CTRP-3: blocking a toll booth to obesity-related inflammation.

Over the last decade, our understanding of adipose tissue has changed significantly, and where it was once thought of as a simple energy storage site, it is now considered an important and immunologically active endocrine organ (1–3). Adipose tissue is composed of both metabolically and immunologically active cells that include adipocytes, preadipocytes, macrophages, endothelial cells, fibroblasts, and leukocytes; and in the omentum, this also includes omental mesothelial cells (1, 4). A network of blood vessels surrounds these cells and allows them to communicate with systemic sites. This coupling of metabolism and immunity in adipose tissue is a clever biological organization that allows efficient cross talk between these two pathways. This allows the host to make rapid metabolic changes in response to activation of host defense mechanisms against pathogens. This cross talk is achieved by more than 100 proinflammatory, antiinflammatory, and immunomodulating proteins and peptides (3). These include adipokines, such as leptin, adiponectin, visfatin, omentin, and resistin, as well as inflammatory cytokines TNF , monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1. The newly identified adipokine C1q/TNF-related protein (CTRP)-3 is a member of the recently described family of proteins called the CTRP superfamily. This family of proteins has developed by divergence from a common ancestor of the innate immune system (5). As such, they all contain a unique globular C1q domain and a common three-dimensional structure. Thus, CTRP family proteins are suitably designed to provide cross talk between the metabolic pathwayandtheinnateimmunesystem.Indeed,adipocyte-secreted CTRP-3 plays a role in regulating adipokine secretion (6). In this issue of Endocrinology, Kopp et al. (7) probe the function and mechanism of CTRP-3 in adipocytes and monocytes and show that it acts as an endogenous antagonist of the toll-like receptor (TLR)-4 pathway. CTRP-3 was initially identified as a TGF -responsive gene in cartilage (8), and it has since been shown to stimulate the proliferation of mesenchymal chondroprogenitor cells (9) and exhibit an antiinflammatory activity in monocytes (10). However, there is limited information on CTRP-3 and its role in adipocyte biology. Given that CTRP-3 is paralog of adiponectin and a potent antiinflammatory regulator of monocytes, Kopp et al. (7) proposed that CTRP-3 may also have antiinflammatory properties in adipocytes. The authors provide evidence that CTRP-3 acts through a toll-like receptor pathway in adipocytes and monocytes (7). Toll-like receptors are innate immune receptors that recognize conserved microbial signature patterns called pathogen-associated molecular patterns. They initiate proinflammatory signaling pathways important for host defense (11). Adipocytes and monocytes express a broad spectrum of TLRs, including TLR-4, which is the main sensor of pathogenic lipopolysaccharide (LPS) (12). LPS activation of TLR-4 leads to a potent stimulation of proinflammatory cytokine (TNF and IL-6) release from adipocytes (Fig. 1) (13). Importantly, and with respect to obesity-related inflammation, TLR-4 is also stimulated by saturated fatty acids in adipocytes and monocytes (14). As such, TLR-4 could provide cross talk between innate immunity and metabolism. It has become evident that proinflammatory adipocytokines such as TNF , IL-6, and MCP-1 contribute to obesity, type2diabetes, and insulin resistance (15–18).Theydosoby causing chronic low-grade systemic inflammation. Interestingly, mice lacking TLR-4 that are fed a high-fat diet are protected from obesity (19). Moreover these mice have de-