Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models

Jing Bai; Shuai Zhang; Jinjing Cao; Hongbin Sun; Zhiguo Mang; Wei L Shen; Hao Li

doi:10.1016/j.phymed.2022.154366

Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models

Phytomedicine. 2022 Oct:105:154366. doi: 10.1016/j.phymed.2022.154366. Epub 2022 Jul 28.

Authors

Jing Bai¹, Shuai Zhang², Jinjing Cao², Hongbin Sun³, Zhiguo Mang², Wei L Shen⁴, Hao Li⁵

Affiliations

¹ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550025, China.
² State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
³ School of Life and Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁴ School of Life and Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: shenwei@shanghaitech.edu.cn.
⁵ State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: hli77@ecust.edu.cn.

PMID: 35933900
DOI: 10.1016/j.phymed.2022.154366

Abstract

Background: AMP-activated protein kinase (AMPK) is an effective target for treating diabetes. However, successful drug development is delayed due to issues including toxicity. Plant-derived natural product AMPK activators have emerged as a new way to treat diabetes due to its potential low safety risks. Here, we studied the effect of hernandezine (HER), a natural product derived from Thalictrum, in activating AMPK and treating T2D in mouse models.

Method: We tested HER in various cells and tissues, including primary hepatocytes, skeletal myotubes cell lines, as well as major metabolic tissues from diabetic (db/db) and diet-induced obesity (DIO) model mice. The effect of HER on glucose uptake via AMPK in vitro and in vivo was confirmed utilizing cell transfection and adenovirus interference analysis. Tissue staining assessed the effect of HER on adipogenesis. Real-time quantitative polymerase chain reaction (real-time PCR) was applied to verify the effect of HER on transcription factors. Western blot analysis was used to determine the activation of phosphorylated AMPK and ACC pathways.

Results: Biochemically, we found that HER prevented pAMPK from dephosphorylation to prolong its activity, disproving previous direct activation model and providing a new model to explain HER-mediated AMPK activation. HER could be orally delivered to animals and has a 3-fold long half-life in vivo as compared to metformin. Importantly, long-term oral HER treatment potently reduced body weight and blood glucose in both type 2 diabetes mullitus (T2DM) mouse models by increasing glucose disposal and reducing lipogenesis, and appeared not to induce cardiac hypertrophy.

Conclusion: Natural product HER indirectly activates AMPK by suppressing its dephosphorylation. Oral HER effectively alleviated hyperglycemia and reduced body weight in T2D mouse models, appeared to have a low risk of causing cardiac hypertrophy, and might be a potential therapeutic option for T2DM.

Keywords: AMPK; Diabetes mellitus; Glucose disposal; Hernandezine; Lipogenesis.

MeSH terms

AMP-Activated Protein Kinases
Animals
Benzylisoquinolines*
Biological Products*
Body Weight
Cardiomegaly
Diabetes Mellitus, Type 2*
Disease Models, Animal
Hypoglycemic Agents
Mice
Mice, Inbred C57BL
Mice, Obese

Substances

Benzylisoquinolines
Biological Products
Hypoglycemic Agents
hernandezine
AMP-Activated Protein Kinases