Preservation of Metabolic Flexibility in Skeletal Muscle by a Combined Use of n-3 PUFA and Rosiglitazone in Dietary Obese Mice

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.

DHA at nutritional doses restores insulin sensitivity in skeletal muscle by preventing lipotoxicity and inflammation

“…Altogether, these observations suggest an improvement in the activity of β-oxidation and a better metabolic coupling between β-oxidation and the TCA cycle to overcome and limit the excess of FA. In agreement with this, metabolic explorations identified a better mitochondrial FA β-oxidation in mice fed with an imbalanced diet and supplemented with LC n-3 PUFA [60]. The modulation of the β-oxidation process by DHA could be a key element against the accumulation of reactive lipid metabolites and the related metabolic disturbances, such as IR.…”

Omega-3 Fatty Acid Improve Non Alcoholic Fatty Liver Induced by High Fat Diet in Rats.

“…The mechanisms governing the accumulation of TGs in hepatic cells include changes in hepatocellular metabolism, [23,24] propagating an imbalance between uptake and de novo fatty acid synthesis, VLDL formation and subsequent export, and oxidation capacity [25].The present study also revealed that treatment with omega-3 fatty acid showed significant reduction in the level of triglycerides and NEFA in plasma compared to those of HFD treated group. This is in agreement with the previous [26,27]which supports the triglyceride-lowering properties of omega-3 fatty acid and decreased NEFA level in plasma. This could be explained by changes in transcription of several nuclear receptors are reported to mediate the TG-reducing effects of omega-3 fatty acid: sterol regulatory element binding proteins (SREBP), liver X receptor-alpha (LXRα), retinoid X receptor alpha (RXRα), farnesoid X receptor (FXR), and peroxisome proliferator-activated receptors (PPARs), and each play prominent roles in controlling lipid metabolism.…”

Omega-3 fatty acids and adipose tissue function in obesity and metabolic syndrome

“…Thus, some studies support that n-3 PUFAs can significantly decrease body weight and fat mass [36][37][38][39][40][41][42][43][44][45][46][47]. Other trials did not find any significant action on body weight loss but a significant reduction in some fat depots was observed in n-3 PUFAs supplemented groups [45,[48][49][50].…”