The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity

Abstract

With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist–treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle–treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator–activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator–activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.

Augmented oxidative stress and preserved vasoconstriction induced by hydrogen peroxide in coronary arteries in obesity: role of COX‐2

“…This was further supported by the enhanced coronary vasodilator effect found for the selective EP 4 receptor agonist TCS 2519 in OZR and confirmed by the augmented COX-2-mediated release of PGE 2 in coronary arteries from obese rats compared with the lean controls, as reported in diabetic mice (Przygodzki et al, 2015). Hence, COX-2 derived PGE 2 acting on vasorelaxant EP 4 receptors might have a protective role against oxidative damage induced by ROS in coronary arteries under conditions of obesity-associated insulin resistance, consistent with the protective role recently ascribed to the EP 4 receptor in obesity-related inflammation (Yasui et al, 2015) and with reports showing that VSM-specific EP 4 receptor deletion exacerbates oxidative and renal injury induced by angiotensin II in mice (Thibodeau et al, 2016). Secondly, inducible COX-2 was found in both endothelium and VSM of coronary arteries from obese rats, and further studies are needed to ascertain the source of PGE 2 in the coronary vascular wall.…”

“…On the one hand, COX-2 represents a major source of oxidative stress and cardiovascular risk in the coronary arterial wall, but on the other, this isoenzyme is involved in protective vascular effects through the increased release of endothelial vasodilator PGE 2 , consistent with recent reports showing both protective and pro-atherogenic/pro-hypertensive effects for COX-2 under conditions of hyperlipidaemia and vascular inflammation (Tang et al, 2014). The present findings further suggest that using selective drugs to target the pathway downstream of COX-2, that is at the level of the EP 4 receptor (Yasui et al, 2015), may shift the balance of cardiovascular efficacy and risk reported for non-steroidal anti-inflammatory drugs (NSAIDS) (Bhala et al, 2013).…”

Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer

“…PGE2/EP4 signaling could regulate the plasticity of the macrophages. Yasui et al showed that treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization [50]. Chang et al showed that the deletion of myeloid EP4 receptors led to the decreased expression of the M2 macrophage markers, arginase-1 and IL-4Rα in APC Min/+ intestinal adenoma macrophages [51].…”

Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F2α: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model

“…Following transport into the cell, tissue-dependent PG clearance mechanisms often take place primarily via rapid β-oxidation in the cytosolic compartment into a number of active and inactive primary metabolites. Present in virtually all nucleated cells, PGs and their receptors have been in the spotlight due to their utility as targets in many instances where these regulatory processes are perturbed, such as inflammation [13,26], cancer [27,28], and obesity [29,30]. In particular, prostaglandin F 2α (PGF2α), also termed dinoprost, is a drug used to induce labor via regulation of uterine contractions.…”