1211-P: The Mechanistic Role of Thymidine Phosphorylase in the Development of Obesity

Obesity is a major independent risk factor for the development of type II diabetes (T2DM), nonalcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD). Consequently, controlling obesity constitutes a key strategy for reducing the prevalence of these diseases. The majority of drugs developed for treating obesity over the past 20 years have been withdrawn due to the increased risk of cardiovascular and psychiatric complications. Therefore, developing novel mechanism-mediated therapeutics for controlling obesity and its consequent complications is a top priority and urgently needed. Our studies indicate that thymidine phosphorylase (TYMP) could be a promising target. The traditional role of TYMP is to catalyze the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose-1 phosphate and maintain the homeostatic nuclear pool of these molecules. TYMP expression is increased in several diseased conditions, including obesity, T2DM, and NAFLD. However, whether TYMP plays a role in the development of these diseases is unknown. We found that Tymp-deficient (Tymp-/-) male mice exhibited significantly limited body weight gain as well as liver and perigonadal fat weight when fed either a western diet (TD.88137) or a prodiabetic high-fat diet (D12492) compared with the wild-type mice. Male Tymp-/- mice showed better glucose tolerance. TYMP-deficiency reduced expression of enzymes that confer glycolysis and de novo lipogenesis in the liver. TYMP-deficiency enhanced the sensitivity of primary hepatocytes to insulin as evidenced by the increase of AKT activation. Inhibition of TYMP with tipiracil, a selective, potent, and the FDA approved TYMP inhibitor, dramatically reduced western diet and high-fat diet-induced body weight gain. We conclude that TYMP plays a pivotal role in liver glucose and lipid metabolism, which promotes the development of obesity and T2DM. Targeting TYMP with tipiracil could be a new therapy for obesity. Disclosure H. Yue: None. A. M. Belcher: None. A. Bicak: None. W. Li: None.