Regulation of Type 1 Inflammation in Diet-induced Obesity

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Obesity is associated with inflammation, particularly in adipose tissue (AT), which has been implicated in obesity-linked diseases including insulin resistance and type 2 diabetes. AT inflammation is evidenced mainly by increases in “type 1 inflammation (T1I),” with elevated CD4+ T helper 1 cells (Th1), CD8+ cytotoxic T effector memory/effector cells (“Tc1”), and M1-like macrophages, but decreases in eosinophils, Th2, and M2-like macrophages. However, the transcriptional mechanisms for T1I, Th1/Tc1 in particular, in obesity have not been fully defined. In our pilot study, STAT1, a key transcription factor for immune cell polarization to T1I, was elevated and phosphorylated, indicating activation, in AT and AT T cells early and persistently in mice on high-fat diet (HFD, high in saturated fat). Strikingly, ablation of STAT1 in T cells (which include CD4+ and CD8+ T cells) in mice (tSTAT1-ko) reduced AT Th1/Tc1, raised eosinophils, and protected against HFD-induced obesity, with enhanced white AT browning, increased energy expenditure, and improved insulin resistance. In vitro study showed that Th1 repress adipocyte browning. Thus, we formed our central hypotheses that in obesity induced by HFD, AT T cells polarize into Th1/Tc1, which repress white AT browning, adversely regulate AT metabolic functions, and accelerate adiposity and insulin resistance; mechanistically, STAT1 is upregulated and activated early and persistently in AT T cells and mediates Th1/Tc1. Ablation or inhibition of STAT1 in T cells suppresses AT Th1/Tc1 polarization, with increased eosinophils but reduced M1-like macrophages, leading to “derepression” of AT browning and enhanced energy expenditure, thereby reducing adiposity and improving insulin resistance. Three aims are proposed: aim 1 will examine how STAT1 is regulated in AT T cells in HFD-induced obesity; aim 2 will examine how T cell STAT1 contributes to AT inflammation and metabolic functions in obesity including the roles of STAT1 in CD4+ vs CD8+ T cells and T cell regulation of adipocyte browning and metabolism; aim 3 will determine whether inhibition of the STAT1 pathway or inducible ablation of STAT1 in T cells reverses AT inflammation and metabolic dysfunctions in established obesity. Tissue culture with T cells from mice and humans and mouse models including mice with cell-specific constitutive or inducible ablation of STAT1, mice treated with pharmacological inhibitors of Jak/STAT1 signaling, and mice with adoptive transfer of immune cells or eosinophil depletion will be used. Flow cytometry, immunostaining, Luminex technology, NanoString system, quantitative PCR, RNA-seq, whole-body and tissue-specific metabolic function assays, and other necessary techniques will be employed. Our approach will identify a novel mechanism that regulates AT T cell T1I in obesity and examine the role of the regulatory pathway in obesity-linked inflammation and metabolic functions and the potential of targeting this pathway to prevent and treat obesity and related inflammation and metabolic disease.