Patients with chronic inflammatory diseases have an increased prevalence of obesity and metabolic syndrome (MetS)

Patients with chronic inflammatory diseases, including rheumatoid arthritis (RA), have an increased prevalence of obesity and metabolic syndrome (MetS). Little is known about the phenotype of adipose tissue (AT) in patients with RA. It is also unknown if experimental inflammatory arthritis stimulates changes in AT and metabolic derangement. An important characteristic of inflammation in both arthritis and AT is activation of the prostaglandin (PG) biosynthetic pathway characterized by markedly increased expression of cyclooxygenase -2 and microsomal PGE synthase-1 (mPGES-1). In inflamed tissues, expression of PGE2 increases disproportionately to other PGs because of coordinated regulation of these two biosynthetic enzymes. When mPGES-1 is genetically deleted in mice (KO), PG synthesis is shunted toward other terminal PG in a cell and tissue specific manner. In adipose tissues, shunting is towards alternate species that may lead to changes in AT phenotype, specifically in the capacity to develop brown-in-white or brite adipocytes. Increased brown/brite adipocyte activity is inversely associated with obesity, age, and type II diabetes. Our preliminary data demonstrate that mPGES-1 KO mice are resistant to weight gain when being fed a high-fat (HF) diet. In addition, we showed that mPGES-1 KO mice exhibit markedly increased expression of UCP-1 mRNA, the marker of brite adipocytes, in white AT and increased energy expenditure. Thus, our preliminary data suggests that mPGES KO mice could be resistant to arthritis-induced MetS due to their ability to promote “browning” of white AT. In this pilot project, we will test the hypotheses that (1) mPGES-1 deficiency reduces weight gain by stimulating brite adipocyte phenotype during HF feeding, (2) inflammatory arthritis increases AT inflammation and induces MetS, and (3) mPGES-1 deficiency blocks arthritis-associated changes in AT and MetS. This will be accomplished by determining the effect of mPGES-1 deficiency on differentiation to the brite adipocyte phenotype, obesity, and energy metabolism during HF feeding and determining if a murine model of RA increases inflammation in AT and alters energy metabolism and test whether the AT phenotype in mPGES-1 deficient mice is modulated by arthritis.