KETONE BODY METABOLISM IN OBESITY AND DIABETES
Creators: Yang, Kunyan
Publisher: name: University of Alberta Library
Year: 2024

<p>The conservation of ketone body metabolism across various domains of life, including eukaryotes, bacteria, and archaea, underscores its pivotal role in physiological processes. Primarily activated during carbohydrate scarcity, ketone body metabolism provides alternative energy, mainly to the brain, heart, and skeletal muscles. The liver orchestrates ketogenesis, finely tuned by hormones, primarily insulin and glucagon. This thesis delves into the intricate dynamics of ketone body metabolism and its implications on human health, focusing on its role in obesity and potential applications in managing type 2 diabetes (T2D). <br>
Over the past four years, our laboratory has been working to identify innovative targets and approaches aimed at ameliorating hyperglycemia and insulin resistance in conditions such as obesity and T2D. Notably, we&#39;ve recently uncovered that the catalytic activity of succinyl-CoA:3-ketoacid CoA transferase (SCOT), the pivotal enzyme driving the oxidation of ketone bodies, is heightened in the skeletal muscles of obese mice. SCOT inhibited by drugs or ablated genetically showed improved glycemia in obese and diabetic mice. We hypothesize that administering dietary ketone esters to obese mice, aiming to elevate circulating ketone levels, could potentially exacerbate their glycemic control. Furthermore, we propose that the genetic upregulation of SCOT in skeletal muscles may lead to compromised glycemic regulation in obese mice, thereby heightening their risk of developing T2D.<br>
Chapter 2 of the study investigates the impact of ketone ester (KE) administration on glycemia in obese mice, examining its influence on glucose tolerance, ketone body oxidation, and insulin’s role in glycemic control. KE can raise the ketones levels in the circulation effectively to boost a secondary elevation of ketone body oxidation. Contrary to expectations, KE administration improved glucose tolerance in obese models without relying on ketone body oxidation in skeletal muscles. The islets perifusion with ketone salts suggested that while ketone body oxidation might influence insulin secretion, it&#39;s not the primary factor responsible for improved blood glucose levels observed in obese mice. Other metabolic or signaling pathways could play a more substantial role in the observed glycemic improvement. Uncovering these pathways can provide insights into the complex interplay of metabolic factors in obesity and potentially lead to novel therapeutic approaches for managing diabetes and metabolic disorders.<br>
Chapter 3, an ongoing work, focuses on the generation and characterization of SCOT/Oxct1 (3-oxoacid CoA-transferase 1) transgenic mice. The comprehensive characterization aims to elucidate the physiological shifts and metabolic profile differences due to a chronic upregulation in ketone body oxidation. The results could shed light on SCOT’s role in metabolic processes and its potential implications for glycemic management in obese mice, increasing their susceptibility to developing T2D.<br>
The study elucidates the nuanced interplay between ketone body metabolism, insulin secretion, and glucose regulation, particularly under varying nutritional states and obesity. The unexpected outcomes from KE administration and the potential role of βOHB in insulin secretion signal a need for deeper exploration. The differences observed between obese and lean models, the transient nature of insulin secretion, and the varying responses to different degrees of high-fat diet (HFD) present a complex scenario requiring further investigation. The study also emphasizes the need for exploring the long-term effects of ketone ester administration and its potential therapeutic applications, especially in metabolic health and T2D management. The generation of pancreas-specific SCOT knockout models and exploring additional signaling pathways are identified as key future directions to deepen our understanding of the underlying mechanisms. In conclusion, this study sheds light on the intricate dynamics of ketone body metabolism, its impact on glycemic control in obesity, and its potential therapeutic implications. The findings underscore the complexity of metabolic regulation, highlighting the need for further research to unravel the mechanisms and explore the potential of ketone body metabolism in human health.</p>