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Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice.
PLoS One. 2013; 8(12):e83264.Plos

Abstract

Evodiamine, an alkaloid extracted from the dried unripe fruit of the tree Evodia rutaecarpa Bentham (Rutaceae), reduces obesity and insulin resistance in obese/diabetic mice; however, the mechanism underlying the effect of evodiamine on insulin resistance is unknown. This study investigated the effect of evodiamine on signal transduction relating to insulin resistance using obese/diabetic KK-Ay mice and an in vitro adipocyte culture. There is a significant decrease in the mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (S6K) signaling in white adipose tissue (WAT) in KK-Ay mice treated with evodiamine, in which glucose tolerance is improved. In addition, reduction of insulin receptor substrate 1 (IRS1) serine phosphorylation, an indicator of insulin resistance, was detected in their WAT, suggesting suppression of the negative feedback loop from S6K to IRS1. As well as the stimulation of IRS1 and Akt serine phosphorylation, insulin-stimulated phosphorylation of mTOR and S6K is time-dependent in 3T3-L1 adipocytes, whereas evodiamine does not affect their phosphorylation except for an inhibitory effect on mTOR phosphorylation. Moreover, evodiamine inhibits the insulin-stimulated phosphorylation of mTOR and S6K, leading to down-regulation of IRS1 serine phosphorylation in the adipocytes. Evodiamine also stimulates phosphorylation of AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, which may cause down-regulation of mTOR signaling in adipocytes. A similar effect on AMPK, mTOR and IRS1 phosphorylation was found in adipocytes treated with rosiglitazone. These results suggest evodiamine improves glucose tolerance and prevents the progress of insulin resistance associated with obese/diabetic states, at least in part, through inhibition of mTOR-S6K signaling and IRS1 serine phosphorylation in adipocytes.

Authors+Show Affiliations

Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan ; Nutritional Health Science Research Center, Chubu University, Kasugai, Japan.Department of Food Science for Health, Minami-Kyushu University, Miyazaki, Japan.Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Japan.Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan ; Nutritional Health Science Research Center, Chubu University, Kasugai, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24391749

Citation

Wang, Ting, et al. "Evodiamine Inhibits Insulin-stimulated mTOR-S6K Activation and IRS1 Serine Phosphorylation in Adipocytes and Improves Glucose Tolerance in Obese/diabetic Mice." PloS One, vol. 8, no. 12, 2013, pp. e83264.
Wang T, Kusudo T, Takeuchi T, et al. Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice. PLoS ONE. 2013;8(12):e83264.
Wang, T., Kusudo, T., Takeuchi, T., Yamashita, Y., Kontani, Y., Okamatsu, Y., Saito, M., Mori, N., & Yamashita, H. (2013). Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice. PloS One, 8(12), e83264. https://doi.org/10.1371/journal.pone.0083264
Wang T, et al. Evodiamine Inhibits Insulin-stimulated mTOR-S6K Activation and IRS1 Serine Phosphorylation in Adipocytes and Improves Glucose Tolerance in Obese/diabetic Mice. PLoS ONE. 2013;8(12):e83264. PubMed PMID: 24391749.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice. AU - Wang,Ting, AU - Kusudo,Tatsuya, AU - Takeuchi,Tamaki, AU - Yamashita,Yukari, AU - Kontani,Yasuhide, AU - Okamatsu,Yuko, AU - Saito,Masayuki, AU - Mori,Nozomu, AU - Yamashita,Hitoshi, Y1 - 2013/12/31/ PY - 2013/04/22/received PY - 2013/11/01/accepted PY - 2014/1/7/entrez PY - 2014/1/7/pubmed PY - 2014/8/26/medline SP - e83264 EP - e83264 JF - PloS one JO - PLoS ONE VL - 8 IS - 12 N2 - Evodiamine, an alkaloid extracted from the dried unripe fruit of the tree Evodia rutaecarpa Bentham (Rutaceae), reduces obesity and insulin resistance in obese/diabetic mice; however, the mechanism underlying the effect of evodiamine on insulin resistance is unknown. This study investigated the effect of evodiamine on signal transduction relating to insulin resistance using obese/diabetic KK-Ay mice and an in vitro adipocyte culture. There is a significant decrease in the mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (S6K) signaling in white adipose tissue (WAT) in KK-Ay mice treated with evodiamine, in which glucose tolerance is improved. In addition, reduction of insulin receptor substrate 1 (IRS1) serine phosphorylation, an indicator of insulin resistance, was detected in their WAT, suggesting suppression of the negative feedback loop from S6K to IRS1. As well as the stimulation of IRS1 and Akt serine phosphorylation, insulin-stimulated phosphorylation of mTOR and S6K is time-dependent in 3T3-L1 adipocytes, whereas evodiamine does not affect their phosphorylation except for an inhibitory effect on mTOR phosphorylation. Moreover, evodiamine inhibits the insulin-stimulated phosphorylation of mTOR and S6K, leading to down-regulation of IRS1 serine phosphorylation in the adipocytes. Evodiamine also stimulates phosphorylation of AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, which may cause down-regulation of mTOR signaling in adipocytes. A similar effect on AMPK, mTOR and IRS1 phosphorylation was found in adipocytes treated with rosiglitazone. These results suggest evodiamine improves glucose tolerance and prevents the progress of insulin resistance associated with obese/diabetic states, at least in part, through inhibition of mTOR-S6K signaling and IRS1 serine phosphorylation in adipocytes. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24391749/Evodiamine_inhibits_insulin_stimulated_mTOR_S6K_activation_and_IRS1_serine_phosphorylation_in_adipocytes_and_improves_glucose_tolerance_in_obese/diabetic_mice_ L2 - http://dx.plos.org/10.1371/journal.pone.0083264 DB - PRIME DP - Unbound Medicine ER -