Additive Effects of Omega-3 Fatty Acids and Thiazolidinediones in Mice Fed a High-Fat Diet: Triacylglycerol/Fatty Acid Cycling in Adipose Tissue.

Kristina Bardova,Pavel Flachs,Radek Pohl,Ilaria Irodenko,Michal Hensler,Petr Zouhar,Martin Rossmeisl,Petra Janovska,Katerina Adamcova,Ondrej Kuda,Jan Kopecky,Jiri Funda,Olga Horakova,Jerry Colca,Lucie Lenkova,Tomas Cajka

doi:10.3390/nu12123737

Abstract

Long-chain n-3 polyunsaturated fatty acids (Omega-3) and anti-diabetic drugs thiazolidinediones (TZDs) exhibit additive effects in counteraction of dietary obesity and associated metabolic dysfunctions in mice. The underlying mechanisms need to be clarified. Here, we aimed to learn whether the futile cycle based on the hydrolysis of triacylglycerol and re-esterification of fatty acids (TAG/FA cycling) in white adipose tissue (WAT) could be involved. We compared Omega-3 (30 mg/g diet) and two different TZDs—pioglitazone (50 mg/g diet) and a second-generation TZD, MSDC-0602K (330 mg/g diet)—regarding their effects in C57BL/6N mice fed an obesogenic high-fat (HF) diet for 8 weeks. The diet was supplemented or not by the tested compound alone or with the two TZDs combined individually with Omega-3. Activity of TAG/FA cycle in WAT was suppressed by the obesogenic HF diet. Additive effects in partial rescue of TAG/FA cycling in WAT were observed with both combined interventions, with a stronger effect of Omega-3 and MSDC-0602K. Our results (i) supported the role of TAG/FA cycling in WAT in the beneficial additive effects of Omega-3 and TZDs on metabolism of diet-induced obese mice, and (ii) showed differential modulation of WAT gene expression and metabolism by the two TZDs, depending also on Omega-3.

Highlights

The prevention and treatment of obesity and associated pathologies, namely, dyslipidemia, type 2 diabetes, hepatosteatosis, cardiovascular disease and cancer, represent major challenges for the healthcare system
Our results indicated that beneficial effects of Omega-3 on plasma lipids, glucose homeostasis and liver fat accumulation in diet-induced obese mice were linked to the stimulation of mitochondrial biogenesis [36] and oxidative phosphorylation (OXPHOS) activity [6] in epididymal white adipose tissue (WAT), and probably TAG/fatty acid (FA) cycling in this tissue [37]
Focused on the mainCycling goal ofActivity this study, verification of the hypothesis that the combined interventions using TZDs and Omega-3 exert an additive effect on TAG/FA cycling in WAT of mice fed

Summary

Introduction

The prevention and treatment of obesity and associated pathologies, namely, dyslipidemia, type 2 diabetes, hepatosteatosis, cardiovascular disease and cancer, represent major challenges for the healthcare system. Long-chain n-3 polyunsaturated fatty acids (Omega-3) in the diet, such as eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), exert broad benefits on health (reviewed in [1,2,3,4,5]). These lipids act as natural hypolipidemics, reduce accumulation of hepatic lipids ([6,7]; reviewed in [8]), increase plasma levels of adiponectin ([9]; reviewed in [10]), ameliorate low-grade inflammation in obesity [11] and enhance intestinal fatty acid (FA) oxidation [12,13]. Animal experiments document the beneficial effects of Omega-3 on insulin sensitivity and glucose metabolism even under conditions of established insulin resistance

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