Objective: Fat-1 transgenic mice were used as a model to study the effect of endogenous n-3 polyunsaturated fatty acids (n-3PUFAs) on the body weight, inflammatory factors and autophagy proteins in hypothalamus to explore the mechanism of n-3PUFAs inhibiting obesity. Method: The mice were divided into two groups after genotype identification: fat-1 transgenic mice and wild-type mice. The body weight and body length of mice were measured at 14th week, and calculated the Lee's index. The autophagosome in arcuate nucleus neurons was observed through electron microscopy; the expression of autophagy protein P62, LC3 and ATG7 in hypothalamus were detected and analyzed quantitatively by immunofluorescence and Western blot techniques. The mRNAs of inflammatory factor TNF-alpha, IL-6, IL-1 beta, NF-kappa B, chemokine MCP-1, CCL5, CXCL12, CX3CL1, microglia markers TMEM119, GFAP were detected by real-time fluorescence quantitative PCR. Result: The Lee's index of fat-1 transgenic mice was lower than that of wild-type mice(P < 0.05). The autophagosome of the arcuate nucleus in fat-1 transgenic mice were more than those in wild-type mice, and the expression of autophagy-related protein P62 was significantly decreased (P < 0.05) in hypothalamus of fat-1 transgenic mice, while the expression of autophagy related protein ATG7 was significantly up-regulated (P < 0.05), and the ratio of LC3 II/I was significantly increased (P < 0.05), The results of qPCR showed that the mRNAs of TNF-alpha, IL-6, IL-1 beta, NF-kappa B, MCP-1, CCL5, CXCL12, and GFAP was significantly down regulated (P < 0.05), but CX3CL1 was significantly up-regulated (P < 0.05) in hypothalamus of fat-1 transgenic mice. Conclusion: Fat-1 gene or n-3 PUFA5 possesses the function of reducing body weight, which involves the enhancement of autophagy and reduction of inflammatory factor in hypothalamus. (C) 2018 Elsevier Inc. All rights reserved.