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 γ (PPARγ), which is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-Δ(12,14)-prostaglandin (PG) J(2) (15d-PGJ(2)) has long been known to be a potent activator of PPARγ, 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 wild-type 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. Macrophage-dependent 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 PPARγ ligand production and adipocyte differentiation.
Highlights
In developed countries, obesity is a significant health problem that is becoming more prevalent
The reduced adiposity in COX-2-deficient mice occurred without a reduction in food intake and was associated with increased metabolic activity as determined by oxygen consumption. These findings suggest that prostanoid synthesis dependent on the activity of COX-2 is important for in vivo regulation of adipose tissue levels
COX-2 is responsible for production of a variety of different prostanoids, those which have been shown to produce the greatest effects on adipocytes are the J-series PGs
Summary
University of Kentucky, Bio/Pharm Complex, Rm. 347, 789 South Limestone St., Lexington, KY 40536-0596. Identification of the endogenous ligand for PPAR␥ has been controversial, but treatment with the prostanoid 15-deoxy-⌬12,14-prostaglandin (PG) J2 (15dPGJ2) has long been known to activate PPAR␥ and induce adipocyte differentiation following exogenous addition [5, 6]. Another report examining this same cell type does show an increase in 15d-PGJ2 production during differentiation, and this increase in 15d-PGJ2 is attenuated by COX inhibition [12]. This report shows that COX inhibition reduces expression of adipocyte-specific genes, an effect that is reversed by the addition of exogenous 15d-PGJ2 [12]. Administration of the COX-2 inhibitor rofecoxib has been shown to reduce adipose tissue mass development in mice without affecting the amount of diet consumed, the PG responsible for these effects is not known [13]. The current study utilized mice of different ages that were deficient in COX-2 to examine the role of COX-2-derived PGs as modulators of adipocyte differentiation in white adipose tissue
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