INBIOMED - Instituto de Investigaciones Biomédicas, UBA-CONICET, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Department of Physiology, School of Dentistry, University of Buenos Aires, Buenos Aires, Argentina.
J Neuroendocrinol. 2019 Feb;31(2):e12673. doi: 10.1111/jne.12673. Epub 2019 Feb 20.
Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress. Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that it triggers a pro-inflammatory response in the brain. Melanocortins are neuropeptides with proven anti-inflammatory and neuroprotective action mediated by melanocortin receptor 4 (MC4R), but little is known about the effect of melanocortins on oxidative stress. The aim of this study was to investigate whether melanocortins could alleviate oxidative stress induced by a high fat diet (HFD) model. We found that NDP-MSH treatment decreased PA-induced reactive oxygen species production in astrocytes, an effect blocked by the MC4R inhibitor JKC363. NDP-MSH abolished nuclear translocation of Nrf2 induced by PA and blocked the inhibitory effect of PA on superoxide dismutase (SOD) activity and glutathione levels while it also per se increased activity of SOD and γ-glutamate cysteine ligase (γ-GCL) antioxidant enzymes. However, HFD reduced hypothalamic MC4R and brain derived neurotrophic factor mRNA levels, thereby preventing the neuroprotective mechanism induced by melanocortins.
最近的研究结果表明，肥胖与体重控制的关键下丘脑区域的炎症有关。下丘脑炎症也与氧化应激有关。棕榈酸（PA）是食物中含量最丰富的游离脂肪酸，体外研究表明它会在大脑中引发炎症反应。黑皮质素是具有抗炎和神经保护作用的神经肽，其作用是通过黑皮质素受体 4（MC4R）介导的，但关于黑皮质素对氧化应激的影响知之甚少。本研究旨在探讨黑皮质素是否可以减轻高脂肪饮食（HFD）模型引起的氧化应激。我们发现，NDP-MSH 处理可减少 PA 诱导的星形胶质细胞中活性氧的产生，而 MC4R 抑制剂 JKC363 可阻断该作用。NDP-MSH 消除了 PA 诱导的 Nrf2 核易位，并阻断了 PA 对超氧化物歧化酶（SOD）活性和谷胱甘肽水平的抑制作用，同时它本身也增加了 SOD 和γ-谷氨酰半胱氨酸连接酶（γ-GCL）抗氧化酶的活性。然而，HFD 降低了下丘脑 MC4R 和脑源性神经营养因子 mRNA 水平，从而阻止了黑皮质素诱导的神经保护机制。
