Cyclooxygenase-2 Deficiency Attenuates Adipose Tissue Differentiation and Inflammation in Mice

Abstract

Obesity is associated with a variety of disorders and is a significant health problem in developed countries. One factor controlling the level of adiposity is the differentiation of cells into adipocytes. Adipocyte differentiation requires expression of peroxisome proliferator-activated receptor ␥ (PPAR␥), which is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-⌬(12,14)-prostaglandin (PG) J 2 (15d-PGJ(2)) has long been known to be a potent activator of PPAR␥, the importance of its synthesis in adipose tissue in vivo is not clear. The current study utilized mice deficient in cyclooxygenase-2 (COX-2) to examine the role of COX-2-derived PGs as in vivo modulators of adiposity. As compared with strain-and age-matched wildtype controls, the genetic deficiency of COX-2 resulted in a significant reduction in total body weight and percent body fat. Although there were no significant differences in food consumption between groups, COX-2-deficient mice showed increased metabolic activity. Epididymal adipose tissue from wild-type mice produced a significantly greater level of 15d-PGJ(2), as compared with adipose tissue isolated from mice deficient in COX-2. Furthermore, production of the precursor required for 15d-PGJ(2) formation, PGD(2), was also significantly reduced in COX-2-deficient adipose tissue. The expression of markers for differentiated adipocytes was significantly reduced in adipose tissue from COX-2-deficient mice, whereas preadipocyte marker expression was increased. Macrophagedependent inflammation was also significantly reduced in adipose tissue of COX-2-deficient mice. These findings suggest that reduced adiposity in COX-2-deficient mice results from attenuated PPAR␥ ligand production and adipocyte differentiation.In developed countries, obesity is a significant health problem that is becoming more prevalent. The increase in adiposity, or the percentage of total body mass comprised of lipid stores, correlates with the development of a variety of disorders including, glucose intolerance, dyslipidemia, and hypertension (1). Recent evidence suggests that in addition to being an energy storage depot, adipose tissue may contribute to disease by producing adipokines, chemokines, and other bioactive substances (2). The level of adiposity is regulated by the amount of lipid taken into individual adipocytes and the number of adipocytes in the body. Adipocyte number is regulated by the differentiation of cells into adipocytes, and understanding this process is important for identifying novel methods for controlling obesity.Adipocyte differentiation requires expression of the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) 2 ␥ (3, 4). When activated by its ligand, PPAR␥ functions as a transcription factor to induce numerous genes involved in adipogenesis. Identification of the endogenous ligand for PPAR␥ has been controversial, but treatment with the prostanoid 15-deoxy-⌬ 12,14 -prostaglandin (PG) J 2 (15d-PGJ 2 ) has long been...

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

“…Although prior studies have demonstrated that experimental induction of obesity reduces EETs in liver, kidney, and mesenteric arteries ( 21,31 ), as well as alters cyclooxygenase-mediated prostaglandin biosynthesis and lipoxygenase-mediated leukotriene biosynthesis in adipose tissue ( 32,33 ), the impact of obesity on EET bioavailability in adipose tissue has not been rigorously investigated . Consequently, we employed a metabolomic approach to characterize the global eicosanoid profi le during adipocyte differentiation in 3T3-L1 cells.…”

Coordinate Functional Regulation between Microsomal Prostaglandin E Synthase-1 (mPGES-1) and Peroxisome Proliferator-activated Receptor γ (PPARγ) in the Conversion of White-to-brown Adipocytes

“…Consistent with this view, mice genetically deficient for mPGES-1 show basal elevations in PPAR␥ expression and transcriptional activity (17). However, more recent studies have shown that transgenic mice overexpressing COX-2 do not exhibit changes in PPAR␥ expression in adipose tissues (18), although PPAR␥ expression has been shown to be significantly reduced in adipose tissue from COX-2-deficient mice (19). The existence of this undefined role of the COX-2/mPGES-1/PGE 2 pathway in WAT physiology led us to investigate the functional interaction between PPAR␥ and mPGES-1 in the process of adipogenesis.…”

Effects of Caffeine, Paracetamol and Βnaphthoflavone on the Lipid Content and Differentiation of Human Adipose Derived Mesenchymal Stem Cells in Vitro

“…Studies conducted on 3T3-L1 cell lines showed that different adipocyte specific markers which includedPPARγ andadiponectinwere found to be decreased after the use of COX inhibitors (Mazid et al, 2006). COX-2 deficient murine models which were supplied with a high fat dietshowed lower body mass than their wild type counterparts were also found to have higher metabolic activity, lower PPARγ, lower inflammatory markers and significantly higher levels of adiponectin (Ghoshal et al, 2011).These variables coincide with other findings linking them to increased lipolysis and lower body fat and BMIthus suggesting that the use of a COX-2 inhibitor (such as paracetamol) can possibly provide a protective treatment opportunity against obesity and can be employed for future anti-obesity medication. However a minor percentage of opposing research showed an activation of PPARγ in adipocyte cell lines when treated with non-steroidal antiinflammatory (NSAID) drugs such as Indomethacin (Lehmann et al, 1997).…”

“…Archadionic acid is first released by phospholipases (PLA 2 s) and undergoes conversion to PGH 2 by one of the two COX isozymes (COX-1 or COX-2). The PGH 2 that is produced is metabolized into different PG's that are involved in adipocyte differentiation which causes the activation of PPARγ (Ueno et al, 2011;Ghoshal et al, 2011). Therefore, bearing this expression mechanism in mind-the inhibition of COX-2 would prevent or decrease the conversion of archadionic acid to PGH 2 which will have the ultimate effect of reducing and/or inhibiting adipocyte differentiation.COX-2 activation has also been found to be significantly involved in development of an inflammatory response in adipose tissue (Hsieh et al, 2010) and has been linked to contributing in brown adipocyte differentiation in mice (Ghoshal et al, 2011).…”