Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany.
Institute of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research (DZD), Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University Tübingen (IDM), Tübingen, Germany.
J Nutr Biochem. 2021 Jan;87:108516. doi: 10.1016/j.jnutbio.2020.108516. Epub 2020 Oct 3.
Dietary obesity compromises brain function, but the effects of high-fat food on synaptic transmission in hypothalamic networks, as well as their potential reversibility, are yet to be fully characterized. We investigated the impact of high-fat feeding on a hallmark of synaptic plasticity, i.e., the expression of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) that contain the subunits GluA1 and GluA2, in hypothalamic and cortical synaptoneurosomes of male rats. In the main experiment (experiment 1), three days, but not one day of high-fat diet (HFD) decreased the levels of AMPAR GluA1 and GluA2 subunits, as well as GluA1 phosphorylation at Ser845, in hypothalamus but not cortex. In experiment 2, we compared the effects of the three-day HFD with those a three-day HFD followed by four recovery days of normal chow. This experiment corroborated the suppressive effect of high-fat feeding on hypothalamic but not cortical AMPAR GluA1, GluA2, and GluA1 phosphorylation at Ser845, and indicated that the effects are reversed by normal-chow feeding. High-fat feeding generally increased energy intake, body weight, and serum concentrations of insulin, leptin, free fatty acids, and corticosterone; only the three-day HFD increased wakefulness assessed via video analysis. Results indicate a reversible down-regulation of hypothalamic glutamatergic synaptic strength in response to short-term high-fat feeding. Preceding the manifestation of obesity, this rapid change in glutamatergic neurotransmission may underlie counter-regulatory efforts to prevent excess body weight gain, and therefore, represent a new target of interventions to improve metabolic control.
饮食性肥胖会损害大脑功能，但是高脂肪食物对下丘脑网络中突触传递的影响，以及它们潜在的可逆转性，尚未得到充分的描述。我们研究了高脂肪喂养对突触可塑性的一个标志的影响，即谷氨酸能 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的表达，该受体包含亚基 GluA1 和 GluA2，在雄性大鼠的下丘脑和皮质突触小体中。在主要实验（实验 1）中，三天的高脂肪饮食（HFD）而不是一天的 HFD 降低了下丘脑而非皮质中的 AMPAR GluA1 和 GluA2 亚基以及 GluA1 在 Ser845 的磷酸化水平。在实验 2 中，我们比较了三天的 HFD 与三天的 HFD 后四天的正常饮食的影响。该实验证实了高脂肪喂养对下丘脑而不是皮质 AMPAR GluA1、GluA2 和 GluA1 在 Ser845 的磷酸化的抑制作用，并表明正常饮食喂养可以逆转这种作用。高脂肪喂养通常会增加能量摄入、体重和血清中胰岛素、瘦素、游离脂肪酸和皮质酮的浓度；只有三天的 HFD 会通过视频分析增加清醒时间。结果表明，短期高脂肪喂养会导致下丘脑谷氨酸能突触强度的可逆下调。在肥胖表现之前，这种谷氨酸能神经传递的快速变化可能是为了防止体重过度增加而进行的代偿性努力的基础，因此，它代表了改善代谢控制的干预措施的新靶点。
