Transcriptomic analysis reveals the mechanisms underlying the differential effects of caffeine, theophylline, and theobromine in regulating hepatic fat accumulation

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease, characterized by excessive fat accumulation in the liver. Caffeine, theophylline, and theobromine are the primary naturally occurring methylxanthines found in various foods and beverages such as coffee, tea, and chocolate. They exhibit diverse pharmacological effects. Although caffeine can inhibit hepatic fat accumulation in mice, the effects and regulatory mechanisms of theophylline and theobromine remain unclear. In this study, we observed that theophylline significantly reduced body weight and triglyceride levels and attenuated hepatic fat accumulation in mice fed a high-fat diet. Conversely, theobromine did not exhibit these effects. Transcriptomic results showed that caffeine and theophylline significantly activated the TNF signaling pathway in C2C12 myoblasts, induced p38MAPK expression and increased Il1b and Il6 secretion, but did not elevate Tnfa and Mcp1 expression. Notably, theobromine neither activated the TNF pathway nor significantly induced p38MAPK expression and Il1b and Il6 secretion. In conclusion, the differences in the regulating NAFLD activity of caffeine, theophylline, and theobromine-three structurally similar compounds used as food ingredients, may be attributed to their distinct regulation of the TNF signaling pathway.