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  • lp-pla2 inhibitor br Introduction Over the past two decades

    2021-10-14


    Introduction Over the past two decades, the prevalence of obesity and obesity-associated metabolic diseases, such as T2D, insulin resistance, atherosclerosis and stroke, have been dramatically increased globally [1], [2], and obesity has been suggested to be the leading cause of the reduced life expectancy forecasted for the next generation [3]. Childhood and/or early adulthood obesity is associated with risk of autoimmune diseases, such as multiple sclerosis and type 1 diabetes [4], [5], [6]. Obesity is now recognized as a chronic low-grade inflammatory disease and is associated with the chronic inflammation within AT [2]. Hotamisligil et al. first established the concept of obesity-induced AT inflammation [7]. They demonstrated that tumor necrosis factor (TNF)-α was elevated in high fat diet (HFD)-induced obese mice, and neutralization of or genetic deletion of TNF-α improved insulin sensitivity in obese mice [7], [8]. Lately, studies demonstrated the priming function of AT in the initiation of inflammation during obesity progression, Lee et al. reported that the expression levels of pro-inflammatory cytokines were selectively induced in AT, but not in other metabolic tissues such as skeletal muscle and liver in the early stage of HFD-induced obese mice [9]. AT is the major metabolic organ for the storage of excessive body fat and is an important endocrine organ for regulating the balance of energy intake and expenditure by the secretion of soluble factors, including adipokines, chemokines, and cytokines [10]. AT was comprised of two parts: adipocytes and stromal vascular structure (SVF), which is a mixture of fibroblasts, endothelial cells, and immune lp-pla2 inhibitor including macrophages, T cells, B cells, and natural killer (NK) cells. Adipocytes are the major constituent of AT. There are two types of adipocytes: white adipocytes and brown adipocytes. White adipocytes store excessive body fat as energy source, while brown adipocytes burn excessive fat to generate heat [11]. Recent studies found that white adipocytes can be transformed into “brown-like/beiging” adipocytes (named as beige cells) upon external stimuli such as exercise and cold exposure [12], [13]. In contrast to lean AT, obese AT is characterized by lower angiogenesis, higher hypoxic and chronic inflammation environment. In the past few years, the roles of multiple innate and adaptive immune cells in obesity-associated chronic inflammation have been extensively investigated [14], [15]. The majority of evidence suggests that the accumulation of macrophages, especially inflammatory AT macrophages (ATMs), were positively associated with the development of obesity and obesity-associated insulin resistance [16], [17]. In addition, the accumulation of ATMs is accompanied by the phenotypic switch from anti-inflammatory M2 (alternatively activated)-macrophages to pro-inflammatory M1 (classically activated)-macrophages during the development of obesity [18], [19], [20]. Moreover, recent studies suggest that alterations in AT-resident immune cell components, such as T cells [21], [22], [23], B cells [24], [25], [26], mast cells [27], [28], [29], invariant NK T (iNKT) cells [30], [31], and eosinophils [32], are also related to the degree of obesity-induced AT inflammation. The accumulation of T cells, B cells and mast cells in obese AT are correlated with inflammation and the progression of insulin resistance [21], [24], [27], whereas iNKT cells and eosinophils reduce inflammation and improve insulin sensitivity (Fig. 1A) [30], [32]. Recent investigations emphasized the important roles of CD4+ T cells in controlling immune-AT crosstalk during the progression of obesity and obesity-associated diseases. Circulating CD4+ T cell frequency is positively associated with increased body mass index (BMI) or obese condition in humans [33]. According to the production of specific cytokines, CD4+ T cells are classified into four categories: Th1 cells (signature cytokine: interferon (IFN)-γ), Th2 cells (signature cytokine: interleukin (IL)-4 and IL-13), Th17 (signature cytokine: IL-17), and regulatory T (Treg) cells (characterized by the expression of transcription factor forkhead box P3 (Foxp3) and the secretion of IL-10) [34]. In general, Th1 and Th17 cells promote pro-inflammatory responses by stimulating M1-macrophages, whereas Th2 and Treg cells correlate with anti-inflammatory responses (Fig. 1A) [35], [36]. Understanding the functions of AT-resident CD4+ T cells in obesity may have important implications for the development of new therapeutic strategies for obesity and obesity-associated diseases.