Abstract
Tetradecylthioacetic acid (TTA) is a non-β-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 PPARα > PPARδ > PPARγ. Expression of PPARγ target genes in adipose tissue was unaffected by TTA treatment, whereas the hepatic expression of PPARα-responsive genes encoding enzymes involved in fatty acid uptake, transport, and oxidation was induced. This was accompanied by increased hepatic mitochondrial β-oxidation and a decreased fatty acid/ketone body ratio in plasma. These findings indicate that PPARα-dependent mechanisms play a pivotal role, but additionally, the involvement of PPARα-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.
Highlights
Tetradecylthioacetic acid (TTA) is a non--oxidizable fatty acid analog, which potently regulates lipid homeostasis
Inclusion of tetradecylthioacetic acid (TTA) in the high fat diet prevented the relative increase in adipose tissue mass (Table 1) without a concomitant decrease in food consumption
We demonstrate that inclusion of TTA in a high fat diet completely prevented the development of insulin resistance and adiposity
Summary
Tetradecylthioacetic acid (TTA) is a non--oxidizable fatty acid analog, which potently regulates lipid homeostasis. 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 -oxidation and a decreased fatty acid/ketone body ratio in plasma. Prolonged feeding of TTA to rats changes the fatty acid composition in liver, heart, kidney, and adipose tissue [15,16,17] These observations prompted us to investigate whether TTA could prevent high fat diet induced insulin resis-
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