T W Jung1, H Kim1, S Y Park1,2, W Cho1, H Oh1, H J Lee3,2, A M Abd El-Aty4,5, A Hacimuftuoglu5, J H Jeong6,7. 1. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. 2. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea. 3. Department of Anatomy and Cell Biology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea. 4. Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt. 5. Department of Medical Pharmacology, Medical Faculty, Ataturk University, 25240, Erzurum, Türkiye. 6. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea. jhjeong3@cau.ac.kr. 7. Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea. jhjeong3@cau.ac.kr.
Abstract
OBJECTIVE: Insulin resistance develops due to skeletal muscle inflammation and endoplasmic reticulum (ER) stress. Stachydrine (STA), extracted from Leonurus heterophyllus, has been shown to suppress proliferation and induce apoptosis in breast cancer cells and exert anti-inflammatory properties in the brain, heart, and liver. However, the roles of STA in insulin signaling in skeletal muscle remain unclear. Herein, we examined the impacts of STA on insulin signaling in skeletal muscle under hyperlipidemic conditions and its related molecular mechanisms. METHODS: Various protein expression levels were determined by Western blotting. Levels of mouse serum cytokines were measured by ELISA. RESULTS: We found that STA-ameliorated inflammation and ER stress, leading to attenuation of insulin resistance in palmitate-treated C2C12 myocytes. STA dose-dependently enhanced AMPK phosphorylation and HO-1 expression. Administration of STA attenuated not only insulin resistance but also inflammation and ER stress in the skeletal muscle of high-fat diet (HFD)-fed mice. Additionally, STA-ameliorated glucose tolerance and insulin sensitivity, as well as serum TNFα and MCP-1, in mice fed a HFD. Small interfering (si) RNA-associated suppression of AMPK or HO-1 expression abolished the effects of STA in C2C12 myocytes. CONCLUSIONS: These results suggest that STA activates AMPK/HO-1 signaling, resulting in reduced inflammation and ER stress, thereby improving skeletal muscle insulin resistance. Using STA as a natural ingredient, this research successfully treated insulin resistance and type 2 diabetes.
OBJECTIVE: Insulin resistance develops due to skeletal muscle inflammation and endoplasmic reticulum (ER) stress. Stachydrine (STA), extracted from Leonurus heterophyllus, has been shown to suppress proliferation and induce apoptosis in breast cancer cells and exert anti-inflammatory properties in the brain, heart, and liver. However, the roles of STA in insulin signaling in skeletal muscle remain unclear. Herein, we examined the impacts of STA on insulin signaling in skeletal muscle under hyperlipidemic conditions and its related molecular mechanisms. METHODS: Various protein expression levels were determined by Western blotting. Levels of mouse serum cytokines were measured by ELISA. RESULTS: We found that STA-ameliorated inflammation and ER stress, leading to attenuation of insulin resistance in palmitate-treated C2C12 myocytes. STA dose-dependently enhanced AMPK phosphorylation and HO-1 expression. Administration of STA attenuated not only insulin resistance but also inflammation and ER stress in the skeletal muscle of high-fat diet (HFD)-fed mice. Additionally, STA-ameliorated glucose tolerance and insulin sensitivity, as well as serum TNFα and MCP-1, in mice fed a HFD. Small interfering (si) RNA-associated suppression of AMPK or HO-1 expression abolished the effects of STA in C2C12 myocytes. CONCLUSIONS: These results suggest that STA activates AMPK/HO-1 signaling, resulting in reduced inflammation and ER stress, thereby improving skeletal muscle insulin resistance. Using STA as a natural ingredient, this research successfully treated insulin resistance and type 2 diabetes.
Authors: Kitt Falk Petersen; Sylvie Dufour; David B Savage; Stefan Bilz; Gina Solomon; Shin Yonemitsu; Gary W Cline; Douglas Befroy; Laura Zemany; Barbara B Kahn; Xenophon Papademetris; Douglas L Rothman; Gerald I Shulman Journal: Proc Natl Acad Sci U S A Date: 2007-07-18 Impact factor: 11.205