Date of Award
Master of Science
Jiangang Chen, Rachel P. McCord
Obesity is a significant global health concern linked to various comorbidities, such as cardiometabolic disorders and cancer. Unfortunately, standardized therapeutic approaches have not demonstrated the ability to adequately alleviate the multifaceted burden of obesity. Therefore, there is a need for safe and innovative strategies to prevent and treat unhealthy adipose tissue expansion. In recent years, enhancing the recruitment and thermogenic activity of brown adipose tissue (BAT) has emerged as an appealing approach to promote energy expenditure and metabolic homeostasis. Further elucidating the involvement of various proteins and pathways in regulating BAT development, function, and homeostasis may reveal novel anti-obesity therapeutic approaches. Given the importance of transcriptional and metabolic changes during brown adipogenesis, it is fitting that the glycolytic enzyme and transcriptional regulator pyruvate kinase muscle isozyme 2 (PKM2) has been recently recognized as a modulator of both adipogenesis and thermogenesis. Additionally, PKM2 is allosterically regulated by various metabolic substrates and, within BAT, is modulated by relevant stimuli such as cold exposure, hypoxia, and nutritional status. While this collectively implies that PKM2 may play an important role integrating stimuli to regulate BAT physiology, PKM2’s impact on brown adipogenesis and the underlying mechanisms have not been explored. Therefore, the purpose of this thesis is to elucidate the potential regulatory function of PKM2 in brown adipocyte differentiation and the underlying effectors. To investigate this, we employed genetic and pharmacological approaches to modulate the expression of PKM2 and potential downstream mediators then assessed effects on the differentiation of brown adipocytes from primary brown preadipocytes. During the differentiation process, we specifically examined lipid accumulation and the expression of brown adipocyte marker proteins involved in lipid metabolism and mitochondrial processes, including uncoupling. Our findings confirm the regulatory role of PKM2 in brown adipocyte differentiation and identify target genes involved in transcriptional regulation as key mediators of PKM2’s effect. Ultimately, this study contributes compelling evidence supporting targeting PKM2 as a potential therapeutic approach to address obesity and its associated metabolic dysfunction through the promotion of BAT recruitment and activity.
Demeter, Jenna Brenda, "Targeting PKM2 to promote the differentiation of thermogenic adipocytes as a potential anti-obesity therapy. " Master's Thesis, University of Tennessee, 2023.
Available for download on Saturday, August 15, 2026