Huperzine A ameliorates obesity-related cognitive performance impairments involving neuronal insulin signaling pathway in mice

Authors: Hong-ying Wang1,2,3,4, Min Wu1,2, Jun-ling Diao1,2, Ji-bin Li5, Yu-xiang Sun4, Xiao-qiu Xiao1,2,3
1 Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
2 The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
3 Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital, Chongqing Medical University, Chongqing 400032, China
4 Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA
5 School of Public Health and Management, Chongqing Medical University, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing 400016, China
Correspondence to: Xiao-qiu Xiao:,
DOI: 10.1038/s41401-019-0257-1
Received: 28 September 2018
Accepted: 21 May 2019
Advance online: 18 June 2019


Type 2 diabetes (T2D) and Alzheimer’s disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, is a specific and reversible inhibitor of acetylcholinesterase, which is clinically used for the treatment of AD. In this study, we investigated whether Hup A improved the metabolic and cognitive functions in the high fat-induced (HFD) obese mice and genetic ob/ob mice. HFD and ob/ob mice were treated with Hup A (0.1, 0.3 mg · kg−1 · d−1, ig) for 3 months. Body weight was monitored and glucose tolerance tests were performed. Novel object recognition test and Morris water maze assay were conducted to evaluate the cognitive functions. We found that the Hup A treatment had no significant effect on peripheral metabolism of obese mice, whereas Hup A (0.1, mg · kg−1 · d−1) improved both the abilities of object recognition and spatial memory in HFD-fed mice, but not in ob/ob mice. Furthermore, Hup A treatment significantly upregulated the insulin and phosphorylated Akt levels in the cortex of HFD-fed mice, but not ob/ob mice. In addition, Hup A (0.3, mg · kg−1 · d−1) significantly decreased cortical β-secretase (BACE1) expression. In conclusion, these results demonstrate that treatment with Hup A (0.1, mg · kg−1 · d−1) can effectively improve the cognitive functions, at least in diet-induced obese mice.
Keywords: obesity; huperzine A; cognitive dysfunction; neuronal insulin signaling

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