Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0081870
Title: AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes
Authors: Jenkins Y.
Sun T.-Q.
Markovtsov V.
Foretz M.
Li W.
Nguyen H.
Li Y.
Pan A.
Uy G.
Gross L.
Baltgalvis K.
Yung S.L.
Gururaja T.
Kinoshita T.
Owyang A.
Smith I.J.
McCaughey K.
White K.
Godinez G.
Alcantara R.
Choy C.
Ren H.
Basile R.
Sweeny D.J.
Xu X.
Issakani S.D.
Carroll D.C.
Goff D.A.
Shaw S.J.
Singh R. 
Boros L.G.
Laplante M.-A.
Marcotte B.
Kohen R.
Viollet B.
Marette A.
Payan D.G.
Kinsella T.M.
Hitoshi Y.
Keywords: branched chain amino acid
glucose
glucose c 13
hydroxymethylglutaryl coenzyme A reductase kinase
hydroxymethylglutaryl coenzyme A reductase kinase activator
metformin
palmitic acid c 13
r 419
radiopharmaceutical agent
reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone)
unclassified drug
adipose tissue
animal cell
animal experiment
animal model
animal tissue
article
catabolism
concentration response
controlled study
diabetes mellitus
drug mechanism
drug potency
drug structure
enzyme activation
enzyme inhibition
fatty acid oxidation
gluconeogenesis
glucose homeostasis
glucose oxidation
glucose transport
human
human cell
in vitro study
in vivo study
lipid metabolism
lipogenesis
liver
male
metabolic parameters
metabolomics
mitochondrial respiration
mouse
muscle cell
nonhuman
nutrient dynamics
signal transduction
skeletal muscle
Amino Acids, Branched-Chain
AMP-Activated Protein Kinases
Animals
Diabetes Mellitus, Experimental
Enzyme Activation
Fatty Acids
Glucose
Hep G2 Cells
Humans
Hypoglycemic Agents
Metformin
Mice
Mitochondria, Liver
Muscle Cells
Oxidation-Reduction
Palmitates
Protein Kinase Inhibitors
Issue Date: 2013
Citation: Jenkins Y., Sun T.-Q., Markovtsov V., Foretz M., Li W., Nguyen H., Li Y., Pan A., Uy G., Gross L., Baltgalvis K., Yung S.L., Gururaja T., Kinoshita T., Owyang A., Smith I.J., McCaughey K., White K., Godinez G., Alcantara R., Choy C., Ren H., Basile R., Sweeny D.J., Xu X., Issakani S.D., Carroll D.C., Goff D.A., Shaw S.J., Singh R., Boros L.G., Laplante M.-A., Marcotte B., Kohen R., Viollet B., Marette A., Payan D.G., Kinsella T.M., Hitoshi Y. (2013). AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. PLoS ONE 8 (12) : e81870. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0081870
Rights: Attribution 4.0 International
Abstract: Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK-dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both 13C-palmitate and 13C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models. Copyright © 2013 Jenkins et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161450
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0081870
Rights: Attribution 4.0 International
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