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

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.