Hypothalamic inflammation is a recently described phenomenon that occurs during consumption of high fat diets (HFD) and is hypothesized to promote diet-induced obesity (DIO) by causing resistance to leptin and other adiposity-related inputs. Since evidence supporting this hypothesis was generated in animals with established DIO, it remains unclear whether hypothalamic inflammation occurs early enough to play a causal role in HFD-induced obesity. We report that whereas inflammation in peripheral tissues develops only after months of HFD consumption, low-grade inflammation is evident in both rat and mouse hypothalamus within the first wk of HFD exposure. This increase in inflammatory gene expression is initially transient (~7 d) and coincides temporally with the early onset of both HFD-induced excessive energy intake and hypothalamic leptin resistance. Remarkably, this early phase of the response to HFD in both rats and mice is accompanied by an accumulation of enlarged microglia and reactive astrocytes within the mediobasal hypothalamus (MBH), a region containing key neurocircuits regulating energy homeostasis. The combination of altered astrocyte cell structure and microglial involvement is characteristic of "gliosis," a histopathological hallmark of acute neuronal injury. While the astrocyte component of MBH gliosis resolves over a similar time frame as hypothalamic inflammation, microglia continue to accumulate in the MBH over months of HFD consumption. These results suggest that the initial gliosis response may be protective, limiting HFD-induced neuronal injury and inflammation. Consistent with this hypothesis, microglia isolated from the MBH show reduced inflammatory gene expression in the first wk of HFD feeding, but later appear to perpetuate hypothalamic inflammation. These findings collectively support an "acute neuronal injury" model of DIO, in which the defense of elevated body weight results from fixed injury to neurons responsible for energy homeostasis, and suggest that interventions to avert or reverse neuronal damage have important potential in obesity treatment and prevention. Nothing to Disclose: JPT, C-XY, BHH, XZ, SJG, DAS, GJM, HTN, JDF, DGB, BEW, MHT, MWS