Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis

Abstract

Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions driving uncontrolled inflammation and fibrosis and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT.

Cyclooxygenase-2 expression in hepatocytes attenuates non-alcoholic steatohepatitis and liver fibrosis in mice

“…To note, PGE 2 in lungs is normally present at much higher concentrations than in plasma, resembling the levels of constitutive COX-2 expression reached in hCOX-2-Tg animals. In line with this, it has been reported that PGE 2 down-regulated the expression of fibrosis-inducing genes in human fat explants from obese individuals as well as the fibrogenic response of differentiated adipocytes to the fibrogenic actions of TGF-β [64].…”

Characterization of Eicosanoids Produced by Adipocyte Lipolysis

“…2D and Supplemental Table 2). As discussed earlier, PGE2 was shown to suppress lipolysis (43)(44)(45)(46). Thus, it is possible that the basal level of PGE2 secreted by adipocytes functions to suppress adipose lipolysis and inflammation, and this process would be reversed somewhat by COX-2 inhibition.…”

“…PGD2, PGJ2, d12-PGJ2, 0 -25 M) were also ineffective. It is possible that exogenous PGE2 dampens COX-2-dependent pro-inflammatory signaling by activating the EP4 receptor (43)(44)(45)(46). Thus, we speculate that either a combination of prostaglandins and/or other lipid mediator(s) could be responsible for the COX-2-mediated up-regulation of CCL2/MCP-1.…”

Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

“…Finally, isoproterenol-induced adipocyte lipolysis was inhibited by PGE 2 . Collectively, these findings suggest that PGE 2 is a critical regulator of inflammation, fibrosis, and impaired adaptive thermogenesis and lipolysis in human obese visceral WAT [101]. …”