Duffy Cayla M, Nixon Joshua P, Butterick Tammy A
Minneapolis Veterans Affairs Health Care System, Research 151, One Veterans Dr, Minneapolis, MN 55417, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA.
Minneapolis Veterans Affairs Health Care System, Research 151, One Veterans Dr, Minneapolis, MN 55417, USA; Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA; Minnesota Obesity Center, University of Minnesota, 1334 Eckles Ave, St. Paul, MN 55108, USA.
Mol Cell Neurosci. 2016 Sep;75:93-100. doi: 10.1016/j.mcn.2016.07.003. Epub 2016 Jul 21.
Palmitic acid (PA), an abundant dietary saturated fatty acid, contributes to obesity and hypothalamic dysregulation in part through increase in oxidative stress, insulin resistance, and neuroinflammation. Increased production of reactive oxygen species (ROS) as a result of PA exposure contributes to the onset of neuronal apoptosis. Additionally, high fat diets lead to changes in hypothalamic gene expression profiles including suppression of the anti-apoptotic protein B cell lymphoma 2 (Bcl-2) and upregulation of the pro-apoptotic protein B cell lymphoma 2 associated X protein (Bax). Orexin A (OXA), a hypothalamic peptide important in obesity resistance, also contributes to neuroprotection. Prior studies have demonstrated that OXA attenuates oxidative stress induced cell death. We hypothesized that OXA would be neuroprotective against PA induced cell death. To test this, we treated an immortalized hypothalamic cell line (designated mHypoA-1/2) with OXA and PA. We demonstrate that OXA attenuates PA-induced hypothalamic cell death via reduced caspase-3/7 apoptosis, stabilization of Bcl-2 gene expression, and reduced Bax/Bcl-2 gene expression ratio. We also found that OXA inhibits ROS production after PA exposure. Finally, we show that PA exposure in mHypoA-1/2 cells significantly reduces basal respiration, maximum respiration, ATP production, and reserve capacity. However, OXA treatment reverses PA-induced changes in intracellular metabolism, increasing basal respiration, maximum respiration, ATP production, and reserve capacity. Collectively, these results support that OXA protects against PA-induced hypothalamic dysregulation, and may represent one mechanism through which OXA can ameliorate effects of obesogenic diet on brain health.
棕榈酸（PA）是一种在饮食中大量存在的饱和脂肪酸，部分通过增加氧化应激、胰岛素抵抗和神经炎症，导致肥胖和下丘脑功能失调。PA暴露导致活性氧（ROS）生成增加，促使神经元凋亡的发生。此外，高脂饮食会导致下丘脑基因表达谱发生变化，包括抗凋亡蛋白B细胞淋巴瘤2（Bcl-2）的抑制和促凋亡蛋白B细胞淋巴瘤2相关X蛋白（Bax）的上调。食欲素A（OXA）是一种对抵抗肥胖很重要的下丘脑肽，也具有神经保护作用。先前的研究表明，OXA可减轻氧化应激诱导的细胞死亡。我们假设OXA对PA诱导的细胞死亡具有神经保护作用。为了验证这一点，我们用OXA和PA处理了一种永生化下丘脑细胞系（命名为mHypoA-1/2）。我们证明，OXA通过减少半胱天冬酶-3/7凋亡、稳定Bcl-2基因表达以及降低Bax/Bcl-2基因表达比值，减轻PA诱导的下丘脑细胞死亡。我们还发现，OXA可抑制PA暴露后的ROS生成。最后，我们表明，mHypoA-1/2细胞暴露于PA会显著降低基础呼吸、最大呼吸、ATP生成和储备能力。然而，OXA处理可逆转PA诱导的细胞内代谢变化，增加基础呼吸、最大呼吸、ATP生成和储备能力。总的来说，这些结果支持OXA可预防PA诱导的下丘脑功能失调，这可能是OXA改善致肥胖饮食对大脑健康影响的一种机制。
