During prolonged fasting (72 hours), the brain's fuel utilization shifts. At this stage, which fuel provides the majority of brain energy, and what regulates this shift?

• A Lactate becomes the predominant brain fuel; regulated by increased lactate production from muscle
• B Brain exclusively uses glucose regardless of fasting duration; ketones are used by muscle only
• C Ketone bodies (beta-hydroxybutyrate and acetoacetate) become the dominant brain fuel; rising ketones driven by low insulin, elevated glucagon, and increased hepatic fatty acid oxidation and ketogenesis ✓
• D Free fatty acids directly cross the BBB and become the major brain fuel after 24 hours of fasting

Explanation

The brain normally uses glucose exclusively, but after 3–4 days of fasting, ketone body utilization can account for up to 60–70% of brain energy needs. During prolonged fasting: low insulin and high glucagon stimulate adipose lipolysis (increased free fatty acids to liver); hepatic beta-oxidation increases, generating excess acetyl-CoA; acetyl-CoA enters ketogenesis (3-hydroxy-3-methylglutaryl-CoA pathway) in hepatic mitochondria, producing beta-hydroxybutyrate (BHB) and acetoacetate. Rising plasma ketones (normally <0.5 mmol/L, rising to 6–8 mmol/L in prolonged starvation) are transported across the BBB via MCT1 transporters and reconverted to acetyl-CoA in neurons for TCA cycle. Free fatty acids (FFA) do NOT cross the BBB efficiently (long-chain FFAs bound to albumin cannot traverse); ketones are their brain-accessible derivative.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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