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CREB3/LUMAN as a novel regulator of energy metabolism

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Title: CREB3/LUMAN as a novel regulator of energy metabolism
Author: Smith, Brandon S.
Department: Department of Molecular and Cellular Biology
Program: Molecular and Cellular Biology
Advisor: Lu, RayBakovic, Marica
Abstract: CREB3 is a cellular stress-associated protein with much of its physiological and cellular functions remain to be elucidated. Stress-associated proteins have been previously well established as metabolic regulators and protect cells from toxic levels of reactive oxygen species (ROS). This thesis investigated a novel role of CREB3 in regulating energy metabolism by utilizing Creb3-deficient mice and mouse embryonic fibroblast (MEF) cells. It was found that Creb3-deficient mice had an increase in energy expenditure with no differences in energy intake. This resulted in the protection from high-fat diet-induced weight gain, hyperglycemia, and sex-specific tissue lipid accumulation in Creb3-deficient mice. Creb3-deficient males in particular were protected from hepatic accumulation of lipids and resisted high-fat diet-induced glucose intolerance while Creb3-deficient females were protected from lipid accumulation in skeletal muscle. These results suggest CREB3 acts as a metabolic brake, presumably under stressed conditions such as feeding on a high-fat diet. CREB3 has previously been linked to the regulation of endoplasmic reticulum (ER)-Ca2+ release which can stimulate ATP production as it enters the mitochondria. ER and mitochondrial Ca2+ homeostasis was investigated in Creb3-deficient MEF cells as a potential mechanism in which CREB3 controls energy metabolism. It was found that CREB3 did indeed inhibit ER-Ca2+ release although the exact mechanism of this remains unknown. Subsequently, Creb3-deficient MEFs had increased mitochondrial Ca2+ levels and thus drastically elevated basal mitochondrial respiration and ATP production along with an increase in basal ROS levels. Since Ca2+, ATP, and ROS have an intricate mutual interplay with one another, when one is dysregulated, often the others are as well. This thesis established a novel role of CREB3 as a potent regulator of energy metabolism homeostasis both at the organism and cellular levels.
Date: 2022
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Related Publications: Smith BS, De Silva KD, Hashemi A, Duncan RE, Grapentine S, Bakovic M, Lu R. Transcription factor CREB3 is a potentregulator of high-fat diet-induced obesity and energy metabolism. Int J Obes. 2022.

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