Item Details

Catecholamine-Induced Lipolysis Inhibits Glucose Uptake and Causes mTOR Complex Dissociation in Adipocytes

Mullins, Garrett
Format
Thesis/Dissertation; Online
Author
Mullins, Garrett
Advisor
Harris, Thurl
Abstract
Acute hyperglycemia often develops after trauma or major surgery. This condition, termed stress-induced hyperglycemia, contributes to morbidity and mortality and delays patient healing in the ICU. It is a result of systemic insulin resistance caused by the adaptive stress response. Although it directly impacts patient health and has been observed for decades, the pathophysiology of stress-induced hyperglycemia is largely unknown. Interestingly, β-adrenergic stimulation by catecholamines results in decreased insulin-stimulated glucose uptake in adipocytes. Although this decrease in glucose uptake likely contributes to stress-induced hyperglycemia, the underlying molecular mechanism has not been defined. The work herein has built on the prior literature by examining how β-adrenergic stimulation by catecholamines leads to inhibited insulin action in adipocytes. We provide evidence that β-adrenergic-mediated inhibition of glucose uptake requires lipolysis. We show that lipolysis suppresses glucose uptake by inhibiting the mammalian Target of Rapamycin (mTOR) complexes 1 and 2. In addition, our work shows the mechanism of mTOR inhibition is through the generation of lipid intermediates, likely oxidized neutral lipids, which directly cause mTOR complex dissociation. This work defines a previously unrecognized intracellular signaling pathway whereby lipids generated from lipolysis block insulin signaling, resulting in decreased glucose uptake. This novel mechanism of mTOR regulation likely contributes to the development of stress-induced hyperglycemia and may also play a role in obesity-induced insulin resistance.
Language
English
Date Received
20150423
Published
University of Virginia, Department of Pharmacology, PHD (Doctor of Philosophy), 2015
Published Date
2015-04-20
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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