Transcriptional programming of thermogenic adipocytes by TLKE3 and the role of MPC1 in Thermogenesis

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Pearson, Stephanie A.
Title Transcriptional programming of thermogenic adipocytes by TLKE3 and the role of MPC1 in Thermogenesis
Date 2019
Description Adipocytes are specialized cells for storing a body's excess energy, yet a subset of adipocytes also have the capacity to oxidize energy stores at very high rates to produce heat. These thermogenic cells, designated brown and beige adipocytes, not only defend the core body temperature against cold, but can modulate metabolism with their high degree of energy usage. Consequently, much research focuses on understanding the regulation of these cells and their metabolism of fuel sources. My dissertation research examines two aspects of thermogenic adipocyte function: first, the thermogenic regulation in beige adipocytes by the transcriptional co-regulator, TLE3; and second, the importance of mitochondrial pyruvate import for thermogenic function and fuel utilization. TLE3 promotes the lipid storage program in adipocytes. It is highly expressed in white adipose tissue, and consequently, we found that the loss of TLE3 promotes the development of beige adipocytes within white adipose tissue. An adipocyte-specific knockout of TLE3 leads to increased energy expenditure and improved glucose metabolism. In addition, an examination of TLE3 by chromatin immunoprecipitation and deep sequencing revealed a novel interaction between TLE3 and a known thermogenic adipocyte transcription factor, EBF2. Further examination showed that TLE3 inhibits the transcriptional activity of EBF2 to block thermogenic gene expression. Brown and beige adipocytes take up large amounts of glucose when stimulated, though the fate of glucose during thermogenesis has been less well understood. Glucose may be stored as glycogen, shunted to the pentose phosphate pathway, or broken down to pyruvate via glycolysis. The mitochondrial pyruvate carrier complex (MPC) consists of two necessary proteins (MPC1 and MPC2) on the inner mitochondrial membrane, and iv controls the uptake of pyruvate into the mitochondria. We demonstrate that the import of pyruvate into the mitochondria is essential for thermogenesis. The loss of MPC1 from adipose tissue creates a cold sensitivity in mice and causes depletion of TCA cycle intermediates as well as fatty acids. Consequently, we observe increased beige adipocyte development and improved systemic glucose metabolism. Taken together, this body of work reinforces the importance of thermogenic adipocytes for both body temperature maintenance and metabolic health.
Type Text
Publisher University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Stephanie A. Pearson
Format Medium application/pdf
ARK ark:/87278/s6s81g0k
Setname ir_etd
Date Created 2021-06-04
Date Modified 2021-06-09
ID 1701240
Reference URL https://collections.lib.utah.edu/ark:/87278/s6s81g0k
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