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Model Systems of Dysregulated Metabolic States

Creative Commons 'BY-NC-SA' version 4.0 license

Dysregulated metabolic states in human health are linked to chronic conditions such as diabetes, insulin resistance, and cancer, and can even impair immune function. Studying dysregulated metabolic states is a critical aspect in current biomedical research, as an aging population and a rise in emerging infectious diseases means that the prevention and management of these conditions is more important than ever. However, metabolism is a highly complex physiological phenomenon that is often inextricable in a practical sense from other systems such as immune function or hormone signaling. Therefore, models of altered metabolism are extremely useful for examining the effects of such perturbed metabolic states in comparative isolation, to elucidate the nature, role, and consequences of such states.

This dissertation presents two examples of model systems that can be used to investigate dysregulated metabolism. The first is the Northern elephant seal, which undergoes temporary, reversible, tissue-specific insulin resistance while it fasts as a normal part of its life cycle. The large-scale shifts in substrate utilization and insulin response observed during long-term fasting in the elephant seal indicate that it can be used to untangle some of the questions about the evolution and regulation of insulin signaling, and provide significant answers to addressing insulin resistance in a clinical context. The second is an engineered cellular model in hepatocellular carcinoma (HCC) cells, examining the hexokinase enzyme switch. As hepatocytes transform into HCC cells during carcinogenesis, they undergo a shift from GCK to HK2 as the main hexokinase enzyme catalyzing the initial step in glycolysis. A unique cellular model was generated by knocking out HK2 in Huh7 HCC cells while simultaneously restoring HK4 expression, thus reversing the isoenzyme switch. The Huh7-GCK+/HK2− cell line displayed a rewired metabolic network, and restored metabolic functions of normal hepatocytes such as lipogenesis and VLDL secretion. It also displayed increased innate immune response and sensitivity to NK cells, indicating the wide-ranging effects of the isoenzyme switch.

Both approaches of model systems – identifying existing organisms with unique metabolic states and engineering specific cellular models – are explored in this work as an overview of the tools available to researchers in studying dysregulated metabolic states.

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