Regulation of the anorectic drug recognition site during glucoprivic feeding

The acute effects of 2-deoxy-D-glucose (2-DG)-induced glucoprivic feeding on the anorectic drug recognition site and Na⁺K⁺ -ATPase in the brain were examined in adult rats and in lean and genetically obese mice. The marked hyperglycemia and the induction of feeding caused by the administration of 2-DG to satiated rats and lean mice were associated with significant increases in Na⁺K⁺-ATPase activity, and in [³H]ouabain binding and [³H]mazindol binding to the anorectic drug recognition site in hypothalamic membranes. Basal and 2-DG-stimulated levels of blood glucose were significantly correlated to the levels of hypothalamic [³H]ouabain (r = + .91, p<0.01) and [³H]mazindol (r = + .87, p<0.01) binding. A significant correlation (r = .74, p<0.05) was also observed between [³H]mazindol binding and [³H]ouabain binding supporting the hypothesis that these hypothalamic binding sites are functionally coupled in their response to circulating glucose. Following the intracerebroventricular (ICV) administration of the diabetogenic drug alloxan, 2-DG did not stimulate feeding or increase [³H]mazindol and [³H]ouabain binding sites in the hypothalamic paraventricular area. Since 2-DG still caused hyperglycemia in alloxan-treated rats, alloxan-induced inactivation of glucoreceptor mechanisms led to an uncoupling of the anorectic drug recognition site from a hypothalamic glucostat. In genetically obese mice (ob/ob), 2-DG also could not induce feeding or increase hypothalamic [³H]ouabain or [³H]mazindol binding, despite a significant hyperglycemic response. In contrast, 2-DG did increase feeding and the binding of [³H]ouabain and [³H]mazindol to the hypothalamus of lean littermates. The dissociation of the anorectic drug recognition site from blood glucose responses to 2-DG suggests that the glucoprivic feeding response in obese mice is impaired. In conclusion, the [³H]mazindol recognition site and the neuronal Na⁺K⁺-ATPase labelled by [³H]ouabain binding constitutes a glucoreceptive system which in response to changes in circulating glucose levels modulates feeding. Since the coupling of this anorectic ding recognition site to brain glucostats is defective in genetically obese mice, this system may have an important role in pathological hyperphagia and the development of obesity.