Puerarin alleviates depressive-like behaviors in high-fat diet-induced diabetic mice via modulating hippocampal GLP-1R/BDNF/TrkB signaling

ABSTRACT

Objective

Depression is one of the most common complications in patients with diabetes. Our previous study demonstrated puerarin, a dietary isoflavone, improved glucose homeostasis and β-cell regeneration in high-fat diet (HFD)-induced diabetic mice. Here, we aim to evaluate the potential effect of puerarin on diabetes-induced depression.

Methods

The co-occurrence of diabetes and depression with related biochemical alterations were confirmed in HFD mice and db/db mice, respectively using behavioral analysis, ELISA and western blotting assay. Furthermore, impacts of puerarin on depression-related symptoms and pathological changes were investigated in HFD mice.

Results

The results showed that puerarin effectively alleviated the depression-like behaviors of HFD mice, down-regulated serum levels of corticosterone and IL-1β, while up-regulated the content of 5-hydroxytryptamine. Simultaneously, puerarin increased the number of hippocampal neurons in HFD mice, and suppressed the apoptosis of neurons to protect the hippocampal neuroplasticity. GLP-1R expression in hippocampus of HFD mice was enhanced by puerarin, which subsequently activated AMPK, CREB and BDNF/TrkB signaling to improve neuroplasticity. Importantly, our data indicated that puerarin had an advantage over fluoxetine or metformin in treating diabetes-induced depression.

Conclusion

Taken together, puerarin exerts anti-depressant-like effects on HFD diabetic mice, specifically by improving hippocampal neuroplasticity via GLP-1R/BDNF/TrkB signaling. Puerarin as a dietary supplement might be a potential candidate in intervention of diabetes with comorbid depression.

KEYWORDS:

• Depression
• diabetes
• GLP-1R
• hippocampus
• neuroplasticity
• puerarin

Abbreviations:

• 5-HT
• 5-hydroxytryptamine
• AMPK
• AMP-activated protein kinase
• BDNF
• brain-derived neurotrophic factor
• CORT
• corticosterone
• CREB
• cAMP-response element binding protein
• ERK
• extracellular regulated protein kinases
• GLP-1R
• glucagon-like peptide 1 receptor
• HFD
• high-fat diet
• T2DM
• type 2 diabetes
• TrkB
• tyrosine kinase receptor B

Acknowledgements

Author contributions: Yumin Liu and Ziqi Hu contributed to the experimental operation, researched data and analysis. Jing Wang and Yanjun Liao contributed to equipment, data analysis. Luan Shu contributed to experimental design, data analysis, wrote and edited the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request.

Additional information

Funding

This work was supported by the Natural Science Foundation of China [grant number 81370924, 81803756], EFSD/CDS/Lilly Program for Collaborative Research between China and Europe, the Foundation for High-Level Talent in Six Areas of Jiangsu Province [grant number 2015-YY010], Central government financial transfer payment for local projects from National Administration of Traditional Chinese Medicine [grant number 2022GJJZDYJS-01].

Notes on contributors

Yumin Liu

Yumin Liu, received the B.S. degree in Pharmacology from Anhui Medical University, Hefei, China, in 2020. He is currently working toward the M.S. degree in Pharmacology in Nanjing University of Chinese Medicine, Nanjing, China. His research interests include pharmacology and Traditional Chinese Medicine.

Ziqi Hu

Ziqi Hu, received the M.S. degree in Pharmacology in Nanjing University of Chinese Medicine, Nanjing, China, in 2021. He is currently working as a research assistant in Pharma Block Sciences (Nanjing) Inc. His research interests include pharmacology and Traditional Chinese Medicine.

Jing Wang

Jing Wang, received the M.S. degree in Pharmacology in Nanjing University of Chinese Medicine, Nanjing, China, in 2016. He is currently working as an associated professor in Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. His research interests include pharmacology and Traditional Chinese Medicine.

Yanjun Liao

Yanjun Liao, received the M.S. degree in Pharmacology in Nanjing University of Chinese Medicine, Nanjing, China, in 2022. She is currently working in the Health Supervision Bureau of Shaoxing, China. Her research interests include pharmacology and Traditional Chinese Medicine.

Luan Shu

Luan Shu, received the Ph.D. degree in Molecular and cellular biology from Nanjing University, Nanjing, China, in 2007. She is currently working as a professor in Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. Her research interests include pharmacology and Traditional Chinese Medicine.