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.