During prolonged starvation (>72 hours), the brain shifts its primary fuel source. What biochemical event triggers and sustains this shift?

• A Liver glycogen stores are mobilized to provide sustained glucose to the brain
• B Gluconeogenesis from muscle amino acids provides sufficient glucose indefinitely
• C The brain switches to fatty acid oxidation directly
• D Rising ketone bodies (beta-hydroxybutyrate and acetoacetate) substitute glucose as the brain's primary fuel when blood glucose falls below 2 mmol/L ✓

Explanation

After glycogen depletion (~24 hours), gluconeogenesis sustains brain glucose needs but at the cost of muscle protein. Beyond 72 hours, rising glucagon activates hepatic fatty acid oxidation, generating ketone bodies (beta-hydroxybutyrate, acetoacetate). The brain upregulates monocarboxylate transporter (MCT) expression and activates ketolytic enzymes (succinyl-CoA:3-ketoacid transferase/SCOT, acetoacetyl-CoA thiolase). At ketosis steady state, ketones supply 60-70% of brain energy, sparing muscle protein. The brain lacks fatty acid beta-oxidation enzymes for direct utilization.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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