AKO) mice upon high fat diet feeding. We used various next generation sequencing (NGS) technologies to explore how the lack of GPS2 impact upon adipose tissue adaptation to the dietary stress on a molecular level. In the first Chapter, I discuss how RNAseq experiments performed in the epididymal white adipose tissue (eWAT), and subcutaneous white adipose tissue (scWAT) reveal a complex role for GPS2 in the regulation of mitochondrial genes, inflammation and metabolism in mature adipocytes. The second chapter utilizes single cell RNA sequencing to examine how loss of GPS2 in mature adipocytes alters the underlying stromal vascular fraction tissue environment. This work has demonstrated key roles for GPS2 in directly regulating the response of adipocytes to high fat diet stress and indirectly affecting the crosstalk between adipocytes and the underlying SVF.
The third chapter explores the role of GPS2 as a key mediator of skeletal muscle cell differentiation. Given the known role of GPS2 as a transcriptional cofactor, we profiled the genomic occupancy of GPS2 across C2C12 differentiation via ChIPseq and found binding to known enhancer regions linked to important muscle differentiation terms. This led to the identification of an unexpected role for GPS2 as a required factor for the differentiation of C2C12 skeletal muscle cells in vitro
