ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA IN DISEASE OF PANCREATIC BETA-CELLS

Expression of peroxisome proliferator-activated receptor alpha(PPAR al pha) and enzymes of fatty acid (FA) oxidation is markedly reduced in t he fat-laden, dysfunctional islets of obese, prediabetic Zucker diabet ic fatty (fa/fa) rats with mutated leptin receptors (OB-R). Leptin, PP AR alpha/ retinoid x receptor ligands, and FA all up-regulate PPAR alp ha and enzymes of FA oxidation and stimulate [H-3]-palmitate oxidation in normal islets but not in islets from fa/fa rats. Overexpression of normal OB-R in islets of fa/fa rats corrects all of the foregoing abn ormalities and reverses the diabetic phenotype. PPAR alpha is a OB-R-d ependent factor required for normal fat homeostasis in islet cells.