5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

Abstract

The presence of the so-called low-grade inflammatory state is recognized as a critical event in adipose tissue dysfunction, leading to altered secretion of adipokines and free fatty acids (FFAs), insulin resistance, and development of hepatic complications associated with obesity. This study was designed to investigate the potential contribution of the proinflammatory 5-lipoxygenase (5-LO) pathway to adipose tissue inflammation and lipid dysfunction in experimental obesity. Constitutive expression of key components of the 5-LO pathway, as well as leukotriene (LT) receptors, was detected in adipose tissue as well as in adipocyte and stromal vascular fractions. Adipose tissue from obese mice, compared with that from lean mice, exhibited increased 5-LO activating protein (FLAP) expression and LTB4 levels. Incubation of adipose tissue with 5-LO products resulted in NF-κB activation and augmented secretion of proinflammatory adipokines such as MCP-1, IL-6, and TNF-α. In addition, LTB4, but not LTD4, reduced FFA uptake in primary adipocytes, whereas 5-LO inhibition suppressed isoproterenol-induced adipose tissue lipolysis. In mice with dietary obesity, elevated FLAP expression in adipose tissue was paralleled with macrophage infiltration, increased circulating FFA levels, and hepatic steatosis, phenomena that were reversed by FLAP inhibition with Bay-X-1005. Interestingly, FLAP inhibition induced AMP-activated protein kinase phosphorylation in parallel with decreases in hormone-sensitive lipase activity and the expression and secretion of TNF-α and IL-6. Similar effects were observed in differentiated 3T3-L1 adipocytes incubated with either Bay-X-1005 or the selective LTB4 receptor antagonist U-75302. Taken together, these findings indicate that the 5-LO pathway signals the adipose tissue low-grade inflammatory state and steatogenic potential in experimental obesity.

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

“…According to this, FLAP is detectable in adipose tissue of lean mice and is overexpressed in high-fat-diet-induced obesity model mice and Zucker rats. This is accompanied with elevated LT formation and pharmacologic inhibition-reduced free circulating fatty acids, alleviated insulin resistance, and hepatic steatosis (37). In addition, FLAP, together with 5-LO, is implicated in the pathology of atherosclerosis.…”

A Novel Non-agonist Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand UHC1 Blocks PPARγ Phosphorylation by Cyclin-dependent Kinase 5 (CDK5) and Improves Insulin Sensitivity

“…It has shown that the products of lipolysis such as fatty acids induce inflammation in adipose tissue (23,24). Therefore, we next analyzed the expression of genes that are associated with lipolysis.…”

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

“…The activation of ALOX5/ALOX5AP is a crucial enzymatic step in the transformation of arachidonic acid into the unstable intermediate leukotriene A 4 (LTA 4 ), which is subsequently transformed into leukotriene B 4 (LTB 4 ) (5S, 12R-dihydroxy-eicosa-6Z, 8E, 10E, 14Z-tetraenoic acid). LTB 4 , in addition to being a potent chemoattractant for leukocytes, enhances the release of proinflammatory adipokines, such as MCP-1 and interleukin (IL)-6, from obese adipose tissue (10,11). LTB 4 levels are elevated in adipose tissue during obesity (11)(12)(13), and LTB 4 has been described to play a role in the development of insulin resistance and to directly decrease insulin signaling in myocytes and hepatocytes in vitro (5,14,15).…”

“…LTB 4 , in addition to being a potent chemoattractant for leukocytes, enhances the release of proinflammatory adipokines, such as MCP-1 and interleukin (IL)-6, from obese adipose tissue (10,11). LTB 4 levels are elevated in adipose tissue during obesity (11)(12)(13), and LTB 4 has been described to play a role in the development of insulin resistance and to directly decrease insulin signaling in myocytes and hepatocytes in vitro (5,14,15). In addition, although the activation of the ALOX5/ALOX5AP complex is key to leukotriene synthesis, it can alternatively lead to the biosynthesis of other compounds, such as lipoxins (16).…”