Journal 1967 [Owen] Brain Metabolism During Fasting

T h e Journal of Clinical Investigation Vol. 4 6 , N c . 10, 1967 Brain Metabolism during Fasting * 0. E . OWEN, A. P . MORGAN, H . G . KEMP, J . M . SULLIVAN, M . G . HERRERA, AND G . F . CAHILL, JR.4 (From the Elliott P . Joslin Research Laboratory, t h e Departments o f Medicine a n d Surgery, Harvard Medical School, t h e Cardiovascular Unit, t h e Peter Bent Brigham Hospital, a n d t h e DiabetesFoundation, Inc., Boston, Massachusetts) Abstract. Catheterization o f cerebral vessels i n three obese patients under- going 5 -6 w k o f starvation demonstrated that /8-hydroxybutyrate a n d acetoacetate replaced glucose as t h e predominant fuel f o r brain metabolism. A strikingly l o w respiratory quotient wa s also observed, suggesting a carboxylation mechanism as a means o f disposing o f some o f the carbon o f the consumed substrates. Introduction Numerous studies performed after brief post- absorptive periods have shown that th e only sig- nificant energy-yielding substrate consumed b y brain is glucose, a t rates of 110-145 g/24 h r (2-4). I n adult m a n glucose a nd glycogen stores amount to 150-300 g , a n d t h e protein mass i s a p - proximately 6-8 kg (5). Although t h e fat depot m a y b e massive a n d glycerol from neutral fat c a n b e converted t o glucose, n e t gluconeogenesis from fatty acid carbon h a s n ot been demonstrated in mammalian systems. I f t h e central nervous system does maintain a n absolute requirement f o r glucose during starvation, this substrate must b e derived from t h e limited carbohydrate stores, from d e novo synthesis from amino acids from protein, a n d from other precursors such a s glycerol from adipose tissue, o r lactate recycled from gly- colytic tissues. * Received f o r publication 17 April 1967 a n d i n r e - vised form 2 3 June 1967. This study was supported i n part b y grants from t h e U . S . Public Health Service AM-09584-02, AM-09748-02, 8 MO1-FR-31-06, Tl-AM-5077-11, 5-RO1-AM-02657-07, 1-Tl-HE-05679-02, a n d HE-08591-02; t h e Adler Founda- tion, Inc., Rye, N . Y . ; t he U. S . Army Medical R e - search a n d Development Command (DA-49-193-MO- 2337) ; t he John A . Hartford Foundation, Inc., N e w York, N. Y . ; a n d t h e Atomic Energy Commission. A preliminary abstract o f part o f this work h a s been published (1). j Investigator, Howard Hughes Medical Institute. Address requests o r reprints t o Dr . G. F . Cahill, Jr., Joslin Research Laboratory, 1 7 0 Pilgrim Road, Boston, Mass. 02215. T h e u se of prolonged starvation f o r t h e treat- ment of obesity h as posed a fascinating problem; namely, that m an i s capable o f fasting f o r periods o f time beyond which h e would have utilized o f his carbohydrate resources a n d a l l of h i s pro- teins f o gluconeogenesis in order t o provide ade- quate calories a s glucose f o r t h e central nervous system. This study w a s designed t o clarify t h e apparent paradox, a n d i t w a s found that f?-hydroxybutyrate a n d acetoacetate replace glucose a s t h e brain's primary fuel during starvation. I n addition, a surprisingly l o w respiratory quotient wa s o b - served du e t o failure to recover substrate carbon a s CO2, suggesting a carboxylation b a pathway n o t y e t defined. Methods Subjects. Three obese subjects were admitted f or study t o T h e Clinical Center o f t h e Peter Bent Brigham Hospital (Table I ) . Subject M . B . ha d intermittent precordial discomfort, initially thought t o be angina pec- toris; F . N . h a d h i p a n d backaches attributed t o osteo- arthritis. He also h a d mild hypertension, latent diabetes mellitus a s detected b y a mildly diabetic intravenous glu- tolerance test a n d electrocardiographic changes com- patible with early left ventricular hypertrophy. Subject M.L. h a d menstrual irregularities unresponsive t o uterine curettage a n d cyclic hormonal therapy. Before admission, a l l three were informed of the procedures t o b e followed a n d t h e potential risks. T h e investigators, a n d t h e patients a s well, felt that t h e procedures were warranted i n order t o elucidate possible metabolic aberrations associated with obesity. O n a d - mission, a l l ha d normal hemograms, urinalyses, chest a n d abdominal roentgenograms, electrocardiograms (ex- 1589

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Journal 1967 [Owen] Brain Metabolism During Fasting