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The PGE(2) EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice
- The PGE(2) EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice
- Ceddia, Ryan P.; Lee, DaeKee; Maulis, Matthew F.; Carboneau, Bethany A.; Threadgill, David W.; Poffenberger, Greg; Milne, Ginger; Boyd, Kelli L.; Powers, Alvin C.; McGuinness, Owen P.; Gannon, Maureen; Breyer, Richard M.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- ENDOCRINOLOGY vol. 157, no. 1, pp. 220 - 232
- OXFORD UNIV PRESS INC
- SCI; SCIE; SCOPUS
- Document Type
- Mice carrying a targeted disruption of the prostaglandin E-2 (PGE(2)) 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 PGE(2)-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-alpha, 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 PGE(2)-evoked inhibition of lipolysis. Adipocytes isolated from EP3(-/-) mice lacked PGE(2)-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 became hyperglycemic and hyperinsulinemic when compared 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.
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