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Title page for ETD etd-11242015-165031


Type of Document Dissertation
Author Ceddia, Ryan Patrick
URN etd-11242015-165031
Title The Role of the Prostaglandin E2 EP3 Receptor in Obesity, Insulin Resistance, and Glycemic Control
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Kevin P. Currie Committee Chair
James M. Luther Committee Member
Maureen A. Gannon Committee Member
Owen P. McGuinness Committee Member
Richard M. Breyer Committee Member
Keywords
  • GPCR
  • knock-out
  • lipid distribution
  • lipolysis
  • metabolism
  • adipose
  • adipocyte
  • pancreas
  • NSAID
  • inflammation
  • triglyceride
  • free fatty acid
  • glucose
  • lipid
  • islet
  • mouse
  • diabetes
  • EP3
  • PGE2
  • prostaglandin
  • obesity
  • insulin
Date of Defense 2015-11-23
Availability unrestricted
Abstract
Mice carrying a targeted disruption of the prostaglandin E2 E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet induced obesity. While no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3-/- mice gained more weight relative to EP3+/+ mice. Overall, EP3-/- mice had increased epididymal fat mass and adipocyte size; paradoxically a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3-/- mice. The EP3-/- mice had increased macrophage infiltration, TNF-α, MCP-1, IL-6 expression, and necrosis in their epididymal fat pads as compared to EP3+/+ animals. Adipocytes isolated from EP3+/+ or EP3-/- mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3-/- mice lacked PGE2-evoked inhibition of isoproterenol stimulated lipolysis compared to EP3+/+. EP3-/- mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3-/- mice became hyperglycemic and hyperinsulinemic when compared to EP3+/+ fed HFD, demonstrating a more severe insulin resistance phenotype in EP3-/-. These results demonstrate that when fed a HFD, EP3-/- mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance.
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