Mechanisms involved in maintaining brain fatty acid concentrations: Uptake and metabolism.

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In the brain, fatty acids regulate many functions including blood flow, signal transduction and inflammation which, ultimately, can influence behavior. However, the mechanisms by which the brain maintains it fatty acid concentrations are not agreed upon. My NSERC-funded laboratory has accumulated evidence that polyunsaturated fatty acids, from the plasma unesterified pool, enter the brain via a non-selective mechanism and then are selectively partitioned to esterification or catabolism within the brain. We now have new and improved methods to answer how polyunsaturated fatty acids enter the brain and are handled in vivo. The objective of this grant application is to identify the mechanisms by which fatty acids enter and are metabolized by the brain in vivo. In this model unesterified fatty acids are infused into the vein of an awake, free-living rat and the experiment is terminated with high-energy, head-focused microwave fixation (NSERC-funded equipment). Thus, our first set of experiments will be to test, upon oral administration, what plasma pools contribute to brain fatty acid uptake. We will also test if radiolabelled DHA and EPA uptake into the brain, in vivo, can be reduced by increasing the concentration of non-labeled DHA and EPA. We also expect EPA to be rapidly and extensively beta-oxidized. Furthermore, in this application, we propose to block the beta-oxidation of EPA with a chemical inhibitor of carnitine palmitoyl transferase-1. This will tell us if EPA beta-oxidation is the reason its concentration is so low within brain phospholipids. By infusing inhibitors of candidate fatty acid transporters into the brain prior to performing our in vivo brain uptake method, we will be able to test if inhibition of candidate fatty acid transporters decreases brain fatty acid uptake in vivo. In the brain, fatty acids are coupled to signal transduction and have selective targets (phosphatidyl inositol) not only will this work improve our basic understanding of brain biology, but it could lead to new or improved imaging methods. HQP in our program will get experience in Nutritional Sciences, mathematical modeling and several methods associated with the field of neurochemistry including animal models, chromatography and MS.