Journal
ENDOCRINOLOGY
Volume 157, Issue 1, Pages 220-232Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2015-1693
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Funding
- National Institutes of Health [DK46205, DK37097]
- National Institutes of Health (NIH) [DK72473, DK89572, DK104211, DK097829, DK69603]
- NIH [DK059637, DK020593]
- Vanderbilt Diabetes Research and Training Center [P30 DK020593]
- Department of Veterans Affairs [1BX000666, 1BX000990-01, 1BX000616]
- Juvenile Diabetes Research Foundation [17-2012-26, 17-2013-321, 17-2013-324]
- Graduate Award for Integrative Research in Pharmacology from The American Society for Pharmacology and Experimental Therapeutics
- Vanderbilt Center for Kidney Disease
- Stem Cell and Regenerative Developmental Biology Training Grant [T32-HD05702]
- Clinical and Translational Science Award from the National Center for Advancing Translational Sciences [UL1TR000445]
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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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