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Lundsgaard, A.M.* ; Fritzen, A.M.* ; Nicolaisen, T.S.* ; Carl, C.S.* ; Sjøberg, K.A.* ; Raun, S.H.* ; Klein, A.B.* ; Sánchez Quant, E.S. ; Langer, J. ; Ørskov, C.* ; Clemmensen, C.* ; Tschöp, M.H. ; Richter, E.A.* ; Kiens, B.* ; Kleinert, M.

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

J. Lipid Res. 61, 10-19 (2020)
Publ. Version/Full Text Preprint DOI PMC
Open Access Gold (Paid Option)
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Brown Adipose Tissue ; Carnitine Palmitoyltransferase 1 ; Hepatic Glucose Production ; Hyperglycemia ; Insulin Resistance ; Lipotoxicity ; Liver ; Mitochondrial Long-chain Fatty Acid Import; Alleviates Insulin-resistance; Skeletal-muscle; Adipose-tissue; Substrate Oxidation; Etomoxir; Metabolism; Obesity; Thermogenesis; Contribute; Lipolysis
ISSN (print) / ISBN 0022-2275
e-ISSN 1539-7262
Journal Journal of Lipid Research
Quellenangaben Volume: 61, Issue: 1, Pages: 10-19 Article Number: , Supplement: ,
Publisher American Society for Biochemistry and Molecular Biology
Publishing Place 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)