This study investigates the impact of genetic deficiency in Toll-like receptor 5 (TLR5) on metabolic syndrome in mice. Mice lacking TLR5 exhibit hyperphagia and develop key features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes are correlated with alterations in the gut microbiota, which can be transferred to wild-type germ-free mice, conferring many aspects of metabolic syndrome. Food restriction prevented obesity but not insulin resistance in TLR5-deficient mice. The findings suggest that the gut microbiota plays a significant role in metabolic disease and that malfunction of the innate immune system may contribute to the development of metabolic syndrome.This study investigates the impact of genetic deficiency in Toll-like receptor 5 (TLR5) on metabolic syndrome in mice. Mice lacking TLR5 exhibit hyperphagia and develop key features of metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance, and increased adiposity. These metabolic changes are correlated with alterations in the gut microbiota, which can be transferred to wild-type germ-free mice, conferring many aspects of metabolic syndrome. Food restriction prevented obesity but not insulin resistance in TLR5-deficient mice. The findings suggest that the gut microbiota plays a significant role in metabolic disease and that malfunction of the innate immune system may contribute to the development of metabolic syndrome.