Degree

Doctor of Philosophy (PhD)

Department

Biological Sciences

Document Type

Dissertation

Abstract

Obesity is a metabolic disorder characterized by excess energy storage in adipose tissue and it increases the risk for Type 2 diabetes. Impaired or altered adipocyte function during obesity can contribute to metabolic dysfunction. DBC1 (deleted in breast cancer 1) and EHMTs 1 and 2 (euchromatic histone lysine methyltransferases 1 and 2) have been shown to have a role in fat cell development and function. DBC1 is typically localized in the nucleus and can regulate a variety of epigenetic modifiers, transcription factors, and nuclear receptors. EHMTs 1 and 2, also known respectively as GLP and G9a, were initially classified as histone methyltransferases that primarily function to catalyze mono- and di-methylation of lysine 9 in histone H3 (H3K9), but more recent studies have shown that these two proteins can methylate non-histone substrates and have the capacity to function as transcriptional co-activators independent of their methyltransferase activity. Although there have been advancements in demonstrating the importance of these proteins in metabolic disease, the underlying mechanisms of DBC1, G9a, and GLP in adipocytes that contribute to the pathogenesis of obesity and Type 2 diabetes are largely unknown. To further understand how DBC1, G9a, and GLP expression in adipocytes contributes to metabolic health, we utilized siRNA-mediated knockdown approaches to determine if loss of these proteins in adipocytes could perturb the action of TNFα, a pro-inflammatory cytokine typically upregulated in obesity and Type 2 diabetes. Although DBC1 knockdown did not have a profound effect on TNFα-regulated gene expression, we observed that loss of DBC1 increased Glut4 mRNA expression and reduced TNFα-induced lipolysis, a phenotype likely to be metabolically favorable in adipocytes. Conversely, we demonstrated that simultaneous knockdown of G9a and GLP enhanced TNFα’s ability to transcriptionally activate pro-inflammatory gene expression and induce lipolysis, a phenotype that could be considered metabolically unfavorable in fat cells. These studies provide novel insight on the contributions of DBC1, G9a, and GLP to adipocyte gene expression and function that is associated with metabolic health. Overall, these findings advance our understanding of adipocyte-autonomous roles for DBC1, G9a, and GLP that potentially contribute to the pathogenesis of obesity and Type 2 diabetes.

Date

10-29-2019

Committee Chair

Stephens, Jacqueline M.

Available for download on Thursday, October 27, 2022

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