title: Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice.
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.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kusudo
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
authors.forename: Tamaki
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan ; Nutritional Health Science Research Center, Chubu University, Kasugai, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Food Science for Health, Minami-Kyushu University, Miyazaki, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Kontani
authors.affiliation: Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okamatsu
authors.affiliation: Department of Nutrition, School of Nursing and Nutrition, Tenshi College, Sapporo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Mori
authors.affiliation: Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan ; Nutritional Health Science Research Center, Chubu University, Kasugai, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yamashita
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D032086:Evodia / Q000737:chemistry; D005260:Female; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008820:Mice, Obese; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D011799:Quinazolines; D012694:Serine; C049639:evodiamine; C546843:mTOR protein, mouse; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose