Nitroalkene derivatives of nitro-oleic acid (OA-NO(2)) are endogenous lipid products with novel signaling properties, particularly the activation of PPARs. The goal of this proposal was to examine the therapeutic potential of this OA-NO(2) in treatment of obesity and obesity-related conditions in obese Zucker rats. The animals were randomly divided to receive OA-NO(2), oleic acid (OA), both at 7.5 mug/kg/d, or vehicle ethanol via osmotic mini-pumps for 2 weeks. Following OA-NO(2) treatment, food intake was decreased as early as the first day and this effect appeared to persist throughout the experimental period. At day 14, body weight gain was significantly reduced by OA-NO(2) treatment. This treatment significantly reduced plasma triglyceride and almost normalized plasma free fatty acid and significantly increased plasma high-density lipid (HDL). The plasma TBARS and proteinuria were paralelly decreased. In contrast, none of these parameters were affected by OA treatment. After 14 days of OA-NO(2) treatment, hematocrit, a surrogate of fluid retention associated with PPARgamma agonists, remained unchanged. Together, these data demonstrated that OA-NO(2) may offer an effective and safe therapeutic intervention for obesity and obesity-related conditions.

Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR) γ and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPAR γ activation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN.