Melatonin alleviates cognition impairment by antagonizing brain insulin resistance in aged rats fed a high‐fat diet

• Published in: Journal of pineal research 2019-09, Vol.67 (2), p.e12584-n/a
• Main Authors: Xu, Jiqu, Gao, Hui, Zhang, Li, Rong, Shuang, Yang, Wei, Ma, Congcong, Chen, Meng, Huang, Qingde, Deng, Qianchun, Huang, Fenghong
• Format: Article
• Language: English
• Subjects: Aging - drug effects; Aging - metabolism; Aging - pathology; amyloid‐β; Animals; brain insulin resistance; Cholinergic Neurons - metabolism; Cholinergic Neurons - pathology; cognition impairment; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Female; Hippocampus - metabolism; Hippocampus - pathology; Insulin Resistance; Maze Learning - drug effects; melatonin; Melatonin - pharmacology; neuroinflammation; oxidative stress; Oxidative Stress - drug effects; Rats; Rats, Sprague-Dawley; TAU phosphorylation; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0742-3098; 1600-079X
• DOI: 10.1111/jpi.12584

Brain insulin resistance, induced by neuroinflammation and oxidative stress, contributes to neurodegeneration, that is, processes that are associated with Aβ accumulation and TAU hyperphosphorylation. Here, we tested the effect of chronic administration of melatonin (MLT) on brain insulin resistance and cognition deficits caused by a high‐fat diet (HFD) in aged rats. Results showed that MLT supplementation attenuated peripheral insulin resistance and lowered hippocampal oxidative stress levels. Activated microglia and astrocytes and hippocampal levels of TNF‐α in HFD‐fed rats were reduced by MLT treatment. Melatonin also prevented HFD‐induced increases in beta‐amyloid (Aβ) accumulation and TAU phosphorylation in the hippocampus. In addition, impairments of brain insulin signaling elicited by long‐term HFD were restored by MLT treatment, as confirmed by ex vivo insulin stimulation. Importantly, MLT reversed HFD‐induced cognitive decline as measured by a water maze test, normalized hippocampal LTP and restored CREB activity and BDNF levels as well as cholinergic neuronal activity in the hippocampus. Collectively, these findings indicate that MLT may exhibit substantial protective effects on cognition, via restoration of brain insulin signaling.