Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance.
Tetradecylthioacetic acid (TTA) is a non-beta-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 PPARalpha > PPARdelta > PPARgamma. Expression of PPARgamma target genes in adipose tissue was unaffected by TTA treatment, whereas the hepatic expression of PPARalpha-responsive genes encoding enzymes involved in fatty acid uptake, transport, and oxidation was induced. This was accompanied by increased hepatic mitochondrial beta-oxidation and a decreased fatty acid/ketone body ratio in plasma. These findings indicate that PPARalpha-dependent mechanisms play a pivotal role, but additionally, the involvement of PPARalpha-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
Lise
L
Department of Clinical Biochemistry, University of Bergen, Haukeland Hospital, N-5021 Bergen, Norway.
Guerre-Millo
Michéle
M
Flindt
Esben N
EN
Berge
Kjetil
K
Tronstad
Karl Johan
KJ
Bergene
Elin
E
Sebokova
Elena
E
Rustan
Arild C
AC
Jensen
Jørgen
J
Mandrup
Susanne
S
Kristiansen
Karsten
K
Klimes
Iwar
I
Staels
Bart
B
Berge
Rolf K
RK
D000273:Adipose Tissue / Q000033:anatomy & histology* / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004041:Dietary Fats / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D012016:Reference Values; D013440:Sulfides / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D000975:Antioxidants; D004041:Dietary Fats; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D013440:Sulfides; D014157:Transcription Factors; D014280:Triglycerides; C062078:1-(carboxymethylthio)tetradecane