The study investigates the protective effects of Sirt1 against high-fat diet (HFD)-induced metabolic damage in mice. Sirt1, a protein deacetylase, has been implicated in protecting against metabolic syndrome through resveratrol-mediated mechanisms, but direct evidence has been lacking. The researchers generated transgenic mice with moderate overexpression of Sirt1 under its natural promoter. These mice showed similar fat mass gain to wild-type controls when exposed to an HFD, despite increased energy expenditure and food intake. Notably, Sirt1 transgenic mice exhibited lower lipid-induced inflammation, better glucose tolerance, and almost complete protection from hepatic steatosis. The beneficial effects were attributed to the induction of antioxidant proteins (MnSOD and Nrf1) and reduced activation of proinflammatory cytokines (TNFα and IL-6) via downmodulation of NFκB activity. These findings provide direct evidence of Sirt1's protective role against metabolic consequences of chronic HFD exposure.The study investigates the protective effects of Sirt1 against high-fat diet (HFD)-induced metabolic damage in mice. Sirt1, a protein deacetylase, has been implicated in protecting against metabolic syndrome through resveratrol-mediated mechanisms, but direct evidence has been lacking. The researchers generated transgenic mice with moderate overexpression of Sirt1 under its natural promoter. These mice showed similar fat mass gain to wild-type controls when exposed to an HFD, despite increased energy expenditure and food intake. Notably, Sirt1 transgenic mice exhibited lower lipid-induced inflammation, better glucose tolerance, and almost complete protection from hepatic steatosis. The beneficial effects were attributed to the induction of antioxidant proteins (MnSOD and Nrf1) and reduced activation of proinflammatory cytokines (TNFα and IL-6) via downmodulation of NFκB activity. These findings provide direct evidence of Sirt1's protective role against metabolic consequences of chronic HFD exposure.