Abstract
Insulin resistance, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. This, in turn, contributes to a further damage of insulin signaling. Effectiveness of T2D treatment depends in large part on the improvement of insulin sensitivity and metabolic adaptability of the muscle, the main site of whole-body glucose utilization. We have shown previously in mice fed an obesogenic high-fat diet that a combined use of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinediones (TZDs), anti-diabetic drugs, preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether n-3 LC-PUFA could elicit additive beneficial effects on metabolic flexibility when combined with a TZD drug rosiglitazone. Adult male C57BL/6N mice were fed an obesogenic corn oil–based high-fat diet (cHF) for 8 weeks, or randomly assigned to various interventions: cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids (cHF+F), cHF with 10 mg rosiglitazone/kg diet (cHF+ROSI), cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combined intervention. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the interventions, with n-3 LC-PUFA supporting complete oxidation of fatty acids in mitochondria and the combination with n-3 LC-PUFA and rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combined use of n-3 LC-PUFA and TZDs could improve the efficacy of the therapy of obese and diabetic patients.
Highlights
Combined treatments with multiple mechanisms of action are required for a better handling of metabolic diseases associated with obesity [1,2,3,4]
Motivated by our findings revealing synergistic effect of the combined use of n-3 LC-PUFA and rosiglitazone on muscle insulin sensitivity in dietary obese mice, and by the fact that skeletal muscle is the main site of glucose uptake [35], we aimed to verify a hypothesis that improvement of metabolic flexibility is an important part of the beneficial effects of the combined intervention
(i) in agreement with a previous study in rats [55], corn oil–based high-fat diet (cHF)+F diet, but not cHF+ROSI diet, increased respiratory exchange ratio (RER) values in mice re-fed Chow, in spite of the absence of an effect on body weight by neither of the single intervention; (ii) both metabolomic and gene expression analyses in the muscle documented several body weight-independent changes induced by the interventions; and (iii) dietary supplementation with n-3 LC-PUFA, either in combination with rosiglitazone [14,32] or pioglitazone [32] resulted in a synergistic induction of adiponectin, while elevated adiponectin levels were found to be associated with enhanced metabolic flexibility [56]
Summary
Combined treatments with multiple mechanisms of action are required for a better handling of metabolic diseases associated with obesity [1,2,3,4]. Occurring n-3 long-chain polyunsaturated fatty acids (n3 LC-PUFA), namely eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) are regarded as healthy constituents of diets for diabetic patients [6,7,8] These lipids, which are abundant in sea fish, act as hypolipidemics and augment the efficacy of the lipid-lowering drugs [4], and reduce cardiac events and decrease progression of atherosclerosis Numerous animal studies demonstrated reduced accumulation of body fat in response to dietary n-3 LC-PUFA supplementation [11,12,13,14,15,16,17,18], especially when combined with calorie restriction [19], reflecting possibly reduced proliferation of fat cells [12,20], and/or metabolic changes in the liver [15,21], adipose tissue [13,19], and intestine [22]. Only few randomized clinical trials demonstrated a reduction of adiposity after n-3 LCPUFA supplementation [23,24,25,26], while other studies in humans
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