(Received I1 Febrmary 1975) 1. After nicotinic acid treatment, rat liver glycogen is depleted and phosphoenolpyruvate carboxykinase activity increased, to about twice the initial value. 2. The increase in phosphoenolpyruvate carboxykinase activity promoted by nicotinic acid is prevented by cycloheximide or actinomycin D, suggest-ing that this effect is produced by synthesis of the enzyme de novo. 3. Despite the enhancement of phosphoenolpyruvate carboxykinase activity and glycogen depletion, which occurs 5h after the injection of nicotinic acid, the gluconeogenic capacity of liver is low and considerably less than the values found in rats starved for 48h. 4. When the livers of well-fed rats are perfused in the presence of low concentrations of glucose, the activity of phosphoenotpyruvate carboxykinase significantly incteases compared with the control. 5. This increase is not related to the glycogen content, but seemns to be also the result of synthesis of the enzyme de novo, since this effect is coumteracted by previous treatment with cycloheximide or actinomycin D. 6. Phosphoenolpyruvate carboxykinase activity is not increased in the presence of low concentrations of circulating glucose when 40mnM-imidaiole (an activator of phosphodiesterase) is added to the perfusion medium. 7. Addition of dibutyryl cyclic AMP to the perfusion medium reguftsg in an incrtease in phosphoenolpyruvate carboxykinase activity, in spite of the presenCe of normal concentrations of circulating glucose. On the other hand, the concentration of cyclic AMP in the liver increases when that of glucose in the medium is low. 8.These results suggest that, in the absence of hormonal factors, the regulation of phosphoenolpyruvate carboxykinase can be accomplished by glucose itself, inadequate concentrations of it resulting in the induction of the enzyme. The mediator in this regulation, as in hormonal regulation, seems to be cyclic AMP.

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The effect of physical training on renal gluconeogenesis has been described by Krebs et al. [ 11, who showed enhanced rates of gluconeogenesis from lactate, pyruvate and fumarate. We have found an increase in the activity of phosphoenolpyruvate carboxykinase (PEPCK) in rat kidney after 2 hr of swimming [2] which is probably related to the accompanying metabolic acidosis. The latter is known to accelerate renal gluconeogenesis by increasing PEPCK activity [3-71. In this paper, we report the effect of short-term exercise on gluconeogenesis from several substrates in slices from rat kidney cortex. To evaluate further the role of acidosis in exercise-induced renal gluconeogenesis, kidney slices from animals given bicarbonate were also studied. ExperimentalFemale Wistar rats weighing 150-200 g were used. The animals were forced to swim in a water bath (22") for 2 hr. In some experiments acidosis was prevented by tubefeeding the rats with 10 ml of a 200 mM NaHC03 solution prior to the exercise, the control animals being fed 10 ml of a 200 mM NaCl solution.The rats were'sacrificed by cervical dislocation. The measurement of gluconeogenesis was carried out according to Krebs [8], by incubating washed cortex slices in a saline medium to which substrates had been added in a 10 mM concentration, at 40" for 1 hr, with 0, t CO2 (95:5) as the gas phase. Tissue North-Holland Publishing Company -Amsterdam(3-10 mg dry wt) was suspended in 4 ml of the medium and shaken in 25 ml conical flasks. After incubation, the slices were removed and weighed after drying at 110". Glucose was determined by the glucase-oxidase method [8,9].The PEPCK activity was assayed spectrophotometrically in the direction of oxalacetate synthesis as previously described [ 21. Results and discussionThe results given in the table show that the production of glucose was significantly greater with slices from exercised animals when L-lactate, pyruvate, L glutamine and L-glutamate were used as gluconeogenie substrates than with slices from control animals. When dihydroxyacetone and fructose were used, the increases of glucose production were lower.These findings indicate that, as expected, glucose production is considerably enhanced only from substrates that enter the gluconeogenic pathway before the step catalysed by PEPCK. They are in agreement with the results obtained by Goodman et al. [lo], who demonstrated an acceleration of gluconeogenesis from glutamine, glutamate, a-ketoglutarate and oxalacetate but not from fructose or glycerol in kidney slices from rats made acidotic by ammoniun chloride administration.The similarity between the metabolic behaviour of rat kidney cortex in experimental metabolic acidosis and after muscular exercise is evident as far as gluconeogenesis is concerned. It suggests that the stimulatory effect of exercise on renal PEPCK activity and gluconeogenesis is produced by the increase in lactic acid production leading to metabolic acidasis. 25