Moraes Juliana C, Coope Andressa, Morari Joseane, Cintra Dennys E, Roman Erika A, Pauli José R, Romanatto Talita, Carvalheira José B, Oliveira Alexandre L R, Saad Mario J, Velloso Licio A
Department of Internal Medicine, University of Campinas, Campinas, Brazil.
PLoS One. 2009;4(4):e5045. doi: 10.1371/journal.pone.0005045. Epub 2009 Apr 2.
Consumption of dietary fats is amongst the most important environmental factors leading to obesity. In rodents, the consumption of fat-rich diets blunts leptin and insulin anorexigenic signaling in the hypothalamus by a mechanism dependent on the in situ activation of inflammation. Since inflammatory signal transduction can lead to the activation of apoptotic signaling pathways, we evaluated the effect of high-fat feeding on the induction of apoptosis of hypothalamic cells. Here, we show that consumption of dietary fats induce apoptosis of neurons and a reduction of synaptic inputs in the arcuate nucleus and lateral hypothalamus. This effect is dependent upon diet composition, and not on caloric intake, since pair-feeding is not sufficient to reduce the expression of apoptotic markers. The presence of an intact TLR4 receptor, protects cells from further apoptotic signals. In diet-induced inflammation of the hypothalamus, TLR4 exerts a dual function, on one side activating pro-inflammatory pathways that play a central role in the development of resistance to leptin and insulin, and on the other side restraining further damage by controlling the apoptotic activity.
膳食脂肪的摄入是导致肥胖的最重要环境因素之一。在啮齿动物中，富含脂肪的饮食通过一种依赖于炎症原位激活的机制，减弱下丘脑的瘦素和胰岛素厌食信号。由于炎症信号转导可导致凋亡信号通路的激活，我们评估了高脂喂养对下丘脑细胞凋亡诱导的影响。在此，我们表明膳食脂肪的摄入会诱导弓状核和下丘脑外侧的神经元凋亡以及突触输入减少。这种效应取决于饮食组成，而非热量摄入，因为配对喂养不足以降低凋亡标志物的表达。完整的Toll样受体4（TLR4）的存在可保护细胞免受进一步的凋亡信号影响。在饮食诱导的下丘脑炎症中，TLR4发挥双重作用，一方面激活在对瘦素和胰岛素抵抗发展中起核心作用的促炎途径，另一方面通过控制凋亡活性来抑制进一步的损伤。
