STAT4: An Initiator of Meta-Inflammation in Adipose Tissue?

Metabolic regulation and immune signaling are closely linked, as evidenced by both the physical proximity between metabolic cells (e.g., adipocytes and hepatocytes) and resident macrophages as well as the progression of inflammation in metabolic syndrome. Contrasting the reactions to pathogen infections, meta-inflammation describes a novel type of lowgrade, unresolvable immune response that is in the causal pathway to metabolic dysregulation (1). Although howmetainflammation is initiated remains unclear, the T-helper cell type 1 (Th1)/Th2 (or M1/M2) paradigm provides a simplified view of how immune cells are involved in readjusting metabolic set points in response to nutrient intake (2). It appears that Th1 cytokines (e.g., interleukin [IL]-12 and interferon-g [IFNg]) or Th1 polarized immune cells promote insulin resistance, whereas Th2 signaling (e.g., IL-4 and IL-13) sustains metabolic homeostasis (3). In mouse genetic models, for example, tipping the Th1/Th2 balance toward one specific spectrum leads to the expected outcome (4). As such, immunometabolism has become an attractive target to treat metabolic diseases. Members of the signal transducer and activator of the transcription (STAT) family are transcription factors that mediate the signaling events of many cytokines in immune and nonimmune cells (5–7). The seven mammalian STAT proteins each contain a DNA-binding domain, a transactivation domain, and an Src homology 2 (SH2) domain; the latter is required for dimerization (5). When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins (5). Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes (6). Previous work has provided a good understanding of the function of STAT proteins in inflammation (7). More recently, alternative roles have been described for STATs in direct regulation of metabolic processes in a variety of tissues (Fig. 1). For example, activation of STAT1 by IFNg facilitates M1 macrophage polarization in adipose tissue, an underlying mechanism of insulin resistance (4,8). Not surprisingly, due to its critical role in IFN-induced responses, STAT1 also contributes to autoimmune b-cell death in the development of type 1 diabetes (9). In contrast, the IL-4/IL-13-STAT6 signaling pathway is required to maintain alternative macrophage polarization in healthy white adipose tissue (3). STAT6deficient mice are more susceptible to developing insulin resistance and glucose intolerance when challenged with a high-fat diet despite less weight gain (10). In hepatocytes, IL-13 has been shown to suppress glucose production through a noncanonical, STAT3-dependent pathway (11). The emerging function of STAT proteins in direct metabolic regulation further underscores the intricate relationship between immune and metabolic pathways and implicates their potential to serve as therapeutic targets. In this issue, Dobrian et al. (12) implicate STAT4 in the development of white adipose tissue (WAT) inflammation and insulin resistance. STAT4 is primarily activated by IL-12 to promote cytotoxic responses and Th1 cell differentiation. Consequently, STAT4 gene deletion leads to a Th2-biased phenotype (7). Dobrian et al. show that STAT4deficient mice have improved insulin sensitivity and glucose tolerance when challenged with a high-fat diet. As expected, STAT4 WAT shows less macrophage infiltration with an M2 polarization phenotype, an observation that is likely due to a reduction in IFNg-producing T cells. There is also an increase in CD3CD25 T-regulatory cells and a decrease in CD8 T cells. CD4 cells are not affected. These results are consistent with a previous study that implicated CD8 T cells in macrophage recruitment, adipose tissue inflammation, and systemic insulin resistance (13). Interestingly, STAT4 appears to play a specific role in CD8 T-cell migration into adipose tissue. Two lines of evidence support this notion. First, IL-12 induces the production of CXCL10 and CCL5—chemokines that attract T cells—in WAT explants in a STAT4-dependent manner. Conditioned media from STAT4-deficient WAT explants were less effective at recruiting both CD4 and CD8 T cells. In addition, CD8 T cells derived from STAT4 mice showed a significant reduction in their migratory activities, indicating an intrinsic defect in migration. Indeed, expression of CCR3 and CCR5, which could serve as CCL5 receptors, is downregulated in STAT4-deficient CD8 cells. To further evaluate this function of STAT4, Dobrian et al. reconstituted Rag1 mice, which lack T, NKT, and B cells, with splenocytes of STAT4 mice and wildtype controls. Mice receiving STAT4-deficient splenocytes are more insulin sensitive and exhibit reduced WAT CD8 T cells. However, the improvement is milder compared with that observed with whole-body STAT4 deficiency. Results from this study suggest that STAT4 activation in CD8 T cells may be one of the initial cues triggering immune cell migration into adipose tissue. Anatomically, WAT CD8 T cells appear to be specifically affected by STAT4 deficiency. Dobrian et al. demonstrate STAT4 is expressed in adipocytes, indicating that adipose STAT4 is also involved in CD8 T-cell recruitment/activation. In line with this notion, STAT4 fat explants were nonresponsive From the Department of Genetics and Complex Diseases, Department of Nutrition, Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts. Corresponding author: Chih-Hao Lee, [email protected]. DOI: 10.2337/db13-1416 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 4109.