Histone H4 stimulates glucose uptake through the insulin receptor

Histone H4 stimulates the uptake of glucose in rat adipocytes and muscle cells. However, the mechanism of this unusual activity is not known. Therefore, we have begun to investigate the mechanism by which histone H4 stimulates the glucose uptake in rat adipocytes. We report that histone H4 requires 15–20 min to achieve its maximum effect and its time course is virtually indistinguishable from the time course of insulin itself. Reduction of the concentration of insulin receptors on the surface of adipocytes, either by trypsin digestion of the receptor, or by insulin-induced down regulation of the receptor, reduced the histone H4 effect as well as the insulin effects. Also, quercetin, a bioflavenoid that inhibits the insulin receptor tyrosine kinase activity, inhibits the action of both histone H4 and insulin. However, histone H4 activity is somewhat more resistant to these interventions that insulin activity. In contrast to the activity of insulin, histone H4 does not appear to be able to down regulate the insulin receptor, since the pretreatment of adipocytes with histone H4 did not affect the subsequent actions of either insulin or histone H4. Finally, Scatchard analysis of the binding of 125I-insulin in the presence and absence of histone H4 revealed that histone H4 increases the specific binding of insulin in a concentration dependent fashion. Histone H2b, a histone that does not have insulin-like activity, does not affect insulin binding. Taken together, these data suggest that the greatest portion of the insulin-like activity of histone H4 is initiated at the insulin receptor. However, the interaction of histone H4 and the insulin receptor is more complex than a simple binding of H4 to the insulin binding site. These studies may provide additional insight into alternate mechanisms for activation of the insulin receptor.