Department of Biomedical Sciences, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, Michigan, USA.
Department of Chemistry, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.
J Neurochem. 2023 Feb;164(4):499-511. doi: 10.1111/jnc.15720. Epub 2022 Nov 22.
Obesity is one of the leading health concerns in the United States. Studies from human and rodent models suggest that inherent differences in the function of brain motivation centers, including the nucleus accumbens (NAc), contribute to overeating and thus obesity. For example, there are basal enhancements in the excitability of NAc GABAergic medium spiny neurons (MSN) and reductions in basal expression of AMPA-type glutamate receptors in obesity-prone vs obesity-resistant rats. However, very little is known about the regulation of extracellular glutamate and GABA within the NAc of these models. Here we gave obesity-prone and obesity-resistant rats stable isotope-labeled glucose ( C -glucose) and used liquid chromatography mass spectrometry (LC-MS) analysis of NAc dialysate to examine the real-time incorporation of C -glucose into glutamate, glutamine, and GABA. This novel approach allowed us to identify differences in glucose utilization for neurotransmitter production between these selectively bred lines. We found that voluntarily ingested or gastrically infused C -glucose rapidly enters the NAc and is incorporated into C -glutamine, C -glutamate, and C -GABA in both groups within minutes. However, the magnitude of increases in NAc C -glutamine and C -GABA were lower in obesity-prone than in obesity-resistant rats, while basal levels of glutamate were elevated. This suggested that there may be differences in the astrocytic regulation of these analytes. Thus, we next examined NAc glutamine synthetase, GAD67, and GLT-1 protein expression. Consistent with reduced C -glutamine and C -GABA, NAc glutamine synthetase and GLT-1 protein expression were reduced in obesity-prone vs obesity-resistant groups. Taken together, these data show that NAc glucose utilization differs dramatically between obesity-prone and obesity-resistant rats, favoring glutamate over GABA production in obesity-prone rats and that reductions in NAc astrocytic recycling of glutamate contribute to these differences. These data are discussed in light of established differences in NAc function between these models and the role of the NAc in feeding behavior.
肥胖是美国主要的健康问题之一。来自人类和啮齿动物模型的研究表明，大脑动机中枢（包括伏隔核）的固有功能差异导致过度进食，从而导致肥胖。例如，肥胖易感大鼠的伏隔核 GABA 能中间神经元（MSN）的兴奋性基础增强，而肥胖抵抗大鼠的 AMPA 型谷氨酸受体基础表达减少。然而，对于这些模型中的伏隔核中细胞外谷氨酸和 GABA 的调节，我们知之甚少。在这里，我们给肥胖易感和肥胖抵抗大鼠稳定同位素标记的葡萄糖（ C -葡萄糖），并使用伏隔核透析液的液相色谱质谱（LC-MS）分析，检查 C -葡萄糖实时掺入谷氨酸、谷氨酰胺和 GABA 中。这种新方法使我们能够识别这些选择性繁殖系之间神经递质产生的葡萄糖利用差异。我们发现，自愿摄入或胃内输注的 C -葡萄糖迅速进入伏隔核，并在几分钟内在两组大鼠中掺入 C -谷氨酰胺、C -谷氨酸和 C -GABA。然而，肥胖易感大鼠伏隔核 C -谷氨酰胺和 C -GABA 的增加幅度低于肥胖抵抗大鼠，而谷氨酸的基础水平升高。这表明星形胶质细胞对这些分析物的调节可能存在差异。因此，我们接下来检查了伏隔核谷氨酰胺合成酶、GAD67 和 GLT-1 蛋白表达。与 C -谷氨酰胺和 C -GABA 的减少一致，肥胖易感大鼠的伏隔核谷氨酰胺合成酶和 GLT-1 蛋白表达降低。综上所述，这些数据表明，肥胖易感和肥胖抵抗大鼠的伏隔核葡萄糖利用存在显著差异，肥胖易感大鼠中谷氨酸的产生优先于 GABA，而伏隔核星形胶质细胞对谷氨酸的再循环减少导致了这些差异。这些数据是根据这些模型中伏隔核功能的既定差异以及伏隔核对摄食行为的作用进行讨论的。
