TY - JOUR

T1 - Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation

AU - Lundsgaard, Annemarie

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 A

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 fatty acids (FAs) have been proposed to promote insulin resistance of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate insulin resistance. 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, in combination with short-term 45% high fat diet feeding to increase FA availability. Etomoxir acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in liver and heart within hours. Several days of FAOX inhibition by daily Etomoxir administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by Etomoxir. Reduced whole body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) UCP1 protein content, diminished BAT glucose clearance, and an increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat insulin resistance and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.

AB - Excessive circulating fatty acids (FAs) have been proposed to promote insulin resistance of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate insulin resistance. 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, in combination with short-term 45% high fat diet feeding to increase FA availability. Etomoxir acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in liver and heart within hours. Several days of FAOX inhibition by daily Etomoxir administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by Etomoxir. Reduced whole body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) UCP1 protein content, diminished BAT glucose clearance, and an increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat insulin resistance 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

VL - 61

SP - 10

EP - 19

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 1

ER -