Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

• Published in: Journal of lipid research Vol. 61; no. 1; pp. 10 - 19
• Main Authors: Lundsgaard, Anne-Marie, Fritzen, Andreas M., Nicolaisen, Trine S., Carl, Christian S., Sjøberg, Kim A., Raun, Steffen H., Klein, Anders B., Sanchez-Quant, Eva, Langer, Jakob, Ørskov, Cathrine, Clemmensen, Christoffer, Tschöp, Matthias H., Richter, Erik A., Kiens, Bente, Kleinert, Maximilian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2020; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; brown adipose tissue; carnitine palmitoyltransferase 1; Diet, High-Fat; Epoxy Compounds - administration & dosage; Epoxy Compounds - pharmacology; Fatty Acids - chemistry; Fatty Acids - metabolism; Glucose - metabolism; Glucose Intolerance - metabolism; hepatic glucose production; hyperglycemia; insulin resistance; lipotoxicity; liver; Male; Mice; Mice, Inbred C57BL; mitochondrial long-chain fatty acid import; Oxidation-Reduction - drug effects; hyperglycemia; hepatic glucose production; brown adipose tissue; liver; carnitine palmitoyltransferase 1; lipotoxicity; insulin resistance; mitochondrial long-chain fatty acid import
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.RA119000177

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.