TY - JOUR
T1 - Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation
AU - Lundsgaard, Anne-Marie
AU - Fritzen, Andreas Mæchel
AU - Nicolaisen, Trine Sand
AU - Carl, Christian Strini
AU - Sjøberg, Kim Anker
AU - Raun, Steffen Henning
AU - Klein, Anders Bue
AU - Sanchez-Quant, Eva
AU - Langer, Jakob
AU - Ørskov, Cathrine
AU - Clemmensen, Christoffer
AU - Tschöp, Matthias H
AU - Richter, Erik
AU - Kiens, Bente
AU - Kleinert, Maximilian
N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Faculty of Science
KW - CPT-1
KW - Mitochondrial long-chain fatty acid import
KW - Hepatic glucose production
KW - Brown adipose tissue
KW - Liver
KW - Hyperglycemia
KW - Lipotoxicity
KW - Fatty acids
KW - Insulin resistance
U2 - 10.1194/jlr.ra119000177
DO - 10.1194/jlr.ra119000177
M3 - Journal article
C2 - 31719103
SN - 0022-2275
JO - Journal of Lipid Research
JF - Journal of Lipid Research
ER -