5-HEPE reduces obesity and insulin resistance by promoting adipose tissue browning through GPR119/AMPK/PGC1α activation

Activating thermogenic program in brown adipocytes serves as a potential therapeutic target for increasing energy expenditure during the treatment of metabolic diseases. 5(S)-hydroxy-eicosapentaenoic acid (5-HEPE), an omega-3 unsaturated fatty acid metabolite, has been shown to enhance insulin secretion in vitro. However, its role in modulating obesity-related diseases remains largely unclear. To investigate this further, mice were fed with a high-fat diet for 12 weeks and then injected intraperitoneally every other day with 5-HEPE for 4 additional weeks. In vivo, our results demonstrated that 5-HEPE alleviated the HFD-induced obesity and insulin resistance, leading to a significant decrease in subcutaneous fat and epididymal fat index and an increase in brown fat index. Compared to the HFD group, the 5-HEPE group mice had lower ITT and GTT AUC and lower HOMA-IR. Moreover, 5HEPE effectively increased energy expenditure of mice. 5-HEPE also significantly promoted brown adipose tissue (BAT) activation and browning in white adipose tissue (WAT) by up-regulating genes and proteins expression of UCP1, Prdm16, Cidea, and PGC1α. In vitro, we found 5-HEPE significantly promoted 3T3-L1 browning. Mechanistically, 5-HEPE acts by activating the GPR119/AMPK/PGC1α pathway. In conclusion, this study emphasizes a critical role of 5-HEPE in improving body energy metabolism and adipose tissue browning in HFD-fed mice. Our results suggest that 5-HEPE intervention may be an effective target for preventing obesity-related metabolic diseases.