DOWN-REGULATION OF THE EXPRESSION OF THE OBESE GENE BY AN ANTIDIABETIC THIAZOLIDINEDIONE IN ZUCKER DIABETIC FATTY RATS AND DB DB MICE/

Obese (ob) is a recently identified gene involved in the regulation of energy balance in the mouse, We report here that AD-5075, a potent th iazolidinedione which lowered plasma glucose and triglyceride in Zucke r diabetic fatty (ZDF) rats and db/db mice, decreased the expression o f the ob gene in these animal models of obesity and non-insulin-depend ent diabetes mellitus, The level of adipose ob mRNA in ZDF rats was 3- fold greater than that detected in the Zucker lean littermates, Chroni c treatment with AD-5075 elicited a 67 and 70% reduction of ob mRNA in ZDF and control lean rats, respectively, Furthermore, the amount of a dipose ob mRNA in db/db mice was 7 times higher than that detected in lean littermates, Treatment of db/db mice with AD-5075 resulted in a 7 8% reduction of the level of ob mRNA with parallel changes in circulat ing level of the ob gene product, leptin, The reduction of the ob mRNA in the Zucker lean rats was accompanied by significantly greater food intake and weight gain, However, in ZDF rats and db/db mice, there wa s profound increase in body weight without hyperphagia, The results de monstrate that the expression of the ob gene is up-regulated in these two rodent models of diabetes compared to their lean counterparts and that such overexpression is attenuated by treatment with an agent that improves insulin sensitivity and glucose homeostasis in vivo.