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Journal of Lipid Research, Vol. 43, 742-750, May 2002
Copyright © 2002 by Lipid Research, Inc.

Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance

Lise Madsen^*, Michéle Guerre-Millo, Esben N. Flindt, Kjetil Berge^*, Karl Johan Tronstad^*, Elin Bergene^**,, Elena Sebokova^**, Arild C. Rustan, Jørgen Jensen, Susanne Mandrup, Karsten Kristiansen, Iwar Klimes^**, Bart Staels^*** and Rolf K. Berge^1,*

^* Department of Clinical Biochemistry, University of Bergen, Haukeland Hospital, N-5021 Bergen, Norway
U465 INSERM, Institut Biomédical des Cordeliers, Paris, France
Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark
^** Diabetes and Nutrition Research Laboratory, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
Department of Pharmacology, School of Pharmacy, University of Oslo, Oslo, Norway
National Institute of Occupational Health, Oslo, Norway
^*** UR545 INSERM, Department d'Athérosclerose, Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France

¹ To whom correspondence should be addressed. e-mail: rolf.berge{at}ikb.uib.no

Tetradecylthioacetic acid (TTA) is a non-ß-oxidizable fatty acid analog, which potently regulates lipid homeostasis. Here we evaluate the ability of TTA to prevent diet-induced and genetically determined adiposity and insulin resistance. In Wistar rats fed a high fat diet, TTA administration completely prevented diet-induced insulin resistance and adiposity. In genetically obese Zucker (fa/fa) rats TTA treatment reduced the epididymal adipose tissue mass and improved insulin sensitivity. All three rodent peroxisome proliferator-activated receptor (PPAR) subtypes were activated by TTA in the ranking order PPAR > PPAR > PPAR. Expression of PPAR target genes in adipose tissue was unaffected by TTA treatment, whereas the hepatic expression of PPAR-responsive genes encoding enzymes involved in fatty acid uptake, transport, and oxidation was induced. This was accompanied by increased hepatic mitochondrial ß-oxidation and a decreased fatty acid/ketone body ratio in plasma. These findings indicate that PPAR-dependent mechanisms play a pivotal role, but additionally, the involvement of PPAR-independent pathways is conceivable. Taken together, our results suggest that a TTA-induced increase in hepatic fatty acid oxidation and ketogenesis drains fatty acids from blood and extrahepatic tissues and that this contributes significantly to the beneficial effects of TTA on fat mass accumulation and peripheral insulin sensitivity.—Madsen, L., M. Guerre-Millo, E. N. Flindt, K. Berge, K. J. Tronstad, E. Bergene, E. Sebokova, A. C. Rustan, J. Jensen, S. Mandrup, K. Kristiansen, I. Klimes, B. Staels, and R. K. Berge. Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance. J. Lipid Res. 2002. 43: 742–750.

Abbreviations: CMC, carboxymethyl cellulose; CPT, carnitine palmitoyltransferase; FATP, fatty acid transport protein; L-FABP, liver fatty acid binding protein; PPAR, peroxisome proliferator-activated receptor; TTA, tetradecylthioacetic acid

Supplementary key words fatty acid analogues • insulin action • fatty acid oxidation • PPAR • CPT-I • CPT-II

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