Veterans exhibit higher incidence of obesity than does the general US population. Dietary fats influence risk of developing peripheral metabolic diseases and cognitive disorders such as Alzheimer’s disease (AD). Inflammation of the brain (neuroinflammation), a state associated with progressive neuronal loss, is known to be heightened in cognitive decline and obesity. While neuroinflammation normally increases with age, risk is greatly exacerbated by chronic consumption of diets high in saturated fatty acids, such palmitic acid. Microglia, the resident immune cells of the brain, play an integral role in neuroinflammation in the brain and represent a common link between diet and neuroinflammatory diseases. Microglia are highly reactive to environmental signals such as those caused by diet. Microglia react to changes in brain milieu by transitioning between multiple states, including neurotoxic pro-inflammatory and neuroprotective anti-inflammatory microglial phenotypes. Palmitic acid directly affects immune cells through stimulation of microglial toll like receptor- 4 (TLR-4)- dependent pathways, thereby activating pro-inflammatory phenotypes and increasing the release of pro- inflammatory cytokines. The linkage of inflammation and lipid metabolism suggests a key unexplored role for fatty acid binding protein-4 (FABP4). We demonstrate for the first time that FABP4 is expressed in microglial cells, and that the loss of FABP4 leads to activation of mitochondrial uncoupling protein 2 (UCP2). Specifically, loss of FABP4 leads to an increase in cellular monounsaturated fatty acids (predominately C16:1) that upregulate the expression of UCP2. Moreover, increased expression of UCP2 leads to reduced expression of inflammatory cytokines in microglia. In peripheral macrophages, loss of UCP2 increases oxidative stress, potentiates the NFκB pathway, and increases secretion of inflammatory cytokines. However, these pathways have not been fully explored in microglia. Importantly for this application, molecular, genetic, or pharmacologic loss of FABP4 results in an anti-inflammatory phenotype and a shift to anti-inflammatory microglial phenotypes, even in the presence of a high saturated fat diet. Inflammation in macrophages requires metabolic state changes in the tricarboxylic cycle (TCA). The transition to pro-inflammatory microglial phenotypes is accompanied by a major shift from glycolysis to oxidative phosphorylation for energy production. Indeed, the molecular basis for this phenotypic switch is due in part to the UCP2-dependent change in redox environment and subsequent changes in intracellular metabolic pathways. Our preliminary data support that the FABP4-UCP2 axis drives shifts in TCA utilization via changes in key mitochondrial enzymes such as immune responsive gene-1 (Irg-1). While this shift in metabolic adaptation can regulate immune response in the development of metabolic syndrome, this mechanism is undefined in microglia. Diet-induced neuroinfl...