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

Abstract

Supplementary key words adipose tissue • cyclooxygenase • eicosanoids • extracellular signal-regulated kinase • fatty acid • infl ammation • lipaseAdipose tissue is the major repository of excess energy stored in the form of triacylglycerol (TAG). During energy need, adipocyte lipolysis involving the hydrolysis of TAG releases FFAs for energy production by different tissues ( 1, 2 ). Adipose tissue also secretes various adipokines, which infl uence energy homeostasis and insulin sensitivity of distant tissues ( 3, 4 ). In addition to its important role in metabolic regulation, adipose tissue modulates the immune system by recruiting and activating lymphoid and myeloid cells when adipocyte fat storage is exaggerated as occurs in obesity ( 5 ). In obese individuals, there is a strong positive correlation between adipocyte size and the accumulation of proinfl ammatory adipose tissue macrophages (ATMs) ( 6, 7 ).However, ATM recruitment also occurs in mice after fasting or with calorie restriction ( 8 ) and in obese patients maintained on low-calorie diets during early weight loss ( 9 ), but under these conditions, it does not associate with infl ammation. The above fi ndings 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 Abstract Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic infl ammation and modulate insulin sensitivity. Adipocyte lipolysis during fasting and weight loss also leads to ATM accumulation, but without proinfl ammatory activation suggesting distinct mechanisms of ATM recruitment. We examined the possibility that specifi c lipid mediators with anti-infl ammatory 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 E 2 (PGE 2 ) and prostaglandin D 2 (PGD 2 ), refl ecting cytosolic phospholipase A 2 ␣ activation and enhanced cyclooxygenase (COX) 2 expression. Reconstituted medium with the anti-infl ammatory PGE 2 potently induced macrophage migration while different FFAs and PGD 2 had 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 PGE 2 levels and COX1 expression. Collectively, our data show that adipocyte-originated PGE 2 with infl ammation suppressive properties plays a signifi cant rol...

Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease

“…21 Accordingly, in preclinical models, antagonism of COX-2 or genetic inhibition of the prostaglandin E2 pathway improves NASH and resolves fibrosis. 22,23 Collectively these data, together with our current findings, support a potential role for aspirin in the prevention of liver fibrogenesis.…”

Perilipin 1 (Plin1) deficiency promotes inflammatory responses in lean adipose tissue through lipid dysregulation

“…For example, adipocyte-specific Mcp-1 transgenic mice exhibit increased ATMs and whole-body insulin resistance (42). It has been demonstrated that several lipid metabolites released from adipocytes or adipose tissue participate in inflammatory cell activation (15,16,32,43,44). Eicosanoids produced from adipocytes promote recruitment of immune cells (16,32), whereas palmitoleate and palmitic acid-9-hydroxy stearic acid from adipose tissue reduce pro-inflammatory response in immune cells (15,43,44).…”

“…Certain lipid metabolites, including leukotriene B 4 , PGD 2 , and PGE 2 , promote monocyte/macrophage migration (18,32). To identify potential secreted mediator(s) that can potentiate monocyte migration in adipose tissue of Plin1 Ϫ/Ϫ mice, CM of adipocytes was subjected to lipidomic analysis by nontargeted LC-MS/MS (Table S1).…”

“…nists or forskolin to stimulate lipolysis, lipid metabolites generated from COX are elevated (16,32). Administration of ␤ 3 -adrenergic agonist increases macrophage infiltration into WAT, which can be abrogated by COX2 inhibitor (16).…”

Correlative Study on Impaired Prostaglandin E2 Regulation in Epicardial Adipose Tissue and Its Role in Maladaptive Cardiac Remodeling via EPAC2 and ST2 Signaling in Overweight Cardiovascular Disease Subjects

“…PGE 2 is a potent lipid mediator secreted by various cell types in visceral adipose tissue and it appears to be implicated in the regulation of inflammation and adipocytes functions [30]. Different studies have noted that the excess accumulation of visceral fat depends on depot-specific expression of key enzymes involved in adipose tissue functions, including PGE 2 biosynthesis-related enzymes [31]. PGE 2 is the principal prostaglandin produced by visceral adipose tissue including EAT deposit [27], which regulates energy metabolism and, particularly in obesity, contributes to fat-inflammation and obesity-related insulin resistance, through the activation of prostaglandin-endoperoxide synthase 2 (PTGES-2) [32], known also as cyclooxygenase 2.…”