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 NF?B 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 neuroinflammation thus represents an unexplored link between brain immune response and metabolic processes to dietary fat within the context of cognitive decline, and may represent a novel clinical therapeutic target. Our overall hypothesis is that diets high in saturated fatty acids alter microglial redox state, resulting in metabolic adaptations that promote neuroinflammation and subsequent cognitive decline. To test this, we will 1) Determine if saturated fatty acids alter metabolic adaptation in microglia in vitro; and 2) Test whether reduced neuroinflammation prevents diet-induced cognitive decline in FABP4 knockout (AKO) mice. Our short-term goal will be to utilize pharmacogenetic approaches to define lipid metabolism in microglia and cognition to better understand relationships between aging, obesity, and memory loss. Our long-term goal is to develop targeted therapies for the treatment of inflammation-induced neurodegeneration and cognitive decline to benefit Veterans impacted by multiple diseases, including obesity and AD.

Public Health Relevance

Obesity and associated comorbidities such as metabolic syndrome and diabetes affect up to 48% of Veterans, and are known risk factors for cognitive impairment and development of Alzheimer?s disease. The incidence of these neurodegenerative diseases may be higher in Veterans than in the general population. Our work supports that the onset of brain immune response (neuroinflammation) represents a link between obesity and cognitive impairment. Dietary metabolites such as fatty acids affect lipid metabolism in brain immune cells (microglia), resulting in a state change to a toxic inflammatory microglial phenotype We hypothesize that dietary fats alter microglial metabolism to directly trigger dysregulated brain immune responses and neuronal cell death, resulting in impaired cognition and altered brain circuitry. Our short term goal is to characterize microglial metabolic state changes that promote neuroinflammation and subsequent cognitive decline. Our long-term goal is to leverage this knowledge to develop targeted therapies to treat cognitive impairment and neurodegenerative disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology D (NURD)
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Minneapolis VA Medical Center
United States
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