The study investigates the role of peroxisome proliferator-activated receptor α (PPARα) in the adaptive response to fasting. PPARα-null mice, when subjected to fasting or a high-fat diet, exhibit severe metabolic disturbances. Fasted PPARα-null mice show increased lipid accumulation in the liver, severe hypoglycemia, hypothermia, and elevated plasma free fatty acid levels, indicating impaired fatty acid uptake and oxidation. In contrast, wild-type mice induce PPARα mRNA during fasting to stimulate hepatic fatty acid oxidation, which is crucial for energy homeostasis. The data highlight the pivotal role of PPARα in managing energy stores during fasting by modulating gene expression to ensure efficient fatty acid oxidation and substrate availability for other tissues.The study investigates the role of peroxisome proliferator-activated receptor α (PPARα) in the adaptive response to fasting. PPARα-null mice, when subjected to fasting or a high-fat diet, exhibit severe metabolic disturbances. Fasted PPARα-null mice show increased lipid accumulation in the liver, severe hypoglycemia, hypothermia, and elevated plasma free fatty acid levels, indicating impaired fatty acid uptake and oxidation. In contrast, wild-type mice induce PPARα mRNA during fasting to stimulate hepatic fatty acid oxidation, which is crucial for energy homeostasis. The data highlight the pivotal role of PPARα in managing energy stores during fasting by modulating gene expression to ensure efficient fatty acid oxidation and substrate availability for other tissues.