Diet-induced obesity can lead to detrimental chronic disorders. The severity of this global epidemic has encouraged ongoing research to characterize the mechanisms underlying obesity and its comorbidities. Recent evidence suggests that saturated fatty acids (SEA) in high-fat diets rapidly generate inflammation in the arcuate nucleus of the hypothalamus (ARC), which centrally regulates whole-body energy homeostasis. Herein, we will review the roles of hypothalamic neurons and resident microglia in the initiation of SFA-induced hypothalamic inflammation. Particularly, we focus on neuronal and microglial free fatty acid-sensing and capacity to produce inflammatory signaling. We also outline a potential role of peripherally-derived monocytes in this inflammation. And finally, we explore synaptic plasticity as a mechanism through which hypothalamic inflammation can modulate ARC circuitry, and thus disrupt energy homeostasis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.