title: AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes.
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 (13)C-palmitate and (13)C-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.
authors: Rigel Pharmaceuticals, Inc., South San Francisco, California, United States of America.
authors: Yonchu
authors: Y
authors: Jenkins
authors: Tian-Qiang
authors: TQ
authors: Sun
authors: Vadim
authors: V
authors: Markovtsov
authors: Marc
authors: M
authors: Foretz
authors: Wei
authors: W
authors: Li
authors: Henry
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authors: Nguyen
authors: Yingwu
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authors: Li
authors: Alison
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authors: Pan
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authors: Uy
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authors: Baltgalvis
authors: Stephanie L
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authors: Tarikere
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authors: Gururaja
authors: Taisei
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authors: Kinoshita
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authors: Owyang
authors: Ira J
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authors: McCaughey
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authors: White
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authors: Godinez
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authors: SD
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authors: David C
authors: DC
authors: Carroll
authors: Dane A
authors: DA
authors: Goff
authors: Simon J
authors: SJ
authors: Shaw
authors: Rajinder
authors: R
authors: Singh
authors: Laszlo G
authors: LG
authors: Boros
authors: Marc-André
authors: MA
authors: Laplante
authors: Bruno
authors: B
authors: Marcotte
authors: Rita
authors: R
authors: Kohen
authors: Benoit
authors: B
authors: Viollet
authors: André
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authors: Marette
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authors: DG
authors: Payan
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authors: Kinsella
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authors: Hitoshi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D032342:Muscle Cells / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010168:Palmitates / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000597:Amino Acids, Branched-Chain; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D010168:Palmitates; D047428:Protein Kinase Inhibitors; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005947:Glucose