Metformin Restores Hippocampal Neurogenesis and Learning and Memory via Regulating Gut Microbiota in the Obese Mouse Model
Abstract
Numerous studies have shown that over-nutritional obesity may lead to pre-diabetes, type 2 diabetes and cognitive decline. As the degree of metabolic disorders increases, the cognitive decline is getting worse. However, the cellular events that cause this cognitive dysfunction is yet to be clarified. We used a high-fat diet (HFD) consumption-induced obesity mouse model to test the effects of metformin on the hippocampal neurogenesis and learning and memory abilities of obese mice. 5-Bromo-2'-deoxyuridine (BrdU) labelling and retrovirus labeling were applied to detect hippocampal newborn neurons. Behavioral experiments were used to detect learning and memory abilities of mice. 16S rRNA gene sequencing was performed to detect the composition of gut microbiota. The positron emission tomography (PET) was conducted to detect the energy metabolism activity of different mouse brain regions. Our results reveal that metformin restores the impairment of neurogenesis in the dentate gyrus and finally prevents the cognitive decline of the obese mice. Moreover, the therapeutic effects of metformin are achieved by regulating the composition of gut microbiota of mice, which may inhibit microglia activation and neuroinflammation in the brain of obese mice. This study suggests that metformin may be taken as a promising candidate for the intervention of cognitive decline related to imbalance of gut microbiota caused by obesity.
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Data from high-fat diet mice linked the learning and memory restorative benefits of metformin in the diet (250 mg/kg/day) to the microbiota with positive data from a fecal transplantation protocol.
“Data from a study with high-fat diet mice has also linked the learning and memory restorative benefits of metformin in the diet (250 mg/kg/day) to the microbiota with positive data from a fecal transplantation protocol [(118): Table 2].”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [118]
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- Authors
- Ma, X., Xiao, W., Li, H., Pang, P., Xue, F., Wan, L., Pei, L., & Yan, H.
- Affiliations
- Sun Yat-sen University (CN)
- Huazhong University of Science and Technology (CN)
- First Affiliated Hospital of Soochow University (CN)
- Washington University in St. Louis (US)
- Corresponding author
- Pei, Lei
- Yan, Huanhuan
- Venue
- Brain Behavior and Immunity
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 95
- Pages
- 68-83
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W3131250905
- Cited by
- 67
- References
- 53
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 14 · 2023: 14 · 2022: 16 · 2021: 5
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shanxi Provincial Key Research and Development Project (2018SF-090 FX)
- National Natural Science Foundation of China (81870932, 81901304 HY)
- Huazhong University of Science and Technology
- China Postdoctoral Science Foundation (2019\u202FT120663, M640704 HY, T120663)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- metformin, hippocampal neurogenesis, gut microbiota, obesity, cognitive decline, learning and memory, high-fat diet, microglial activation, neuroinflammation, dentate gyrus, brain energy metabolism, type 2 diabetes
- MeSH terms
- Gastrointestinal Microbiome, Animals, Diabetes Mellitus, Type 2, Hippocampus, Metformin, Mice, Inbred C57BL, Mice, Obese, Obesity, RNA, Ribosomal, 16S, Mice, Neurogenesis, Diet, High-Fat
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