Hepatic Gamma-Amino Butyric Acid Release Drives Hyperinsulinemia and Insulin Resistance
AuthorGeisler, Caroline Elyse
AdvisorRenquist, Benjamin J.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
EmbargoRelease after 08/02/2021
AbstractType 2 diabetes, non-alcoholic fatty liver disease, and obesity are paramount threats to the health, finances, and quality of life of hundreds of millions of Americans. Dysregulated macronutrient metabolism and energy homeostasis are central to these highly comorbid conditions, and current therapeutics fail to address the underlying cause of this metabolic dysfunction. We hypothesize that obesity-induced hepatic lipid accumulation drives hyperinsulinemia, insulin resistance, and hyperphagia by dysregulating peripheral parasympathetic nervous system activity. Chapter 1, previously published in the Journal of Endocrinology, reviewed multiple causes of fatty liver and their relationship to homeostatic glucose dysregulation. To better understand the mechanism linking hepatic lipid accumulation to insulin resistance and hyperinsulinemia, we conducted studies aimed at understanding the role of hepatocyte membrane potential in regulating insulin homeostasis. Chapter 2 established that 1) obesity depolarized hepatocytes and that hepatocyte depolarization increased serum insulin, 2) preventing hepatocyte depolarization in obesity limited the insulin resistance and hyperinsulinemia in obesity, 3) the obese liver released more of the inhibitory neurotransmitter GABA, 4) GABA-Transaminase (GABA-T) inhibition, hepatocyte hyperpolarization, and extracellular NaCl prevented liver GABA release, and 5) pharmacological inhibition of GABA-T reversed obesity associated hyperinsulinemia and insulin resistance. Together this data led to a series of new hypotheses that were tested in subsequent chapters. In chapter 3, we used an antisense oligonucleotide (ASO) targeted to GABA-T to knockdown peripheral gene expression. GABA-T ASO treatment effectively eliminated hepatic GABA-T expression and restored normal liver GABA release, serum insulin, and insulin sensitivity in obesity. Furthermore, hepatic GABA-T knockdown decreased food intake and caused body weight loss in obesity. In turn, hepatic GABA-T is involved in the dysregulated glucose and energy homeostasis of obesity. The research presented in chapters 2 and 3 also showed that the hepatic vagal nerve was integral to the improved gluco-regulation and energy homeostasis with GABA-T inhibition and knockdown. We hypothesize decreased hepatic vagal afferent nerve (HVAN) activity increases parasympathetic efferent acetylcholine release onto β-cells to stimulate hyperinsulinemia and decreases acetylcholine release onto skeletal muscle endothelial cells to induce insulin resistance. In chapter 4, we performed a series of studies to better understand the role of efferent parasympathetic signaling in the dysregulated glucose metabolism of obesity. β-cell muscarinic signaling amplifies insulin release while endothelial cell muscarinic signaling increases muscle microvasculature perfusion and glucose clearance. We established that muscarinic 3 receptor (M3R) signaling does not mediate obesity-induced hyperinsulinemia but a loss of endothelial cell M3R signaling exaggerates insulin resistance. We further showed that chronically increasing endothelial cell M3R signaling can improve insulin sensitivity in diet-induced obese mice. The relatively minor phenotype of these mouse models with altered muscarinic signaling may be due to compensation by M1R or altered sympathetic nervous system activity, both of which warrant future research. Together, the research described in this dissertation mechanistically implicates hepatic GABA-HVAN signaling in the metabolic and energy dysregulation of obesity, and identifies new therapeutic targets (hepatocyte membrane potential, GABA-T, GABA transporters/receptors, M3R) to more effectively treat the underlying cause of disease.
Degree ProgramGraduate College