Abstract 4144892: Thymidine phosphorylase plays a mechanistic role in lipid metabolism and obesity

Background: Obesity is an independent risk factor for the development of type II diabetes (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease (CVD). Imbalanced lipid metabolism and chronic inflammation are the major contributing factors for the development of obesity and T2DM, and their associated MASLD and CVD. Thymidine phosphorylase (TYMP) plays an important role in platelet activation and thrombosis in response to vascular injury, including in obese and diabetic mice. Scattered studies suggest that TYMP is increased in obese individuals and is present in the lipid-rich core of human atherosclerotic lesions. Hypothesis: TYMP is essential for lipid metabolism and the development of obesity. Methods: WT and male Tymp –/– mice were fed a Western diet (WD), starting from 8 weeks of age, and food intake and body weight gain were monitored for 8 weeks. Liver and perigonadal fat tissue weights and the small intestine length were measured upon sacrifice. Fecal density was measured by the time taken to sink into water. TYMP and CD36 expressions in the small intestine of mice fed a chow diet or the WD were measured by qPCR and immunostaining. Results: TYMP deficiency dramatically reduced the gain of body weight, liver, and visceral fat weight in male, but not female, mice ( Figure 1 ). The length of the small intestine was significantly longer in male Tymp –/– mice compared to WT mice, but similar in females ( Figure 2 ). Male Tymp –/– mice showed an increased sensitivity to insulin ( Figure 3 ). The liver exhibited the highest TYMP expression in mice, followed by the lungs and small intestine. Fecal density was lower in male Tymp –/– mice consuming the WD, but there was no difference in mice consuming a normal laboratory diet. These data suggest that the feces of male Tymp –/– mice may contain more fat. WD feeding increased the expression of TYMP and CD36 in the small intestine, while CD36 expression was dramatically reduced in Tymp –/– mice. TYMP deficiency also attenuated CD36 expression in the liver of WD-fed mice. Conclusion: Our data suggest that TYMP plays a key role in regulating lipid metabolism, likely by upregulating intestinal CD36 expression, thus leading to increased lipid absorption and the development of obesity. Targeted TYMP inhibition may be a novel anti-obesity therapy.