Berberine, and its more Biologically Available Derivative Dihydroberberine,
Inhibit Mitochondrial Respiratory Complex I: A Mechanism for the Action of
Berberine to Activate AMPK and Improve Insulin Action
Nigel Turner1* (PhD), Jing-Ya Li2* (PhD), Alison Gosby1* (PhD), Sabrina W.C. To1 (BSc),Zhe Cheng2 (MSc), Hiroyuki Miyoshi3 (PhD), Makoto M. Taketo3 (PhD), Gregory J.
Cooney1 (PhD), Edward W. Kraegen1 (PhD), David E. James1 (PhD), Li-Hong Hu2† (PhD),
Jia Li 2† (PhD) and Ji-Ming Ye1† (PhD)
*These authors contributed equally to this work
1Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;
2Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
3Department of Pharmacology, Graduate School of Medicine, Kyoto University, Japan
Objective: Berberine (BBR) activates AMP-activated protein kinase (AMPK) and improves insulin sensitivity in rodent models of insulin resistance. We investigated the mechanism of activation of AMPK by BBR and explored whether derivatization of BBR could improve its in vivo efficacy.
Methods: AMPK phosphorylation was examined in L6 myotubes and LKB1-/- cells, with or without the CAMKK inhibitor STO-609. Oxygen consumption was measured in L6 myotubes and isolated muscle mitochondria. The effect of a BBR derivative,
dihydroberberine (dhBBR), on adiposity and glucose metabolism was examined in rodents fed a high-fat diet (HFD).
Results: We have made the following novel observations: (1) BBR dose-ependently
inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory Complex 1, similar to that observed with metformin and rosiglitazone. (2) Activation of AMPK by BBR did not rely on the activity of either LKB1 or CAMKKβ, consistent with major regulation at the level of the AMPK phosphatase. (3) A novel BBR derivative, dhBBR, was identified that displayed improved in vivo efficacy in terms of counteracting increased adiposity, tissue triglyceride accumulation and insulin resistance in HFD rodents. This effect is likely due to enhanced oral bioavailability.
Conclusions: Complex 1 of the respiratory chain represents a major target for compounds that improve whole body insulin sensitivity through increased AMPK activity. The identification of a novel derivative of BBR with improved in vivo efficacy highlights the potential importance of BBR as a novel therapy for the treatment of type 2 diabetes.
Diabetes 57: 1414-1418; published online before print as 10.2337/db07-1552