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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.

journal_name

Mol Metab

journal_title

Molecular metabolism

authors

Marcinko K,Bujak AL,Lally JS,Ford RJ,Wong TH,Smith BK,Kemp BE,Jenkins Y,Li W,Kinsella TM,Hitoshi Y,Steinberg GR

doi

10.1016/j.molmet.2015.06.002

subject

Has Abstract

pub_date

2015-06-15 00:00:00

pages

643-51

issue

issn

2212-8778

pii

S2212-8778(15)00096-4

journal_volume

pub_type

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The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice.