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

Abstract

Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase–activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

“…Other possible determinants of the balance of 5-LOX products include factors that affect the nuclear versus non-nuclear location of 5-LOX, such as oxysterols/OS as demonstrated here, and SPMs themselves, as recently published by us 16 . Other processes that can affect SPM production and that could, in theory, play roles in atherosclerosis include cell-cell communication and transcellular biosynthesis 5 ; release of LX precursors from cellular phospholipids 43 ; and action of 5-LOX activating protein (FLAP), which may play a role in LX production 44 45 46 47 . Leukotriene A 4 hydrolase (LTA 4 H) is also emerging as an intriguing target for atherosclerosis, because inhibition of this enzyme has been linked to the decrease of leukotriene B 4 and the increase of lipoxins 32 44 48 .…”

Macrophage functions in lean and obese adipose tissue

“…Mice overexpressing ALOX5AP have increased lipoxin A4 production and reduced mRNA levels of the macrophage markers F4/80 and IL-6 in epididymal white adipose tissue 39 . Lipoxin A4 promotes ABCA expression and cholesterol efflux from macrophages and increases high-density lipoprotein (HDL) levels.…”

Dietary Quercetin Attenuates Adipose Tissue Expansion and Inflammation and Alters Adipocyte Morphology in a Tissue-Specific Manner

“…Browning of adipose tissue occurs in both visceral and subcutaneous white adipose tissues; however, a larger degree of browning has been noted in subcutaneous white adipose tissue in response to various environmental stimuli, including cold exposure, exercise and dietary manipulations such as methionine restriction [ 20 , 21 , 22 , 23 , 24 ]. Browning is also associated with alterations in inflammatory gene expression [ 17 , 25 , 26 , 27 ]. Thus, it has been proposed that expansion or activation of white adipose tissue browning may improve metabolic outcomes, such as amelioration of insulin resistance.…”