JBC, Vol. 251, Issue 23, 7295-7303, Dec, 1976

Glucocorticoid action on rat thymic lymphocytes. Experiments utilizing adenosine to support cellular metabolism lead to a reassessment of catabolic hormone actions

S. K. Nordeen and D. A. Young

Inhibition of glucose uptake has been proposed as a primary cause of many of the subsequent inhibitory effects of glucocorticoids. This hypothesis has been tested in experiments where adenosine is substituted for glucose. Like glucose, adenosine maximally supports glycolytic and oxidative ATP generation, and by its use the hormonal inhibition of glucose uptake is circumvented. With adenosine, inhibition by cortisol is seen at at least one other metabolic site, respiratory ATP synthesis. This action can be observed by hormone-induced increases in levels of lactate, pyruvate, and AMP that accompany a lowering of ATP. Evidence for this metabolic action is also seen when cells are provided with a limiting amount of glucose; despite inhibition of glucose uptake, a cortisol-induced increase in lactate accompanies the reduction in levels of ATP. Decreased respiratory ATP synthesis is also suggested by a hormonal reduction in the metabolism of labeled exogenous pyruvate to 14CO2. Several experimental approaches suggest that inhibition of oxidative ATP production, rather than of glucose uptake, is the event most responsible for glucocorticoid-induced changes in the balance of adenine nucleotides, which in turn contribute to effects on protein synthesis and uridine uptake. First, the characteristic inhibitory cortisol effects on adenine nucleotides and protein synthesis are undiminished when adenosine is substituted for glucose. Second, in adenosine-supported cells the onset of the hormone-induced increase in levels of lactate corresponds closely to the appearance of measurable reductions in ATP. In contrast, when cells are supported by glucose, the hormonal inhibition of glucose uptake is maximal by 30 to 35 min, nearly an hour before effects on levels of ATP are detectable. Third, when cells are made strongly dependent upon glucose for ATP production by deprivation of exogenous substrate and cortisol is added at 90 min, a characteristic inhibition of the uptake of glucose added 40 min later is seen; nevertheless, this is insufficient to prevent added glucose from immediately and fully restoring ATP, rates of protein synthesis, and uridine uptake. Inhibitory effects on ATP, protein synthesis, and uridine do appear after an additional hour or so, a time commensurate with the development of an inhibition of oxidative metabolism. Fourth, limiting added glucose can reduce uptake more than cortisol, without reducing levels of ATP.
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