title: Global metabolite profiling of mice with high-fat diet-induced obesity chronically treated with AMPK activators R118 or metformin reveals tissue-selective alterations in metabolic pathways.
abstract: BACKGROUND
  The novel small molecule R118 and the biguanide metformin, a first-line therapy for type 2 diabetes (T2D), both activate the critical cellular energy sensor 5'-AMP-activated protein kinase (AMPK) via modulation of mitochondrial complex I activity. Activation of AMPK results in both acute responses and chronic adaptations, which serve to restore energy homeostasis. Metformin is thought to elicit its beneficial effects on maintenance of glucose homeostasis primarily though impacting glucose and fat metabolism in the liver. Given the commonalities in their mechanisms of action and that R118 also improves glucose homeostasis in a murine model of T2D, the effects of both R118 and metformin on metabolic pathways in vivo were compared in order to determine whether R118 elicits its beneficial effects through similar mechanisms.
  
  
  RESULTS
  Global metabolite profiling of tissues and plasma from mice with diet-induced obesity chronically treated with either R118 or metformin revealed tissue-selective effects of each compound. Whereas metformin treatment resulted in stronger reductions in glucose and lipid metabolites in the liver compared to R118, upregulation of skeletal muscle glycolysis and lipolysis was apparent only in skeletal muscle from R118-treated animals. Both compounds increased β-hydroxybutyrate levels, but this effect was lost after compound washout. Metformin, but not R118, increased plasma levels of metabolites involved in purine metabolism.
  
  
  CONCLUSIONS
  R118 treatment but not metformin resulted in increased glycolysis and lipolysis in skeletal muscle. In contrast, metformin had a greater impact than R118 on glucose and fat metabolism in liver tissue.
authors.affiliation: Rigel Pharmaceuticals, Inc,, South San Francisco, CA, USA. yjenkins@rigel.com.
authors.forename: Yonchu
authors.initials: Y
authors.lastname: Jenkins
authors.forename: Tian-Qiang
authors.initials: TQ
authors.lastname: Sun
authors.forename: Yingwu
authors.initials: Y
authors.lastname: Li
authors.forename: Vadim
authors.initials: V
authors.lastname: Markovtsov
authors.forename: Gerald
authors.initials: G
authors.lastname: Uy
authors.forename: Lisa
authors.initials: L
authors.lastname: Gross
authors.forename: Dane A
authors.initials: DA
authors.lastname: Goff
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Shaw
authors.forename: Luke
authors.initials: L
authors.lastname: Boralsky
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Hitoshi
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D008687:Metformin; D000263:Adenylate Kinase