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Adipose tissue is comprised of a community of different immune cells that contributes to regulation of energy storage and release by adipocytes. The population of various immune cells is dynamic, undergoing phenotypic and compositional changes in response to physiologic (e.g., fasting vs. feeding) and pathologic (e.g., lean vs. obese) stimuli. Cumulative evidence suggests that a regulatory or anti-inflammatory immune phenotype promotes metabolic homeostasis, whereas a proinflammatory response is associated with metabolic dysregulation (1). Accordingly, lean, healthy white adipose tissue (WAT) is home to a population of alternatively activated macrophages (M2s) as well as immune cells that mediate M2 polarization, such as eosinophils, CD4+ T-helper type (Th) 2 cells, and regulatory T cells (Tregs) (1). During obesity, WAT is infiltrated by additional classically activated macrophages (M1s), neutrophils, mast cells, and CD8+ T cells that release proinflammatory cytokines, thereby sustaining metabolic inflammation, or meta-inflammation (2). Although the changes in immune repertoires associated with different metabolic states are well characterized, mechanisms underlying the switches in immune phenotypes remain unclear. Due to their roles in skewing immune cell responses, multiple cytokines have been suggested to play a role in the development of meta-inflammation in obesity. The first studies to recognize that obesity is associated with inflammation identified tumor necrosis factor-α (TNFα) as a mediator of WAT insulin resistance. TNFα produced by infiltrating M1s triggers the activation of Jun NH2-terminal kinase and inhibitor of κB kinase β causing antagonistic phosphorylation of insulin receptor …

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 low-grade, unresolvable immune response that is in the causal pathway to metabolic dysregulation (1). Although how meta-inflammation 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-γ [IFNγ]) 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 …