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Berberine and Its More Biologically Available Derivative, Dihydroberberine, Inhibit Mitochondrial Respiratory Complex I

A Mechanism for the Action of Berberine to Activate AMP-Activated Protein Kinase and Improve Insulin Action

¹ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia
² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
³ Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Corresponding authors: Ji-Ming Ye, PhD, Diabetes and Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail: j.ye{at}garvan.org.au; Jia Li, PhD, or Li-Hong Hu, PhD, Shanghai Institute of Materia Medica, 199 Guo Shou Jing Rd., Zhangjiang Hi-Tech Park, Shanghai 201203, China. E-mail: jli{at}mail.shcnc.ac.cn or simmhull{at}mail.shcnc.ac.cn

Abbreviations: ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMPK, AMP-activated protein kinase; BBR, berberine; CAMKK, Ca²⁺/calmodulin-dependent protein kinase kinase; dhBBR, dihydroberberine; HFD, high-fat diet; MEF, mouse embryonic fibroblast

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.

RESEARCH DESIGN AND METHODS—AMPK phosphorylation was examined in L6 myotubes and LKB1^–/– cells, with or without the Ca²⁺/calmodulin-dependent protein kinase kinase (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.

RESULTS—We have made the following novel observations: 1) BBR dose-dependently inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory complex I, 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; and 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 high-fat–fed rodents. This effect is likely due to enhanced oral bioavailability.

CONCLUSIONS—Complex I 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.

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