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Biased Agonism of the G Protein-Coup...

Villa, Stephanie R.

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Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass./
Author:	Villa, Stephanie R.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
Description:	140 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-02(E), Section: B.
Contained By:	Dissertation Abstracts International78-02B(E).
Subject:	Endocrinology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10160464
ISBN:	9781369153712

Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass.
Villa, Stephanie R.

Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 140 p.

Source: Dissertation Abstracts International, Volume: 78-02(E), Section: B.

Thesis (Ph.D.)--Northwestern University, 2016.

Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass The regulation of pancreatic beta-cell mass and function is critical to the maintenance of normoglycemia during insulin resistance states such as pregnancy and obesity. Multiple indicators of nutrient status such as glucose, amino acids, and free fatty acids contribute to the precise regulation of these aspects of beta-cell function. Additionally, nutrient-sensing G protein-coupled receptors (GPCR) are well-described to contribute to beta-cell mass and glucose stimulated insulin secretion (GSIS). Free Fatty Acid Receptor 2 (FFA2) is a GPCR activated by short chain fatty acids, particularly acetate. Ffar2 is expressed in pancreatic islets, where its expression is increased during states of insulin resistance. Further, recent studies of FFA2 suggest that it may act as a regulator of beta-cell function.

ISBN: 9781369153712Subjects--Topical Terms:

610914
Endocrinology.

Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass.
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245 1 0 $a Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2016
300 $a 140 p.
500 $a Source: Dissertation Abstracts International, Volume: 78-02(E), Section: B.
500 $a Adviser: Brian T. Layden.
502 $a Thesis (Ph.D.)--Northwestern University, 2016.
520 $a Biased Agonism of the G Protein-Coupled Receptor, FFA2, Selectively Regulates Pancreatic Beta Cell Function and Mass The regulation of pancreatic beta-cell mass and function is critical to the maintenance of normoglycemia during insulin resistance states such as pregnancy and obesity. Multiple indicators of nutrient status such as glucose, amino acids, and free fatty acids contribute to the precise regulation of these aspects of beta-cell function. Additionally, nutrient-sensing G protein-coupled receptors (GPCR) are well-described to contribute to beta-cell mass and glucose stimulated insulin secretion (GSIS). Free Fatty Acid Receptor 2 (FFA2) is a GPCR activated by short chain fatty acids, particularly acetate. Ffar2 is expressed in pancreatic islets, where its expression is increased during states of insulin resistance. Further, recent studies of FFA2 suggest that it may act as a regulator of beta-cell function.
520 $a This thesis describes a role for FFA2 in regulating aspects of beta-cell function, including GSIS, beta-cell mass, and beta-cell proliferation. To examine the role of FFA2 in beta-cell biology, we have used in vivo, ex vivo, and in vitro approaches in combination with genetic and pharmacologic manipulation of FFA2. First, examining the effect of genetic Ffar2 deletion, we found that although genetic deletion of Ffar2 does not confer an overt metabolic phenotype, Ffar2-/- mice exhibit a marginally significant defect in insulin secretion during hyperglycemic clamp studies. In ex vivo insulin secretion studies, we observed diminished GSIS from Ffar2-/- islets under high glucose conditions, indicating that tonic FFA2 signaling may contribute to the regulation of GSIS. Further, activation of FFA2 with the primary endogenous ligand, acetate, was found to potentiate GSIS at physiologic concentrations in ex vivo insulin secretion assays.
520 $a Assessing the effect of Ffar2 deletion on beta-cell mass, we found that Ffar2-/- mice exhibit diminished beta-cell mass from birth through adulthood, along with dramatic increases in beta-cell death at adolescent time points, suggesting a role for FFA2 in establishment and maintenance of beta-cell mass throughout the lifespan of the mouse. Lastly, we found that treatment with FFA2-specific agonists resulted in either potentiation or inhibition of GSIS and beta-cell proliferation, which resulted from selective signaling through either Galpha q/11 or Galphai/o, respectively.
520 $a Collectively, these studies suggest that FFA2 may be a novel therapeutic target to stimulate GSIS and beta-cell growth and proliferation, and highlight that biased agonists can selectively activate distinct FFA2 signaling pathways.
590 $a School code: 0163.
650 4 $a Endocrinology. $3 610914
650 4 $a Cellular biology. $3 3172791
650 4 $a Biochemistry. $3 518028
650 4 $a Physiology. $3 518431
650 4 $a Pharmacology. $3 634543
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710 2 $a Northwestern University. $b Driskill Graduate Training Program in Life Sciences. $3 3282984
773 0 $t Dissertation Abstracts International $g 78-02B(E).
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791 $a Ph.D.
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793 $a English
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