title: Differential effects of diet and obesity on high and low affinity sulfonylurea binding sites in the rat brain.
abstract: The brain contains neurons which alter their firing rates when ambient glucose concentrations change. An ATP-sensitive K+ (Katp) channel on these neurons closes and increases cell firing when ATP is produced by intracellular glucose metabolism. Binding of the antidiabetic sulfonylurea drugs to a site linked to this channel has a similar effect. Here rats with a propensity to develop diet-induced obesity (DIO) 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 [3H]glyburide in the presence or absence of Gpp(NH)p. Before HE diet exposure, chow-fed DIO- and DR-prone rats were separated by their high vs. low 24 h urine NE levels. In DR-prone rats, low affinity [3H]glyburide binding sites comprised up to 45% of total binding with highest concentrations in the hypothalamus and amygdala. But DIO-prone rats had few or no low affinity binding sites throughout the forebrain. High affinity [3H]glyburide binding was similar between phenotypes. When rats developed DIO after 3 months on 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 DIO levels and both were significantly lower than chow-fed controls. By contrast, high affinity [3H]glyburide binding was increased in DR rats throughout the forebrain so that it significantly exceeded that in both DIO and chow-fed 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.
authors.affiliation: Neurology Service (127C), DVA Medical Center, NJ 07018, USA. levin@umdnj.edu
authors.forename: B E
authors.initials: BE
authors.lastname: Levin
authors.forename: K L
authors.initials: KL
authors.lastname: Brown
authors.forename: A A
authors.initials: AA
authors.lastname: Dunn-Meynell
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004032:Diet; D004198:Disease Susceptibility; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D009765:Obesity / Q000378:metabolism*; D010641:Phenotype; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D015430:Weight Gain / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D005947:Glucose