ScopePeople suffering from famine in early life and overnutrition in adulthood may have an increased risk for liver steatosis. We aimed to investigate the effects and mechanisms of early nutrition restriction and overnutrition on de novo lipogenesis in the liver.Methods and resultsThree‐wk‐old male rats were food restricted for 4 wk and refed a high‐fat or normal fat diet individually in metabolic cages for 9 wk. Weight‐matched groups were also set up. Fatty acid synthetase expression was measured to estimate de novo lipogenesis in the liver. Parameters of glucose and lipid metabolism were measured with isotope assays. All four groups had comparable body weights. However, the famine high‐fat diet group had the highest degree of liver steatosis, the greatest body fat ratio, and insulin resistance. Lipid accumulation, fatty acid synthetase expression, and gluconeogenesis in the liver were significantly higher in the famine and high‐fat diet groups (p < 0.05). Moreover, these groups also had markedly lower muscle glucose uptake.ConclusionUnder famine and high‐fat refeeding stress, rats were extremely susceptible to developing hepatic steatosis. This is presumably a consequence of upregulation of de novo lipogenesis and enhanced glucose flux from muscle to de novo lipogenesis in the liver.