The role of ketone bodies in caloric homeostasis

Abstract

In order to obtain information on the factors which control the rate of ketone body utilization in rat tissues the activities of the enzymes involved in the utilization of ketone bodies—3-hydroxybutyrate dehydrogenase, 3-oxoacid CoA-transferase and acetoacetyl-CoA thiolase—were assayed in various tissues. The activities of the transferase (which initiates acetoacetate utilization) were highest in kidney and heart. In submaxillary gland and adrenals the activities were about one-quarter of those in kidney and heart. In brain they were about one-tenth and they were lower still in lung, spleen, skeletal muscle and adipose tissue. No activity was measurable in liver. The activities of the thiolase were roughly parallel to those of the transferase, with the exception of liver and adrenals. The high activity in the latter two tissues may be connected with the additional function of thiolase in the production of acetyl-CoA from fatty acids for the tricarboxylic acid cycle and for steroid synthesis. The activities of the two enzymes in tissues of mouse, hamster, guinea pig and sheep were similar to those of rat tissues, except that the activities were rather low in sheep heart and brain. Starvation, alloxan diabetes or fat feeding—conditions where the rates of ketone body utilization are increased—did not appreciably change the activity of the transferase. Thiolase activity increased in kidney and heart on fat feeding. The activity of 3-hydroxybutyrate dehydrogenase in rat brain did not change during starvation. The findings indicate that the activities of the ketone body utilizing enzymes are not major mechanisms controlling the variations in the rate of ketone body utilization in starvation or alloxan diabetes. The controlling factor in these situations is the concentration of ketone bodies, in particular acetoacetate, in plasma and tissue. At birth the activities of 3-hydroxybutyrate dehydrogenase and of the transferase in rat brain were about two-thirds of those of adult rat brain. The activities rose rapidly throughout the suckling period and at the time of weaning reached values about three times higher than those for adult brain. Later they gradually declined. The thiolase activity remained fairly constant during the suckling period. In rat kidney and rat heart the activities of the three enzymes at birth were less than one-third of those at maturity. They gradually rose and after 5 weeks approached, but never exceeded, the adult value. Throughout the suckling period the total ketone body concentration in the blood was about 6 times higher than in adult fed rats and the concentration of free fatty acids in the blood was 3–4 times higher. Thus, the rate of ketone body utilization in the brain of the suckling rat is determined by both greater amounts of key enzymes and higher concentrations of ketone bodies. The latter may be specially directed to the brain because of the low activities of the relevant enzymes in kidney and heart of suckling rats. The concentration dependence of ketone body utilization has also been demonstrated by measurements of the arterio-venous differences of ketone bodies across the rat brain in vivo. On starvation the arterio-venous difference rose about 6-fold. When, by acetoacetate infusion, the ketone body concentration in the blood of fed rats was raised to that of starved rats, the arterio-venous difference was about the same as in starvation. Both in adult and suckling rats the arterio-venous differences were roughly proportional to the acetoacetate concentration in the blood. Experiments on human volunteers show that post-exercise ketosis is preceded by a rise of the plasma free fatty acid concentration. The degree of post-exercise ketosis is much greater in untrained subjects than in trained athletes. Post-exercise ketosis is probably the consequence of the persistence of raised plasma free fatty acid levels after cessation of exercise.