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.
Highlights
Prostaglandin (PG) E2 is one of the most abundant lipid mediators in the human body
A statistically significant up-regulation of the fibrosis marker TIMP1 was seen in white adipose tissue (WAT) from obese individuals, whereas changes in collagen type I alpha 1 (Col1α1), α-smooth muscle actin and TGF-β expression did not reach statistical significance (Fig 1D and 1E)
The increased levels of this prostanoid were not related to an overexpression of mPGES-1, the main PGE synthase in adipose tissue cells [21], but rather with COX-2, which expression was found remarkably up-regulated in obese adipose tissue
Summary
Prostaglandin (PG) E2 is one of the most abundant lipid mediators in the human body. It is constitutively produced in most tissues by the coordinate enzymatic activities of cyclooxygenases (COX) and terminal PGE synthases [1,2,3,4]. WAT expands its energy-buffering capacity by fat cell hypertrophy and/or by hyperplasia from committed progenitors [8] This adipose tissue expansion leads to a plethora of functional derangements including hypoxia, lack of nutrients and tissue remodeling, which are major contributors to the chronic “low-grade” state of mild inflammation present in WAT of obese individuals [9,10,11]. This persistent and unresolved inflammatory state in WAT is, in turn, responsible for the excessive synthesis of extracellular matrix components and the subsequent interstitial deposition of fibrotic material [12,13]. The ultimate consequence of these derangements is the development of a number of comorbidities associated with obesity including insulin resistance and type 2 diabetes, nonalcoholic fatty liver disease, atherosclerosis and cardiovascular disease [14,15]
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