Physiological and metabolic effects of fatty acids are determined by their degree of saturation and chain length. Effects of 18-carbon fatty acids with various degrees of saturation on inflammatory, oxidative, and neuropeptide gene transcription, especially in the hypothalamus, in response to LPS-induced acute inflammation have not been well studied. We conducted this study to test whether diets with distinct 18-carbon fatty acid differentially affect inflammatory and metabolic response to LPS exposure in the hypothalamus, liver, and muscle tissues. Four experimental diets were fed for 4 weeks to male C57BL/6J mice, and a terminal 4-h lipopolysaccharide (LPS) injection was administered. Diets included a control diet (CON) containing 5.6% kcal fat from lard and 4.4% kcal fat from soybean oil, and three high-fat diets (HFD) containing 25% kcal fat from lard and 20% kcal fat from either shea butter (SHB; saturated fatty acid-rich fat), olive oil (OLO; monounsaturated fatty acid-rich oil), or soybean oil (SBO; polyunsaturated fatty acid-rich fat). Compared to CON, HFD-fed mice had higher weight gain and body fat accumulation. The SBO group had lowest Cpt1b expression in the liver, and OLO group had the lowest Pomc and the highest Lepr expression in the hypothalamus. LPS challenge increased pro-inflammatory cytokine mRNA expression in the brain and peripheral tissues. However, the diets did not exert distinguishable effects on LPS-induced inflammatory responses. Therefore, saturation degree of 18-carbon fatty acids may not play a critical role in their effects on inflammatory and metabolic indicators in response to acute inflammation induced by LPS.