Obesity results in increased macrophage recruitment to adipose tissue that promotes a chronic low-grade inflammatory state linked to increased fatty acid efflux from adipocytes. Activated macrophages produce a variety of pro-inflammatory lipids such as leukotriene C4 (LTC4) and 5-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) suggesting the hypothesis that fatty acids may stimulate eicosanoid synthesis. To assess if eicosanoid production increases with obesity, adipose tissue of leptin deficient ob/ob mice was analyzed. In ob/ob mice, LTC4 and 12-HETE levels increased in the visceral (but not subcutaneous) adipose depot while the 5-HETE levels decreased and 15-HETE abundance was unchanged. Since macrophages produce the majority of inflammatory molecules in adipose tissue, treatment of RAW264.7 or primary peritoneal macrophages with free fatty acids led to increased secretion of LTC4 and 5-HETE, but not 12- or 15-HETE. Fatty acid binding proteins (FABPs) facilitate the intracellular trafficking of fatty acids and other hydrophobic ligands and in vitro stabilize the LTC4 precursor leukotriene A4 (LTA4) from non-enzymatic hydrolysis. Consistent with a role for FABPs in LTC4 synthesis, treatment of macrophages with HTS01037, a specific FABP inhibitor, resulted in a marked decrease in both basal and fatty acid-stimulated LTC4 secretion but no change in 5-HETE production or 5-lipoxygenase expression. These results indicate that the products of adipocyte lipolysis may stimulate the 5-lipoxygenase pathway leading to FABP-dependent production of LTC4 and contribute to the insulin resistant state.
|Original language||English (US)|
|Number of pages||9|
|Journal||Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids|
|State||Published - Jul 2013|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health grants DK053189 and AES MN-70-043 to DAB, F32 DK091004 to EKL and NIH DK050456 (The Minnesota Obesity Center) . KH was supported by the Cargill Fellowship in Systems Biology and a Doctoral Dissertation Fellowship from the University of Minnesota . We thank Jonathan Marchant for his advise on calcium studies and the members of the Bernlohr laboratory for their comments and suggestions in preparation of this manuscript. We also thank the staff of the University of Minnesota Center for Mass Spectrometry and Proteomics and the Minnesota Supercomputing Institute for their assistance.
- Fatty acid
- Fatty acid binding protein