This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Sequential Ordered Fatty Acid aOxidation and ?9 Desaturation Are Major Determinants of Lipid Storage and Utilization in Differentiating Adipocytes: Herein, we exploit the power of global lipidomics to identify the critical role of peroxisomal processing of fatty acids in adipocyte lipid storage and metabolism. Remarkably, 3T3-L1 differentiating adipocytes rapidly acquired the ability to a-oxidize unbranched fatty acids, which is manifested in the accumulation of odd chain length unbranched fatty acids in all major lipid classes. Moreover, in differentiating adipocytes, unsaturated odd chain length fatty acids in TAG molecular species contained exclusively ?9 olefinic linkages. Unsaturated fatty acids (e.g., oleic and palmitoleic acids) were not subject to oxidation, resulting in the absence of ?8 unsaturated odd chain length fatty acids. This highly selective substrate utilization resulted in the obligatory sequential ordering of oxidation prior to ?9 desaturation. On the basis of these results, a putative type 2 peroxisomal localization sequence was identified at the N-terminus of mouse stearoyl-CoA desaturase I (SCD I) comprised of 30KVKTVPLHL38. Kinetic analysis demonstrated that the rate of oxidation of exogenously administered [9,10-3H]palmitic acid increased 4-fold during differentiation. Similarly, quantitative PCR demonstrated a 4-fold increase in phytanoyl-CoA a-hydroxylase (PAHX) and fatty acyl-CoA oxidase (FACO) mRNA levels during differentiation. Collectively, these results underscore the role of peroxisomal fatty acid processing as an important determinant of the metabolic fate of fatty acids in the differentiating adipocyte.
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