Brain amino acid metabolism and ketosis

The relationship between ketosis and brain amino acid metabolism was studie d in mice that consumed a ketogenic diet (> 90% of calories as lipid). Afte r 3 days on the diet the blood concentration of 3-OH-butyrate was similar t o5 mmol/l (control = 0.06-0.1 mmol/l). In forebrain and cerebellum the conc entration of 3-OH-butyrate was similar to 10-fold higher than control. Brai n [citrate] and [lactate] were greater in the ketotic animals. The concentr ation of whole brain free coenzyme A was lower in ketotic mice. Brain [aspa rtate] was reduced in forebrain and cerebellum, but [glutamate] and [glutam ine] were unchanged. When [N-15]leucine was administered to follow N metabo lism, this labeled amino acid accumulated to a greater extent in the blood and brain of ketotic mice. Total brain aspartate (N-14 + N-15) was reduced in the ketotic group. The [N-15]aspartate/[N-15]glutamate ratio was lower i n ketotic animals, consistent with a shift in the equilibrium of the aspart ate aminotransferase reaction away from aspartate. Label in [15N]GABA and t otal [15N]GABA was increased in ketotic animals. When the ketotic animals w ere injected with glucose, there was a partial blunting of ketoacidemia wit hin 40 min as well as an increase of brain [aspartate], which was similar t o control. When [U-C-13(6)]glucose was injected, the C-13 label appeared ra pidly in brain lactate and in amino acids. Label in brain [U-C-13(3)] lacta te was greater in the ketotic group. The ratio of brain C-13-amino acid/C-1 3-lactate, which reflects the fraction of amino acid carbon that is derived from glucose, was much lower in ketosis, indicating that another carbon so urce, i.e., ketone bodies, were precursor to aspartate, glutamate, glutamin e and GABA. (C) 2001 Wiley-Liss, Inc.