Characterization of Eicosanoids Produced by Adipocyte Lipolysis

Abstract

Excessive adipocyte lipolysis generates lipid mediators and triggers inflammation in adipose tissue. However, the specific roles of lipolysis-generated mediators in adipose inflammation remain to be elucidated. In the present study, cultured 3T3-L1 adipocytes were treated with isoproterenol to activate lipolysis and the fatty acyl lipidome of released lipids was determined by using LC-MS/MS. We observed that ␤-adrenergic activation elevated levels of approximately fifty lipid species, including metabolites of cyclooxygenases, lipoxygenases, epoxygenases, and other sources. Moreover, we found that ␤-adrenergic activation induced cyclooxygenase 2 (COX-2), not COX-1, expression in a manner that depended on activation of hormone-sensitive lipase (HSL) in cultured adipocytes and in the epididymal white adipose tissue (EWAT) of C57BL/6 mice. We found that lipolysis activates the JNK/NFB signaling pathway and inhibition of the JNK/NFB axis abrogated the lipolysis-stimulated COX-2 expression. In addition, pharmacological inhibition of COX-2 activity diminished levels of COX-2 metabolites during lipolytic activation. Inhibition of COX-2 abrogated the induction of CCL2/MCP-1 expression by ␤-adrenergic activation and prevented recruitment of macrophage/monocyte to adipose tissue. Collectively, our data indicate that excessive adipocyte lipolysis activates the JNK/NFB pathway leading to the up-regulation of COX-2 expression and recruitment of inflammatory macrophages.

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).…”

“…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).…”

“…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). Because Plin1 in adipocytes plays an important role in the regulation of basal lipolysis (24), we assessed whether Plin1 deficiency in adipocytes would change the repertoire of released lipid metabo-lites.…”

“…Lipid dysregulation is closely related to various pathophysiologies, such as rheumatoid arthritis, multiple sclerosis, and obesity-induced insulin resistance (13,14). Although lipid metabolites have been considered as simple energy sources, recent findings have revealed that lipid metabolites can also act as signaling molecules for immune responses (15,16). In obesity, elevated fatty acids are a potential trigger for macrophage activation (17).…”

Periparturient lipolysis and oxylipid biosynthesis in bovine adipose tissues

“…The most abundant oxylipid substrates are linoleic (LA) and arachidonic (ArA) acids. Studies in rodent models of lipolysis demonstrate that the activation of cyclooxygenase 2 (COX2) and 5- and 15- lipoxygenases (5LOX, 15LOX) during lipolytic events enhances oxylipid biosynthesis [ 11 ]. LA-derived oxylipids, including 9- and 13-hydroxyl-octadecadienoic acids (HODE), promote inflammatory responses within AT by acting as chemoattractants of AT macrophages [ 12 ].…”