Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment

Xiaoqian Hu,Vincenza Cifarelli,Shishuo Sun,Ondrej Kuda,Nada A Abumrad,Xiong Su

doi:10.1194/jlr.m066530

Abstract

Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic inflammation and modulate insulin sensitivity. Adipocyte lipolysis during fasting and weight loss also leads to ATM accumulation, but without proinflammatory activation suggesting distinct mechanisms of ATM recruitment. We examined the possibility that specific lipid mediators with anti-inflammatory properties are released from adipocytes undergoing lipolysis to induce macrophage migration. In the present study, we showed that conditioned medium (CM) from adipocytes treated with forskolin to stimulate lipolysis can induce migration of RAW 264.7 macrophages. In addition to FFAs, lipolytic stimulation increased release of prostaglandin E2(PGE2) and prostaglandin D2(PGD2), reflecting cytosolic phospholipase A2α activation and enhanced cyclooxygenase (COX) 2 expression. Reconstituted medium with the anti-inflammatory PGE2potently induced macrophage migration while different FFAs and PGD2had modest effects. The ability of CM to induce macrophage migration was abolished by treating adipocytes with the COX2 inhibitor sc236 or by treating macrophages with the prostaglandin E receptor 4 antagonist AH23848. In fasted mice, macrophage accumulation in adipose tissue coincided with increases of PGE2levels and COX1 expression. Collectively, our data show that adipocyte-originated PGE2with inflammation suppressive properties plays a significant role in mediating ATM accumulation during lipolysis.

Highlights

Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic inflammation and modulate insulin sensitivity
To begin to examine the effect of adipocyte lipolysis on macrophage migration, we first compared the effect of FSK-conditioned medium (CM) with that of control medium not incubated with adipocytes or CM from untreated adipocytes with only vehicle included in the preincubation medium (DMSO-CM)
Macrophage chemotaxis was examined in response to media containing 100 ␮M individual FFAs: palmitic acid (PA), oleic acid (OA), linoleic acid (LA), or 100 ␮M of a FFA mixture (PA, OA, and LA) all added complexed to BSA at a ratio of 4:1 (FA:BSA)

Summary

Introduction

Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic inflammation and modulate insulin sensitivity. The above findings suggest that the mechanisms that operate in ATM recruitment in obesity or calorie restriction are not identical Both fasting and pharmaceutically induced lipolysis increase macrophage content in adipose tissue, and lipolysis measures correlate with increased ATM content independent of adiposity [10]. This suggests that lipid turnover and not lipid accumulation per se is. The recruited ATMs play an adaptive role during lipid flux conditions such as with weight loss and fasting by buffering the local concentration of FFAs through their ability to accumulate TAG in lipid droplets [8]. Whether adipocyte release of FFAs or FA-derived molecules might signal for ATM recruitment in addition to driving ATM lipid accumulation is not known

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