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

Abstract

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 Ϫ/Ϫ cells, with or without the Ca 2ϩ /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 CAMKK␤, 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.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

“…Palmitate and pyruvate oxidation rates were determined as described elsewhere [4]. Mitochondria from control and test TC muscle were isolated as described in Turner et al [30]. Respiration was measured polarographically using a Clarktype electrode (Strathkelvin Instruments, Glasgow, UK) at 30°C.…”

A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake

“…Respiration measurements were conducted using a Clark-type oxygen electrode (Strathkelvin Instruments, Motherwell, UK) as described [22]. The procedure of respiration measurement is described in electronic supplementary material (ESM) Methods.…”

Berberine Inhibits Oxygen Consumption Rate Independent of Alteration in Cardiolipin Levels in H9c2 Cells

“…BBR has been shown to inhibit mitochondrial respiratory function through inhibition of Complex I [2,3]. We initially examined if BBR altered mitochondrial OCR in differentiated H9c2 cells.…”

“…Thus, BBR may exhibit promise as an oral medication for type 2 diabetes and diabetes related complications. However, recent in vitro studies have indicated that BBR may also be a potent inhibitor of cell proliferation through reduced mitochondrial oxygen consumption mediated via inhibition of Complex I [2][3][4]. Currently, there are no well-controlled, long-term clinical trials to evaluate BBRs effectiveness and safety on mitochondrial function.…”