Abstract 1378: Genetic Deficiency of Cyclooxygenase-2 Reduces Adiposity in Mice
Obesity is associated with a variety of disorders including dyslipidemia and hypertension, 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 the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is activated by ligands to regulate expression of genes involved in adipocyte differentiation. Although 15-deoxy-delta(12,14)-prostaglandin (PG) J2 (15d-PGJ(2)) has long been known to be a potent activator of PPARgamma, the importance of its synthesis in adipose tissue in vivo is not clear. The current study utilized mice deficient in COX-2 to examine the role of COX-2-derived PGs as modulators of adiposity in vivo. As compared to strain and age -matched wild-type controls, the genetic deficiency of COX-2 resulted in a 65% reduction in total body fat. Although there were no significant differences in food consumption between groups, COX-2-deficient mice showed increased metabolic activity as determined by oxygen consumption. Epididymal adipose tissue from COX-2 wild-type mice produced a significantly greater level of 15d-PGJ(2), as compared to adipose tissue isolated from mice deficient in COX-2. Furthermore, levels of the precursor required for the formation of all PGJ(2) series PGs, PGD(2), was also significantly reduced in COX-2-deficient adipose tissue. In contrast, there was no significant difference between adipose tissue from COX-2 wild-type and COX-2-deficient mice in the production of PGE(2), PGF(2alpha) or 6 keto-PGF(1alpha). Expression of the mature adipocyte marker adipocyte fatty acid-binding protein was significantly reduced in adipose tissue and serum from COX-2-deficient mice. In contrast, COX-2 deficiency increased mRNA expression of preadipocyte factor-1 and resistin, two genes down-regulated by PPARgamma activation in adipose tissue. These findings suggest that reduced adiposity in COX-2-deficient mice results from attenuated PPARgamma ligand production and adipocyte differentiation.