Levin B E, Brown K L, Dunn-Meynell A A
Neurology Service (127C), DVA Medical Center, NJ 07018, USA.
Brain Res. 1996 Nov 11;739(1-2):293-300. doi: 10.1016/s0006-8993(96)00835-9.
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.
大脑中含有神经元，当周围葡萄糖浓度发生变化时，这些神经元会改变其放电频率。这些神经元上的一种ATP敏感性钾离子（Katp）通道在细胞内葡萄糖代谢产生ATP时会关闭，并增加细胞放电。抗糖尿病磺脲类药物与该通道相连的位点结合也有类似效果。在此，给倾向于在喂食高脂肪、高能量和高蔗糖（HE饮食）时发生饮食诱导性肥胖（DIO）或具有饮食抗性（DR）的大鼠，在有或没有Gpp(NH)p存在的情况下，用[3H]格列本脲通过放射自显影法评估低亲和力和高亲和力磺脲类结合情况。在接触HE饮食之前，喂食普通饲料的易患DIO和DR的大鼠通过其24小时尿去甲肾上腺素水平的高低进行区分。在易患DR的大鼠中，低亲和力[3H]格列本脲结合位点占总结合量的比例高达45%，在下丘脑和杏仁核中的浓度最高。但易患DIO的大鼠在前脑几乎没有或没有低亲和力结合位点。两种表型的高亲和力[3H]格列本脲结合情况相似。当大鼠在HE饮食3个月后出现DIO时，它们的低亲和力结合略有增加。喂食HE饮食的DR大鼠体重增加量与喂食普通饲料的对照组相同，但其低亲和力结合位点减少到DIO水平，且两者均显著低于喂食普通饲料的对照组。相比之下，DR大鼠前脑的高亲和力[3H]格列本脲结合增加，以至于显著超过DIO和喂食普通饲料的对照大鼠。这些研究表明，在前脑存在大量低亲和力磺脲类结合位点，它们与高亲和力位点一起，作为体重增加表型和饮食组成的函数受到调节。
