Whether PUFA diets affect inflammatory mediators in central and peripheral sites is not clear. We investigated the effect of high-fat PUFA diets on the expression of proteins involved in inflammatory pathways in hypothalamus, muscle, and liver. Male rats were fed for 2 months with either chow or high-fat diets enriched with either soy (n-6 PUFAs) or fish oil (n-3 PUFAs). The fish group had normal body weight, low serum NEFA, reduced hypothalamic levels of TNF- α , IL-6, and TRAF6, and increased levels of IL-10 receptor. In contrast, the soy group had increased body weight and hypothalamic levels of TRAF6 and NF κ Bp65. In muscle, the fish diet reduced TNF- α and IL-6 levels. Both PUFA diets increased muscle IL-10 levels and reduced liver TNF- α and IL-6 levels. The data showed that the high-fat soy diet induced activation of the hypothalamic NF κ B inflammatory pathway, a feature predisposing to feeding and energy expenditure disturbances associated with the development of obesity. On the other hand, the high-fat fish diet improved the central and the peripheral inflammatory profile via reduction of intracellular inflammatory mediators, suggesting a protection against obesity.