TY - JOUR
T1 - The PGE2 EP3 receptor regulates diet-induced adiposity in male Mice
AU - Ceddia, Ryan P.
AU - Lee, Daekee
AU - Maulis, Matthew F.
AU - Carboneau, Bethany A.
AU - Threadgill, David W.
AU - Poffenberger, Greg
AU - Milne, Ginger
AU - Boyd, Kelli L.
AU - Powers, Alvin C.
AU - McGuinness, Owen P.
AU - Gannon, Maureen
AU - Breyer, Richard M.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants DK46205 (to R.M.B.) and DK37097 (to R.M.B.) and by National Institutes of Health (NIH) Grants DK72473, DK89572, DK104211, DK097829, and DK69603 (to A.C.P.) The Mouse Metabolic Phenotyping Center is supported in part by the NIH Grant DK059637. The Islet Procurement and Analysis Core is supported by the Vanderbilt Diabetes Research and Training Center Grant P30 DK020593. The Vanderbilt University Hormone Assay and Analytical Services Core was supported by NIH Grants DK020593 and DK059637. Merit Awards from the Department of Veterans Affairs to A.C.P. (1BX000666), M.G. (1BX000990-01), and R.M.B. (1BX000616) also supported this work. A.C.P. and M.G. have awards from the Juvenile Diabetes Research Foundation (17-2012-26, 17-2013-321, and 17-2013-324). R.P.C. was supported in part by a Graduate Award for Integrative Research in Pharmacology from The American Society for Pharmacology and Experimental Therapeutics and by funding provided by the Vanderbilt Center for Kidney Disease. B.A.C. is supported by the Stem Cell and Regenerative Developmental Biology Training Grant T32-HD05702. This work was also supported in part by Clinical and Translational Science Award UL1TR000445 from the National Center for Advancing Translational Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences, the National Institutes of Health, or the United States Department of Veterans Affairs or the United States Government.
Publisher Copyright:
Copyright © 2016 by the Endocrine Society.
PY - 2016/1
Y1 - 2016/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84954526085&partnerID=8YFLogxK
U2 - 10.1210/en.2015-1693
DO - 10.1210/en.2015-1693
M3 - Article
C2 - 26485614
AN - SCOPUS:84954526085
SN - 0013-7227
VL - 157
SP - 220
EP - 232
JO - Endocrinology
JF - Endocrinology
IS - 1
ER -