Fish Oil and EPA Improve Insulin Sensitivity, in Part Through Adipocyte mTORC2 Activation in Diet‐Induced Obese Male Mice

ABSTRACT Fish oil rich in omega‐3 polyunsaturated fatty acids ( n ‐3 PUFAs) improves rodent glucose homeostasis and insulin sensitivity through unknown mechanisms. We investigated the involvement of adipocyte Rictor/mTORC2 as a mediator of fish oil and n ‐3 PUFA eicosapentaenoic acid (EPA) effects. Male mice bearing or not Rictor/mTORC2 deficiency in adipocytes were fed isocaloric high fat diets produced either with lard (HFD) or fish oil (HFn3) and evaluated for glucose homeostasis and insulin sensitivity. HFn3 intake improved glucose tolerance and insulin sensitivity, increased glucose uptake in adipose tissue and skeletal muscle per unit of insulin, and reduced hepatic glucose production as well as adipose tissue and liver de novo fatty acid synthesis. Interestingly, this improvement in glucose homeostasis was concurrent with low serum insulin levels and increased content of Ser473 phosphorylated (p) Akt in adipose tissue, but not skeletal muscle and liver. Intake of an HFD supplemented with EPA increased, in an mTORC2‐dependent manner, insulin sensitivity and adipocyte pAkt Ser473, but not glucose tolerance. In conclusion, adipocyte mTORC2 mediates in part the improvement in insulin sensitivity induced by fish oil and EPA, while the improvement in glucose tolerance induced by fish oil seems to be triggered by mTORC2‐independent actions in muscle and liver.