Long‐term dietary EPA or DHA supplementation do not ameliorate obesity but improve glucose homeostasis via gut‐adipose axis in already obese mice

Abstract

Obesity has reached pandemic levels and brought increased epidemic of obesity‐related metabolic disorders. Numerous works have reported the preventive effect of omega‐3 fatty acids on the development of obesity. But it is still unclear how omega‐3 fatty acids improve the obesity‐driven homeostatic imbalance. Here we investigated the biological effects of eicosapentaenoic acid (EPA; 20:5n3) and docosahexaenoic acid (DHA; 22:6n3) from long‐term dietary intake on lipid, glucose and energy homeostasis in high‐fat‐diet (HFD) induced obese (DIO) mice. Four‐week‐old C57Bl/6 mice were fed with high‐fat‐diets (HFD; 45% fat) for 10 weeks to introduce obesity. The HFD fed mice were then trisected and fed with DHA or EPA enriched HFD (HFD+DHA or HFD+EPA; 1% wt/wt) or HFD for 15 weeks. DHA or EPA supplementation did not significantly change the bodyweight of mice (HFD+DHA or HFD+EPA vs HFD). Nonetheless, DHA supplementation significantly reduced subcutaneous fat in male mice and both DHA and EPA lowered liver weight in female mice. Interestingly, DHA or EPA administration improved hypercholesterolemia but aggravated hypertriglyceridemia. Importantly, DHA or EPA administration reversed HFD‐induced gut dysbiosis and maintained mucosal thickness followed by alleviated metabolic endotoxemia. Notably, short chain fatty acids (SCFA) production was not affected whereas circulating serotonin was significantly increased in DHA or EPA‐fed mice. In addition, DHA or EPA ameliorated glucose tolerance and insulin resistance through the up‐regulation of Glut4 and phosphorylation of Akt in adipose tissue. Micro‐positron emission tomography/computed tomography (micro‐PET/CT) analysis showed that DHA or EPA administration promoted thermogenesis of brown adipose tissue in both male and female mice. Though oxygen consumption was not affected, DHA or EPA significantly lowered the respiratory exchange ratio (RER) of DIO mice, suggesting enhanced lipid mobilization. In conclusion, these findings reveal the effects of DHA and EPA on obesity‐driven imbalance of lipid, glucose and energy homeostasis and further clinical investigations are warranted to formulate recommendations of DHA and EPA intakes for obese subjects.