title: The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice.
abstract: OBJECTIVE
  Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects.
  
  
  METHODS
  Glucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK β1β2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation.
  
  
  RESULTS
  There was no change in weight gain, adiposity, glucose tolerance or insulin sensitivity between HFD-fed WT and AMPK-MKO mice. In both HFD-fed WT and AMPK-MKO mice, R419 enhanced insulin tolerance, insulin-stimulated glucose disposal, skeletal muscle 2-deoxyglucose uptake, Akt phosphorylation and glucose transporter 4 (GLUT4) content independently of alterations in body mass. In WT, but not AMPK-MKO mice, R419 improved treadmill running capacity. Treatment with R419 increased muscle electron transport chain content and activity in WT mice; effects which were blunted in AMPK-MKO mice.
  
  
  CONCLUSIONS
  Treatment of obese mice with R419 improved skeletal muscle insulin sensitivity through a mechanism that is independent of skeletal muscle AMPK. R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK. These findings suggest that R419 may be a promising therapy for improving whole-body glucose homeostasis and exercise capacity.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Katarina
authors.initials: K
authors.lastname: Marcinko
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Bujak
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: James S V
authors.initials: JS
authors.lastname: Lally
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Tammy H
authors.initials: TH
authors.lastname: Wong
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Brennan K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Protein Chemistry and Metabolism, St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Yonchu
authors.initials: Y
authors.lastname: Jenkins
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kinsella
authors.affiliation: Rigel Pharmaceuticals Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada ; Department of Biochemistry, McMaster University, 1280 Main St. W., Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
keywords: 2-DG, 2-deoxyglucose; ACC, acetyl-CoA carboxylase; AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; AMPK; AMPK, AMP-activated protein kinase; AMPK-MKO, skeletal muscle-specific AMPK β1β2 floxed Cre-; AUC, area under the curve; COX, cytochrome c oxidase; CT, computed tomography; Complex-I; Diabetes; EDL, extensor digitorum longus; Exercise-mimetic; GDR, glucose disposal rate; GIR, glucose infusion rate; GLUT4, glucose transporter 4; HFD, high-fat diet (45% kcal fat); HGO, hepatic glucose output; Mitochondrial; OXPHOS, proteins involved in oxidative phosphorylation (electron transport chain); Obesity; R419; R419, N-(1-(4-cyanobenzyl) piperidin-4-yl)-6-(4-(4-methoxybenzoyl) piperidine-1-carbonyl; TA, tibialis anterior; Tbp, TATA-binding protein; WT, wildtype