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The Role of Tanshinone IIA in the Treatment of Obesity through Peroxisome Proliferator-Activated Receptor Antagonism

Key Laboratory of Nutrition and Metabolism (Z.G., C.H., X.S., Y.Z., Y.Q.Z.), Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; The National Center for Drug Screening (Q.L., M.-W.W.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; and State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology (L.P.), Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Address all correspondence and requests for reprints to: Dr. Ying Qin Zang, Institute for Nutritional Sciences, Chinese Academy of Sciences, 294 Tai Yuan Road, Shanghai 200031, China. E-mail: yqin{at}sibs.ac.cn.

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that coordinates carbohydrate and lipid metabolism, and is a therapeutic target for type 2 diabetes. Tanshinone IIA (Tan) is a lipophilic diterpene that is widely used to treat cardiovascular diseases in traditional Chinese medicine, and has recently been found to reduce body weight and lower blood lipids. However, its underlying mechanism of antiadipogenic effects remains unknown. Here, we report that Tan inhibits 3T3-L1 preadipocyte differentiation and transcriptional activities of full-length PPAR and PPAR ligand-binding domains. The effects of Tan are mediated through its property as a natural antagonist of PPAR (dissociation constant of an inhibitor value, 2.562 ± 0.711 µM). Tan treatment reduced adipose mass and body weight, improved glucose tolerance, and lowered the low-density lipoprotein to high-density lipoprotein ratio without changing the food intake in a high-fat diet-induced obese animal model. Our results suggest that the combined properties of Tan in adipogenesis, glucose tolerance, lipogenesis, and cardiovascular protection are beneficial for treating diabetic patients with complex metabolic conditions, in which modulating a single target is often not sufficient to achieve the desired effect.