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Two Ways from the Golgi: Integrating...

Li, Don Tianmu.

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Two Ways from the Golgi: Integrating Glucose and Energy through TUG Protein.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Two Ways from the Golgi: Integrating Glucose and Energy through TUG Protein./
作者:	Li, Don Tianmu.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	273 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
Contained By:	Dissertations Abstracts International81-10B.
標題:	Biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=22619653
ISBN:	9798607313227

Two Ways from the Golgi: Integrating Glucose and Energy through TUG Protein.
Li, Don Tianmu.

Two Ways from the Golgi: Integrating Glucose and Energy through TUG Protein. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 273 p.

Source: Dissertations Abstracts International, Volume: 81-10, Section: B.

Thesis (Ph.D.)--Yale University, 2019.

This item must not be sold to any third party vendors.

Insulin stimulates the exocytic translocation of specialized vesicles in adipocytes, which inserts GLUT4 glucose transporters into the plasma membrane to enhance glucose uptake. Previous results support a model in which TUG proteins trap these GLUT4 storage vesicles at the Golgi matrix, and in which insulin triggers endoproteolytic cleavage of TUG to translocate GLUT4. Here, I study the behavior of the N-terminal and C-terminal TUG cleavage products. Previous results show that TUG proteolysis generates a ubiquitin-like protein known as TUGUL as the N-terminal product. I now show that TUGUL modifies the kinesin motor protein, KIF5B, and that TUG proteolysis is required to load GLUT4 on to these motors. Insulin stimulates TUG proteolytic processing independently of phosphatidylinositol-3-kinase. In rodents with diet-induced insulin resistance, TUG proteolysis is reduced in adipose tissue. Together with previous data, my results support a model by which insulin acts through Usp25m to mediate TUG cleavage and produce TUGUL. This action liberates GLUT4 storage vesicles from the Golgi matrix and activates their microtubule-based movement to the plasma membrane. This TUG proteolytic pathway for insulin action is independent of Akt and is impaired by nutritional excess. Simultaneously, I show that the C-terminal product activates transcription to promote energy expenditure. In muscle of transgenic mice, similar increases in glucose uptake result from constitutive TUG cleavage and TUG deletion, but only constitutive TUG cleavage increases energy expenditure. On a high-fat diet, mice with muscle-specific TUG deletion have reduced energy expenditure and increased weight gain. The TUG C-terminal enters the nucleus, binds the transcriptional factors PPAR-γ and PGC-1α, and acts at specific promoters to increase expression of genes that mediate thermogenesis such as sarcolipin. Nutritional excess attenuates TUG cleavage, contributing to impaired insulin-regulated glucose uptake and reducing association of the TUG product at these promoters. These data support a similar mechanism in adipose with regards to Ucp1 and also imply muscle-adipose crosstalk. Furthermore, this mechanism may help to explain why nutrient intake causes a transient increase in the production of body heat known as the thermic effect of food. By going two ways from the Golgi, the TUG cleavage products may therefore help to mediate both GSV translocation and induction of energy expenditure. Together, these results describe a model for how TUG serves as a central regulator of insulin response in both fat and muscle.

ISBN: 9798607313227Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

Adipocyte

Two Ways from the Golgi: Integrating Glucose and Energy through TUG Protein.
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500 $a Source: Dissertations Abstracts International, Volume: 81-10, Section: B.
500 $a Advisor: Bogan, Jonathan S.
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520 $a Insulin stimulates the exocytic translocation of specialized vesicles in adipocytes, which inserts GLUT4 glucose transporters into the plasma membrane to enhance glucose uptake. Previous results support a model in which TUG proteins trap these GLUT4 storage vesicles at the Golgi matrix, and in which insulin triggers endoproteolytic cleavage of TUG to translocate GLUT4. Here, I study the behavior of the N-terminal and C-terminal TUG cleavage products. Previous results show that TUG proteolysis generates a ubiquitin-like protein known as TUGUL as the N-terminal product. I now show that TUGUL modifies the kinesin motor protein, KIF5B, and that TUG proteolysis is required to load GLUT4 on to these motors. Insulin stimulates TUG proteolytic processing independently of phosphatidylinositol-3-kinase. In rodents with diet-induced insulin resistance, TUG proteolysis is reduced in adipose tissue. Together with previous data, my results support a model by which insulin acts through Usp25m to mediate TUG cleavage and produce TUGUL. This action liberates GLUT4 storage vesicles from the Golgi matrix and activates their microtubule-based movement to the plasma membrane. This TUG proteolytic pathway for insulin action is independent of Akt and is impaired by nutritional excess. Simultaneously, I show that the C-terminal product activates transcription to promote energy expenditure. In muscle of transgenic mice, similar increases in glucose uptake result from constitutive TUG cleavage and TUG deletion, but only constitutive TUG cleavage increases energy expenditure. On a high-fat diet, mice with muscle-specific TUG deletion have reduced energy expenditure and increased weight gain. The TUG C-terminal enters the nucleus, binds the transcriptional factors PPAR-γ and PGC-1α, and acts at specific promoters to increase expression of genes that mediate thermogenesis such as sarcolipin. Nutritional excess attenuates TUG cleavage, contributing to impaired insulin-regulated glucose uptake and reducing association of the TUG product at these promoters. These data support a similar mechanism in adipose with regards to Ucp1 and also imply muscle-adipose crosstalk. Furthermore, this mechanism may help to explain why nutrient intake causes a transient increase in the production of body heat known as the thermic effect of food. By going two ways from the Golgi, the TUG cleavage products may therefore help to mediate both GSV translocation and induction of energy expenditure. Together, these results describe a model for how TUG serves as a central regulator of insulin response in both fat and muscle.
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653 $a Themogenesis
653 $a TUG
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710 2 $a Yale University. $b Cell Biology in MD/PhD Program. $3 3550197
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