Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation.

Abstract

Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.

• Authors: Anne-Marie Lundsgaard, Andreas M Fritzen, Trine S Nicolaisen, Christian S Carl, Kim A Sjøberg, Steffen H Raun, Anders B Klein, Eva Sanchez-Quant, Jakob Langer, Cathrine Ørskov, Christoffer Clemmensen, Matthias H Tschöp, Erik A Richter, Bente Kiens, Maximilian Kleinert
• Journal: Journal of lipid research (J Lipid Res) Vol. 61 Issue 1 Pg. 10-19 (01 2020) ISSN: 1539-7262 [Electronic] United States
• PMID: 31719103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Lundsgaard et al.

Chemical References

• Epoxy Compounds
• Fatty Acids
• Glucose
• etomoxir

Topics

• Animals
• Diet, High-Fat
• Epoxy Compounds (administration & dosage, pharmacology)
• Fatty Acids (chemistry, metabolism)
• Glucose (metabolism)
• Glucose Intolerance (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidation-Reduction (drug effects)