Sirt1 protects against high-fat diet-induced metabolic damage. Researchers found that mice with moderate Sirt1 overexpression under its natural promoter showed reduced lipid-induced inflammation, better glucose tolerance, and were largely protected from hepatic steatosis when exposed to a high-fat diet. These protective effects were attributed to two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via PGC1α activation, and reduced activation of proinflammatory cytokines like TNFα and IL-6 through down-regulation of NFκB activity. Sirt1 overexpression also increased energy expenditure, which was balanced by increased food intake, leading to balanced energy homeostasis. Sirt1 transgenic mice were protected from HFD-induced hepatic inflammation, glucose intolerance, and steatosis. The study highlights Sirt1's role in preventing metabolic syndrome by modulating inflammation and oxidative stress. Sirt1's protective effects are likely due to its ability to inhibit NFκB activity and enhance antioxidant defenses. These findings suggest that Sirt1 could be a promising target for treating metabolic disorders such as non-alcoholic fatty liver disease. The study provides direct evidence of Sirt1's protective role against metabolic damage caused by chronic high-fat diet exposure.Sirt1 protects against high-fat diet-induced metabolic damage. Researchers found that mice with moderate Sirt1 overexpression under its natural promoter showed reduced lipid-induced inflammation, better glucose tolerance, and were largely protected from hepatic steatosis when exposed to a high-fat diet. These protective effects were attributed to two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via PGC1α activation, and reduced activation of proinflammatory cytokines like TNFα and IL-6 through down-regulation of NFκB activity. Sirt1 overexpression also increased energy expenditure, which was balanced by increased food intake, leading to balanced energy homeostasis. Sirt1 transgenic mice were protected from HFD-induced hepatic inflammation, glucose intolerance, and steatosis. The study highlights Sirt1's role in preventing metabolic syndrome by modulating inflammation and oxidative stress. Sirt1's protective effects are likely due to its ability to inhibit NFκB activity and enhance antioxidant defenses. These findings suggest that Sirt1 could be a promising target for treating metabolic disorders such as non-alcoholic fatty liver disease. The study provides direct evidence of Sirt1's protective role against metabolic damage caused by chronic high-fat diet exposure.