title: Inhibition of mitochondrial fatty acid oxidation in vivo only slightly suppresses gluconeogenesis but enhances clearance of glucose in mice.
abstract: Mitochondrial fatty acid oxidation (mFAO) is considered to be essential for driving gluconeogenesis (GNG) during fasting. However, quantitative in vivo data on de novo synthesis of glucose-6-phosphate upon acute inhibition of mFAO are lacking. We assessed hepatic glucose metabolism in vivo after acute inhibition of mFAO by 30 mg kg(-1) 2-tetradecylglycidic acid (TDGA) in hypoketotic hypoglycemic male C57BL/6J mice by the infusion of [U-(13)C]glucose, [2-(13)C]glycerol, [1-(2)H]galactose, and paracetamol for 6 hours, which was followed by mass isotopomer distribution analysis in blood glucose and urinary paracetamol-glucuronide. During TDGA treatment, endogenous glucose production was unaffected (127 +/- 10 versus 118 +/- 7 micromol kg(-1) minute(-1), control versus TDGA, not significant), but the metabolic clearance rate of glucose was significantly enhanced (15.9 +/- 0.9 versus 26.3 +/- 1.1 mL kg(-1) minute(-1), control versus TDGA,P < 0.05). In comparison with control mice, de novo synthesis of glucose-6-phosphate (G6P) was slightly decreased in TDGA-treated mice (108 +/- 19 versus 85 +/- 6 micromol kg(-1) minute(-1), control versus TDGA, P < 0.05). Recycling of glucose was decreased upon TDGA treatment (26 +/- 14 versus 12 +/- 4 micromol kg(-1) minute(-1), control versus TDGA, P < 0.05). Hepatic messenger RNA (mRNA) levels of genes encoding enzymes involved in de novo G6P synthesis were unaltered, whereas glucose-6-phosphate hydrolase mRNA expressions were increased in TDGA-treated mice. Glucokinase and pyruvate kinase mRNA levels were significantly decreased, whereas pyruvate dehydrogenase kinase isozyme 4 expression was increased 30-fold; this suggested decreased glycolytic activity.
  
  
  CONCLUSIONS
  Acute pharmacological inhibition of mFAO using TDGA had no effect on endogenous glucose production and only a marginal effect on de novo G6P synthesis. Hence, fully active mFAO is not essential for maintenance of hepatic GNG in vivo in fasted mice.
authors.affiliation: Department of Pediatrics, Laboratory of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Terry G J
authors.initials: TG
authors.lastname: Derks
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Rake
authors.forename: G Peter A
authors.initials: GP
authors.lastname: Smit
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
mesh_terms: D000818:Animals; D004852:Epoxy Compounds / Q000494:pharmacology; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism* / Q000494:pharmacology; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
chemical_list: D004852:Epoxy Compounds; D005227:Fatty Acids; D012333:RNA, Messenger; D005941:Glucokinase; D011770:Pyruvate Kinase; D005952:Glucose-6-Phosphatase; D005947:Glucose; C021756:2-tetradecylglycidic acid