Microparticles Release by Adipocytes Act as “Find-Me” Signals to Promote Macrophage Migration

Abstract

Macrophage infiltration of adipose tissue during weight gain is a central event leading to the metabolic complications of obesity. However, what are the mechanisms attracting professional phagocytes to obese adipose tissue remains poorly understood. Here, we demonstrate that adipocyte-derived microparticles (MPs) are critical “find-me” signals for recruitment of monocytes and macrophages. Supernatants from stressed adipocytes stimulated the attraction of monocyte cells and primary macrophages. The activation of caspase 3 was required for release of these signals. Adipocytes exposed to saturated fatty acids showed marked release of MPs into the supernatant while common genetic mouse models of obesity demonstrate high levels of circulating adipocyte-derived MPs. The release of MPs was highly regulated and dependent on caspase 3 and Rho-associated kinase. Further analysis identified these MPs as a central chemoattractant in vitro and in vivo. In addition, intravenously transplanting circulating MPs from the ob/ob mice lead to activation of monocytes in circulation and adipose tissue of the wild type mice. These data identify adipocyte-derived MPs as novel “find me” signals that contributes to macrophage infiltration associated with obesity.

Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress

“…Corresponding to these changes in glucose tolerance, we have previously reported that macrophage (F4/80 positive cells) infiltration in the epididymal AT is increased at 2 weeks of HF diet and becomes significantly higher after 6 weeks on HF diet compared to lean controls [7, 28, 29]. In addition, we have recently reported that sadEVs may contribute to the initiation of inflammation in AT by recruiting macrophages [15]. Our current results demonstrate that increase in circulating EVs strongly correlate with the development of glucose intolerance (Fig.…”

“…Supplementary Table 1 lists all of the proteins identified in sadEVs generated by stressing adipocytes with the free fatty acid palmitic acid, a treatment that results in hypertrophy of adipocytes and significant production and release of EVs [15]. The most abundant proteins include proteins involved in translation, carbohydrate and lipid metabolism, cytoskeleton (e.g., clathrin, tubulins and annexins), extracellular matrix (e.g., fibronectin), ribonucleoproteins, and nucleosomes.…”

“…EV acquisition was performed by BD LSRII Flow Cytometer System (BD Biosciences, San Jose, CA) and data was analyzed using FlowJo software (TreeStar Inc., Ashland, OR) [15]. …”

“…We have recently demonstrated that adipocyte hypertrophy is associated with increased production and release of extracellular vesicles (EVs) [15] and that these EVs are critical “find-me” signals for recruitment of monocytes and macrophages acting as chemoattractants both in vitro and in vivo . We further demonstrated that intravenously transplanting circulating EVs from the ob/ob mice, a genetic model of obesity and insulin resistance, lead to activation of monocytes in circulation and AT of the wild type lean mice.…”

Mitochondrial DNA–enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity

“…Whether this mechanism also contributes to caspase-1-induced MP release in our E10d + 1B model required further studies. In addition, activation of the caspase apoptotic pathway (caspase-3 and caspase-8) promotes MP release in several types of cells, including neutrophils (37), adipocytes (38), and hepatocytes (21). It will be interesting to investigate whether caspase-1 activation of pyroptosis, a type of programed cell death that is different from apoptosis (39), also contributes to MP formation and release.…”