Date of Award

Spring 5-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Mammalian ketone body metabolism partially oxidizes hepatic acyl-chains to ketone body intermediates, which can serve as alternative fuels in extrahapetic tissues during carbohydrate restricted states. Ketone body production (ketogenesis) occurs primarily in liver, due to hepatocyte-specific expression of the fate committing ketogenic enzyme, mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In contrast, the fate committing enzyme of ketone body oxidation, mitochondrial Succinyl-CoA:3-oxoacid CoA Transferase (SCOT), is expressed ubiquitously, except in liver. Here I demonstrate novel roles for ketone body metabolism during a classically ketogenic period, the transition to birth, and in a classically `non-ketogenic' state, overnutrition, using novel genetic mouse models, high-resolution measures of dynamic metabolism using 13C-labeled substrates, and systems physiology approaches. I show that germline SCOT-knockout (KO) mice cannot oxidize ketone bodies in any tissue. These mice developed lethal hyperketonemia and hypoglycemia within the first 48 hr of life and died in a manner that phenocopied human sudden infant death syndrome. Nonetheless, my studies of tissue-specific SCOT-KO mice revealed that ketone body oxidation is dispensable during the transition to birth and during starvation in the adult when individually eliminated in neurons, cardiomyocytes, or skeletal myocytes, which comprise the three largest consumers of ketone bodies. Surprisingly, the inability to dispose of ketone bodies in germline SCOT-KO mice drove derangements of carbohydrate and fatty acid metabolism, oxidized redox potential, and inhibited ketogenesis in liver. Moreover, I show that adult-onset loss of HMGCS2 ablated the liver's capacity to effectively convert fat into ketone bodies, and thus induced ketogenesis insufficiency. Ketogenesis insufficient mice exhibited increased hepatic gluconeogenesis from pyruvate and mild hyperglycemia in the fed state. High-fat diet feeding of ketogenesis insufficient mice caused extensive hepatocyte injury and inflammation that was associated with decreased glycemia due to fatty acid-induced sequestration of free coenzyme A that caused secondary derangements of hepatic tricarboxylic acid (TCA) cycle intermediate concentrations and impaired gluconeogenesis. Together, my studies have revealed a critical and novel role for ketone body metabolism in preservation of the dynamic intermediary metabolic network in liver during the adaptation to birth and in overnutrition.


English (en)

Chair and Committee

Peter A Crawford


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