School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
The Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
Mol Neurobiol. 2023 Aug;60(8):4595-4617. doi: 10.1007/s12035-023-03360-5. Epub 2023 May 1.
Increasing data suggest a crucial role of circadian rhythm in regulating metabolic and neurological diseases, and Bmal1 is regarded as a key regulator of circadian transcription. The aim of this study is to investigate the role of Bmal1 in the disruption of circadian rhythm and neuropsychiatric injuries in type 2 diabetes mellitus (T2DM). A T2DM model was induced by the combination of high-fat-diet (HFD) and streptozotocin (STZ) in vivo or HT-22 cells challenged with palmitic-acid (PA) in vitro. The glucolipid metabolism indicators, behavioral performance, and expression of synaptic plasticity proteins and circadian rhythm-related proteins were detected. These changes were also observed after interference of Bmal1 expression via overexpressed plasmid or small interfering RNAs in vitro. The results showed that HFD/STZ could induce T2DM-like glycolipid metabolic turmoil and abnormal neuropsychiatric behaviors in mice, as indicated by the increased concentrations of fasting blood-glucose (FBG), HbA1c and lipids, the impaired glucose tolerance, and the decreased preference index of novel object or novel arm in the novel object recognition test (NOR) and Y-maze test (Y-maze). Consistently, the protein expression of synaptic plasticity proteins and circadian rhythm-related proteins and the positive fluorescence intensity of MT1B and Bmal1 were decreased in the hippocampus of HFD/STZ-induced mice or PA-challenged HT-22 cells. Furthermore, overexpression of Bmal1 could improve the PA-induced lipid metabolic dysfunction and increase the decreased expressions of synaptic plasticity proteins and circadian rhythm-related proteins, and vice versa. These results suggested a crucial role of Bmal1 in T2DM-related glycolipid metabolic disorder and neuropsychiatric injury, which mechanism might be involved in the regulation of synaptic plasticity and circadian rhythms.
越来越多的证据表明，生物钟节律在调节代谢和神经疾病方面起着关键作用，Bmal1 被认为是生物钟转录的关键调节因子。本研究旨在探讨 Bmal1 在 2 型糖尿病（T2DM）中昼夜节律紊乱和神经精神损伤中的作用。体内采用高脂饮食（HFD）联合链脲佐菌素（STZ）诱导 T2DM 模型，或体外用棕榈酸（PA）处理 HT-22 细胞。检测糖脂代谢指标、行为表现以及突触可塑性蛋白和昼夜节律相关蛋白的表达。体外通过过表达质粒或小干扰 RNA 干扰 Bmal1 表达后，观察到这些变化。结果表明，HFD/STZ 可诱导小鼠出现类似 T2DM 的糖脂代谢紊乱和神经精神行为异常，表现为空腹血糖（FBG）、HbA1c 和血脂升高、葡萄糖耐量受损以及新物体识别试验（NOR）和 Y 迷宫试验（Y-maze）中新物体或新臂偏好指数降低。同样，HFD/STZ 诱导的小鼠或 PA 处理的 HT-22 细胞中海马突触可塑性蛋白和昼夜节律相关蛋白的蛋白表达以及 MT1B 和 Bmal1 的阳性荧光强度降低。此外，过表达 Bmal1 可改善 PA 诱导的脂质代谢功能障碍，增加下调的突触可塑性蛋白和昼夜节律相关蛋白的表达，反之亦然。这些结果表明 Bmal1 在 T2DM 相关糖脂代谢紊乱和神经精神损伤中起着至关重要的作用，其机制可能涉及调节突触可塑性和昼夜节律。
