A comprehensive metabolic characterization of mice fed a chow diet or a high-fat diet for 6 weeks has determined the effects of a genetically altered immune system. Nonobese diabetic (NOD) mice have reduced fat mass and increased insulin sensitivity compared with C57BL/6 wild-type mice. SCID mice also have increased insulin sensitivity, along with increased glucose metabolism in muscle and resistance to diet-induced obesity as a result of increased energy expenditure and physical activity. NSG mice (which lack some immune cells and have deficient cytokine signalling) do not develop diet-induced obesity or insulin resistance. These findings demonstrate the importance of genetic background, lymphocytes and cytokine signalling in diet-induced obesity and insulin resistance.