Inhibition of mitochondrial fatty acid oxidation in vivo only slightly suppresses gluconeogenesis but enhances clearance of glucose in mice
Open Access
- 7 January 2008
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 47 (3), 1032-1042
- https://doi.org/10.1002/hep.22101
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-13C]glucose, [2-13C]glycerol, [1-2H]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 μmol 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 μmol kg−1 minute−1, control versus TDGA, P < 0.05). Recycling of glucose was decreased upon TDGA treatment (26 ± 14 versus 12 ± 4 μmol 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. Conclusion: 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.(HEPATOLOGY 2008.)Keywords
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