This study investigated brain metabolism during prolonged fasting in three obese patients. Catheterization of cerebral vessels revealed that β-hydroxybutyrate and acetoacetate replaced glucose as the primary fuel for brain metabolism during starvation. A low respiratory quotient was observed, suggesting a carboxylation mechanism for carbon disposal. The study aimed to resolve the paradox of how the brain maintains energy during prolonged fasting when glucose is limited. It was found that the brain primarily uses ketone bodies (β-hydroxybutyrate and acetoacetate) as fuel, with a low respiratory quotient indicating that carbon from substrates is not fully oxidized to CO₂, implying a carboxylation pathway. Methods involved catheterization of cerebral and systemic vessels to measure blood flow and metabolic substrates. Blood samples were analyzed for oxygen, carbon dioxide, glucose, and other metabolites. Calorimetry was used to measure energy expenditure, and cerebral blood flow was determined using radioactive tracers. Results showed that cerebral blood flow was 45 ml/100 g per minute, and the brain's primary fuel shifted to ketone bodies. The calculated oxygen consumption matched direct measurements, while CO₂ production was significantly lower than expected, supporting the carboxylation hypothesis. The study also found that glucose utilization was reduced, and lactate and pyruvate were produced. Discussion highlighted that the brain can adapt to use ketone bodies as an energy source, reducing reliance on glucose and nitrogen. This adaptation is crucial for survival during prolonged fasting. The study also noted that ketone bodies effectively meet the brain's energy needs without significant metabolic deficits. The findings suggest that the brain can utilize fat-derived ketone bodies as a primary fuel during starvation, which may help conserve nitrogen and support survival. The study's results have implications for understanding metabolic adaptations during fasting and may inform therapeutic strategies for obesity and related conditions.This study investigated brain metabolism during prolonged fasting in three obese patients. Catheterization of cerebral vessels revealed that β-hydroxybutyrate and acetoacetate replaced glucose as the primary fuel for brain metabolism during starvation. A low respiratory quotient was observed, suggesting a carboxylation mechanism for carbon disposal. The study aimed to resolve the paradox of how the brain maintains energy during prolonged fasting when glucose is limited. It was found that the brain primarily uses ketone bodies (β-hydroxybutyrate and acetoacetate) as fuel, with a low respiratory quotient indicating that carbon from substrates is not fully oxidized to CO₂, implying a carboxylation pathway. Methods involved catheterization of cerebral and systemic vessels to measure blood flow and metabolic substrates. Blood samples were analyzed for oxygen, carbon dioxide, glucose, and other metabolites. Calorimetry was used to measure energy expenditure, and cerebral blood flow was determined using radioactive tracers. Results showed that cerebral blood flow was 45 ml/100 g per minute, and the brain's primary fuel shifted to ketone bodies. The calculated oxygen consumption matched direct measurements, while CO₂ production was significantly lower than expected, supporting the carboxylation hypothesis. The study also found that glucose utilization was reduced, and lactate and pyruvate were produced. Discussion highlighted that the brain can adapt to use ketone bodies as an energy source, reducing reliance on glucose and nitrogen. This adaptation is crucial for survival during prolonged fasting. The study also noted that ketone bodies effectively meet the brain's energy needs without significant metabolic deficits. The findings suggest that the brain can utilize fat-derived ketone bodies as a primary fuel during starvation, which may help conserve nitrogen and support survival. The study's results have implications for understanding metabolic adaptations during fasting and may inform therapeutic strategies for obesity and related conditions.