The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism.
Peroxisome proliferator-activated receptor (PPAR) gamma 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 PPARgamma and PPARgamma ligand-binding domains. The effects of Tan are mediated through its property as a natural antagonist of PPARgamma (dissociation constant of an inhibitor value, 2.562 +/- 0.711 microm). 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.
Gong
Zhenwei
Z
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Huang
Cheng
C
Sheng
Xiaoyan
X
Zhang
Yuebo
Y
Li
Qunyi
Q
Wang
Ming-Wei
MW
Peng
Linling
L
Zang
Ying Qin
YQ
D016475:3T3 Cells / Q000187:drug effects / Q000502:physiology*; D045784:Abietanes; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D017930:Genes, Reporter; D005951:Glucose Tolerance Test; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000517:prevention & control*; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D010616:Phenanthrenes / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014162:Transfection
D045784:Abietanes; D019440:Anti-Obesity Agents; D001786:Blood Glucose; D018076:DNA, Complementary; D008055:Lipids; D047495:PPAR gamma; D010616:Phenanthrenes; C021751:tanshinone; D012313:RNA