Berberine, a Natural Plant Product, Activates AMP-Activated Protein Kinase With Beneficial Metabolic Effects in Diabetic and Insulin-Resistant States*
Yun S. Lee1,2, Woo S. Kim1,2, Kang H. Kim1,2, Myung J. Yoon1, Hye J. Cho1, Yun Shen3,4, Ji-Ming Ye3, Chul H. Lee5, Won K. Oh5, Chul T. Kim5, Cordula Hohnen-Behrens3, Alison Gosby3, Edward W. Kraegen3, David E. James3, and Jae B. Kim1,2*
Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat?fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3' kinase?independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.*
Obesity poses a serious health risk contributing to the increased prevalence of a host of other diseases including type 2 diabetes, hyperlipidemia, hypercholesterolemia, and hypertension (1,2). Peripheral insulin resistance, which is often associated with obesity, is one of the earliest detectable defects identified in individuals at risk of type 2 diabetes. For this reason, pharmacologic agents that overcome insulin resistance, so-called insulin-sensitizing agents, have received considerable attention. In recent years, several major insulin-sensitizing agents have been developed, including the thiazolidinediones (TZDs) (3) and metformin (4). Both of these agents are thought to have beneficial effects, at least in part, by activating the stress-activated kinase AMP-activated protein kinase (AMPK) (5,6). AMPK is activated under a variety of conditions that signify cellular stress, usually in response to a change in the intracellular ATP-to-AMP ratio. Active AMPK orchestrates a variety of metabolic processes, most of which lead to reduced energy storage and increased energy production. TZDs and metformin are thought to activate AMPK via discrete mechanisms; TZDs stimulate the proliferation of small adipocytes that secrete adipokines such as adiponectin, which have been shown to stimulate AMPK activity in muscle and liver cells (7). Conversely, it appears that metformin activates AMPK directly via an ill-defined mechanism (8). These studies emphasize the potential utility of targeting the AMPK pathway in the treatment of type 2 diabetes and obesity.*
The use of natural products for the treatment of metabolic diseases has not been explored in depth despite the fact that a number of modern oral hypoglycemic agents such as metformin are derivatives of natural plant products (9,10). Although several traditional medicines have been reported to have antidiabetic effects (10), the molecular targets of such compounds have not been revealed, and a careful analysis of their mode of action in animal models has not been undertaken. In the present study, we have focused on berberine because this natural product has been reported in the Chinese literature and several recent studies (11?14) to have beneficial effects in human type 2 diabetes, although its mechanism of action is not known. Here, we show that in vivo administration of berberine has insulin sensitizing as well as weight- and lipid-lowering properties in both db/db mice and in high-fat?fed rats. Strikingly, berberine acutely stimulated AMPK activity in both myotubes and adipocytes in vitro, contributing to enhanced GLUT4 translocation in myotubes and reduced lipid mass in adipocytes.
Based on these studies, we propose that berberine may have a major application as a new treatment for obesity and/or insulin resistance in humans.”