Effects of distinct n-6 to n-3 polyunsaturated fatty acid ratios on insulin resistant and AD-like phenotypes in high-fat diets-fed APP/PS1 mice.
Effects of distinct n-6 to n-3 polyunsaturated fatty acid ratios on insulin resistant and AD-like phenotypes in high-fat diets-fed APP/PS1 mice.
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DOI：
10.1016/j.foodres.2022.112207
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发表时间：
2022-11
影响因子：
8.1
通讯作者：
Xiaojun Ma;Yujie Guo;Jingjing Xu;Xixiang Wang;S. Dong;Yanyan Gao;N. V. Van Halm-Lutterodt;Linhong Yuan
中科院分区：
文献类型：
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作者：
Xiaojun Ma;Yujie Guo;Jingjing Xu;Xixiang Wang;S. Dong;Yanyan Gao;N. V. Van Halm-Lutterodt;Linhong Yuan
2型糖尿病(T2 DM)和阿尔茨海默病(AD)是两种常见疾病，具有相似的病理生理特征和遗传易感性。多不饱和脂肪酸(PUFAs)是维持正常大脑功能所必需的。然而，关于饮食中n-6/n-3多不饱和脂肪酸比例对类AD病理的影响，尤其是在高脂饮食(HFD)喂养的AD模型小鼠中，人们知之甚少。在本研究中，APP/PS1小鼠以60%的HFD喂养3.5个月以诱导胰岛素抵抗。之后，应用不同n-6/n-3多不饱和脂肪酸比例(n-6/n-3=1：1、5：1或16：1)的45%HFD再治疗3.5个月。采用水迷宫观察饮食干预后小鼠的行为变化。动物在行为测试后被安乐死，并采集血清和组织样本进行生化、组织学和病理学测试和评估。高脂饲料引起胰岛素抵抗，血清IL-6、肿瘤坏死因子-α水平升高，皮质可溶性A-β1-40、A-β1-42含量及n-6/n-3PUFA比值升高。60%高脂饲料喂养的APP/PS1小鼠大脑皮层APP和BACE1蛋白表达增加，p-IR/IR比值增加，而促炎细胞因子mRNA表达降低。高N-3多不饱和脂肪酸饮食(n-6/n-3=1：1)可减轻60%高脂饲料所致的胰岛素抵抗和高脂血症。皮质可溶性Aβ1-40和Aβ1-42含量以及促炎症细胞因子下游皮质APP、GLUT1、GLUT 3、胰岛素代谢相关分子和NF-κB通路的表达与n-6/n-3多不饱和脂肪酸比例相关，表明膳食n-6/n-3多不饱和脂肪酸比例在调节血清炎性细胞因子、AD病理、皮质n-6/n-3多不饱和脂肪酸比例、胰岛素信号和神经炎症反应中起重要作用。
Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are prevalent diseases with similar pathophysiological characteristics and genetic predispositions. Polyunsaturated fatty acids (PUFAs) are essential in maintaining normal brain function. However, little is known about the effect of dietary n-6/n-3 PUFA ratio on AD-like pathology, particularly in high-fat diet (HFD)-fed AD model mice. In the present study, the APP/PS1 mice were fed with 60 % HFD for 3.5 months to induce insulin resistance. After that, 45 % HFD with various n-6/n-3 PUFA ratios (n-6/n-3 = 1:1, 5:1 or 16:1) was applied for an additional 3.5 months of treatment. The behavior of mice was observed using the water maze after dietary intervention. The animals were euthanized after behavioral testing, and serum and tissue samples were collected for biochemical, histological, and pathological tests and evaluation. HFD caused insulin resistance, increased serum IL-6 and TNF-α levels, cortical soluble Aβ1-40, Aβ1-42content, and cortical n-6/n-3 PUFA ratio in APP/PS1 mice. Increased APP and BACE1 protein expression and p-IR/IR ratio but decreased pro-inflammatory cytokines mRNA expression was detected in the cortex of 60 % HFD-fed APP/PS1 mice. N-3 PUFAs-rich diet (n-6/n-3 = 1:1) alleviated insulin resistance and hyperlipidemia caused by 60 % HFD. Cortical soluble Aβ1-40and Aβ1-42contents, as well as the expression of cortical APP, GLUT1, GLUT3, insulin metabolism-related molecules, and NF-κB pathway downstream pro-inflammatory cytokines, were found to be n-6/n-3 PUFAs ratio-dependent, indicating that dietary n-6/n-3 PUFA ratio plays a critical role in modifying the responses of serum inflammatory cytokines, AD pathology, cortical n-6/n-3 PUFAs ratio, insulin signaling, and neuroinflammation to HFD treatment.