DIFFERENTIAL-EFFECTS OF DIET AND OBESITY ON HIGH AND LOW-AFFINITY SULFONYLUREA BINDING-SITES IN THE RAT-BRAIN

yThe brain contains neurons which alter their firing rates when ambien t glucose concentrations change. An ATP-sensitive K+ (K-atp) channel o n these neurons closes and increases cell firing when ATP is produced by intracellular glucose metabolism. Binding of the antidiabetic sulfo nylurea drugs to a site linked to this channel has a similar effect. H ere rats with a propensity to develop diet-induced obesity (DIG) or to be diet-resistant (DR) when fed a diet moderately high in fat, energy and sucrose (HE diet) had low and high affinity sulfonylurea binding assessed autoradiographically with [H-3]glyburide in the presence or a bsence of Gpp(NH)p. Before HE diet exposure, chow-fed DIO- and DR-pron e rats were separated by their high vs. low 24 h urine NE levels. In D R-prone rats, low affinity [H-3]glyburide binding sites comprised up t o 45% of total binding with highest concentrations in the hypothalamus and amygdala. But DIG-prone rats had few or no low affinity binding s ites throughout the forebrain. High affinity [H-3]glyburide binding wa s similar between phenotypes. When rats developed DIO after 3 months o n HE diet, their low affinity binding increased slightly. DR rats fed the HE diet gained the same amount of weight as chow-fed controls but their low affinity binding sites were reduced to DIG levels and both w ere significantly lower than chow-fed controls. By contrast, high affi nity [H-3]glyburide binding was increased in DR rats throughout the fo rebrain so that it significantly exceeded that in both DIO and chow-fe d control rats. These studies demonstrate a significant population of low affinity sulfonylurea binding sites throughout the forebrain which , along with high affinity sites, are regulated as a function of both weight gain phenotype and diet composition.