Katherine G . Langley Endogenous , Adipocyte - Derived Lipids Signal the Recruitment of Proin fl ammatory 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-1a (IL-1a) levels were markedly increased in the peritoneum following the injection of EOs, and that IL-1a was absolutely required to promote immune cell recruitment. Of note, the immunostimulatory effects of EOs were independent of IL-1b 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