The PGE2 EP3 receptor regulates diet-induced adiposity in male Mice

Ryan P. Ceddia, Daekee Lee, Matthew F. Maulis, Bethany A. Carboneau, David W. Threadgill, Greg Poffenberger, Ginger Milne, Kelli L. Boyd, Alvin C. Powers, Owen P. McGuinness, Maureen Gannon, Richard M. Breyer

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, werefed a high-fat diet (HFD), or a micronutrientmatchedcontrol diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although 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-κ, monocyte chemoattractant protein-1, IL-6 expression, and necrosis in their epididymal fat pads as compared with 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 with 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 becamehyperglycemic and hyperinsulinemicwhencompared with 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.

Original languageEnglish
Pages (from-to)220-232
Number of pages13
JournalEndocrinology
Volume157
Issue number1
DOIs
StatePublished - Jan 2016

Bibliographical note

Publisher Copyright:
Copyright © 2016 by the Endocrine Society.

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