Endogenous, Adipocyte-Derived Lipids Signal the Recruitment of Proinflammatory Immune Cells
Obesity, insulin resistance, and type 2 diabetes have reached epidemic levels in Western countries. Work over the past decade has established that the adipose tissue in obesity is characterized by a state of chronic, low-grade inflammation, which plays a primary role in the development of systemic insulin resistance (1). Critical to the development of adipose tissue inflammation in obesity is the recruitment of specific immune cells, such as proinflammatory macrophages (M1 macrophages) and neutrophils (1–3). However, the precise signals that stimulate the recruitment of these immune cells into the expanding adipose tissue are not well understood. In this issue, Tynan et al. (4) demonstrate that endogenous oils (EOs) isolated from human adipocytes are a potent inflammatory signal.
Initially, the authors sought to determine whether EOs derived from human omental adipocytes could enhance antigen-specific immune responses in mice. Remarkably, EOs were as effective as incomplete Freund’s adjuvant at inducing antigen-specific antibody responses. Importantly, fractionation of EOs into lipid and nonlipid components demonstrated that the lipid fraction of EOs were the immunogenic component. To explore their inflammatory properties further, the authors used a model of inflammation in which the recruitment of immune cells was examined following the injection of EOs into the peritoneum of mice. EOs induced a marked shift in the immune cell profile of the peritoneum, characterized by an increase in neutrophils and M1 macrophages and a decrease in M2 macrophages (Fig. 1A).
The site of fat accumulation in humans has a critical role in the development of obesity-associated metabolic disease, with visceral fat considered to be detrimental and subcutaneous fat to be beneficial (5,6). However, EOs from visceral and subcutaneous adipocytes promoted a similar degree of recruitment of proinflammatory immune cells. Furthermore, EOs obtained from the omental adipocytes of lean and obese individuals also had comparable effects on the recruitment of proinflammatory immune cells. Collectively, these data demonstrate, perhaps somewhat surprisingly, that the immunostimulatory effects of EOs are intrinsic to the adipocyte per se, and are not influenced by diet or the anatomic location of the fat. Consistent with this notion, the authors show that the fatty acid profile of omental adipocytes from lean individuals, and both metabolically healthy and unhealthy obese individuals, is nearly identical. Next, the authors addressed the mechanism by which EOs recruited proinflammatory immune cells. Toll-like receptor 4 (TLR4) is proposed to be a receptor for long-chain saturated free fatty acids (FFAs) and to mediate their proinflammatory effects (1,7). However, by injecting EOs into C3H/HeJ mice, which express a form of TLR4 that is unable to respond to ligand, the authors show that TLR4 is not required for the proinflammatory effects of EOs. Importantly, however, the authors were able to demonstrate that interleukin-1α (IL-1α) levels were markedly increased in the peritoneum following the injection of EOs, and that IL-1α was absolutely required to promote immune cell recruitment. Of note, the immunostimulatory effects of EOs were independent of IL-1β and the NLRP3 inflammasome, another proposed sensor of fatty acids (8).
While Tynan et al. provide a powerful demonstration of the proinflammatory effects of adipocyte-derived endogenous lipids, a limitation is that the lipid class responsible for the immunostimulatory capacity of EOs is not identified. However, in a wonderfully complimentary recent study, Freigang et al. (9) demonstrated that oleic acid, a long-chain unsaturated fatty acid, had many of the same effects as reported for EOs. Given that oleic acid is the most abundant fatty acid present in EOs isolated from human adipocytes, accounting for over 50% of the total fatty acid pool, it is tempting to speculate that the immunostimulatory effects observed by Tynan et al. are due to the presence of oleic acid in EOs. However, if EOs from healthy and lean, visceral and subcutaneous adipose tissue all promote the recruitment of proinflammatory immune cells, then why are proinflammatory immune cells primarily recruited to obese, visceral adipose tissue depots in vivo? Adipocyte death is a characteristic of obese visceral adipose tissue, but not subcutaneous or lean visceral adipose tissue. Given that fatty acids stored as triglycerides are the predominant stored lipid in adipocytes, a potential scenario is that adipocyte death leads to the release of EOs enriched in fatty acids, and that this promotes the recruitment of proinflammatory immune cells into the adipose tissue (Fig. 1B). Indeed, it is noteworthy that the increase in M1 macrophages and neutrophils, coincident with a decrease in M2 macrophages observed following the injection of EOs, is highly reminiscent of the situation in the adipose tissue in vivo during the transition from the lean to obese state (1).
However, this scenario raises an intriguing paradox. Ferrante and colleagues (10) have shown that FFAs released from adipocytes during fasting promote the recruitment of macrophages into the adipose tissue. Importantly, those macrophages that are recruited into the adipose tissue in response to fasting-induced increases in FFA concentrations are not polarized to the M1 proinflammatory state. Instead, it is hypothesized that these newly recruited macrophages act as a sink to buffer the increased local FFA concentrations (10). So why, on the one hand, can FFAs promote the recruitment of proinflammatory immune cells, such as neutrophils and M1 macrophages, which likely play an important role in adipose tissue inflammation and insulin resistance, but on the other hand, also signal the recruitment of macrophages during physiologic processes such as fasting? These observations may be best explained by differences in the concentration and the duration of the increase in the fatty acid levels that are likely to be present when comparing the physiologic release of fatty acids due to lipolysis with the large and uncontrolled release of fatty acids that will occur with adipocyte death. Furthermore, the composition of the fatty acids released may differ between adipocyte death and lipolysis. Regardless of any outstanding questions, the study by Tynan et al. (4) provides several important insights into the regulation of proinflammatory immune cell recruitment, with implications on our understanding of how adipose tissue becomes inflamed in obesity.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
See accompanying article, p. 2037.
- © 2014 by the American Diabetes Association.
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