Peroxisomal and mitochondrial fatty acid metabolism in brown adipose tissue and liver

Abstract: Brown adipose tissue (BAT) produces heat in response to cold. The heat produced is mainly due to oxidation of fatty acids. In animal tissues, fatty acid 9-oxidation has generally been assumed to occur in mitochondria. The discovery of a 9-oxidation system in rat liver peroxisomes raised questions as to whether a similar system is present in BAT (a tissue with very active fatty acid metabolism) and what the physiological significance of such a system would be in heat production. BAT has very high activity of mitochondrial 9-oxidation enzymes, but nonetheless the results showed that BAT also contains peroxisomes with a 9-oxidation activity. The peroxisomal fatty acid capacity is increased several-fold during acclimation to cold. However, in spite of this pronounced increase, peroxisomes were found to contribute only 5-10% to overall cellular fatty acid oxidation.When substrate specificities were studied for the two systems, they showed qualitative differences. Peroxisomes preferentially oxidised medium- -chain fatty acids, and showed highest affinity towards medium-chain and long-chain unsaturated fatty acids, whereas mitochondria showed highest oxidation rates and affinity with long-chain saturated fatty acids.BAT peroxisomal 9-oxidation enzymes were identified by antibodies raised against the corresponding rat liver peroxisomal enzymes. Acyl-CoA oxidase (the rate-limiting enzyme of peroxisomal 9-oxidation) was found to increase selectively, thus causing the increase in peroxisomal 9-oxidation capacity. Both peroxisomal and mitochondrial 9-oxidation enzymes were found to increase also in liver in rats exposed to cold. However, these increases may primarily be a response to an increased caloric intake.The intraparticulate localization of various enzymes was investigated in rat liver peroxisomes. The data suggest that the peroxisomal matrix contains some poorly soluble enzymes that may form a matrix structure.Mitochondrial 9-oxidation in BAT was found to be sensitive to eru- coyl-carnitine. When the mechanism for the inhibition was studied, the inhibition was found to be due to sequestration of CoA, thus all CoA- -dependent substrates were found to be inhibited to an extent which was correlated to the intramitochondrial level of free CoA.Three different acyl-CoA hydrolases with very high activities were found in rat and hamster BAT. The hydrolases were found to have different substrate specificities and a complex regulation by ADP, NADH and ions. These data suggest that the acyl-CoA hydrolases have an important function in BAT fatty acid metabolism.The results presented here show that BAT contains cold-inducible 9-oxidation systems in both peroxisomes and mitochondria. The marked proliferation of peroxisomes in BAT differs from drug-induced peroxisome proliferation and brown adipose tissue may thus be an interesting tissue in which to study peroxisome proliferation in response to physiological stimuli.