Mast cells (MCs) participate in cardiometabolic diseases, including obesity, diabetes, and atherosclerosis, that affect more than one-third of the American adult population. MC deficiency or inactivation protects mice from these cardiometabolic diseases. The pro-inflammatory hormone leptin, acts as a satiety factor that regulates body weight gain by suppressing appetite and stimulating energy expenditure. While inflammatory cytokines induce adipocyte leptin expression, this hormone also activates most other tested cells, including those closely related to cardiometabolic diseases, such as dendritic cells, basophils, monocytes/macrophages, smooth muscle cells (SMCs), endothelial cells (ECs), neutrophils, and effector and regulatory T cells. MCs also express leptin and its receptor. Obese humans have elevated plasma leptin levels that associate with white adipose tissue (WAT) inflammation and MC accumulation. Our preliminary studies revealed unexpected observations: WAT from lean humans and mice contained much more leptin than WAT from obese humans and diet-induced obese (DIO) mice, but MCs in WAT from lean humans and mice expressed negligible leptin, significantly less than MCs from obese humans and mice. In the absence of MCs, leptin-deficient ob/ob mice gained significantly more body weight and developed worse diabetes than MC-sufficient ob/ob mice. In MC-deficient KitW-sh/W-sh mice, reduced body weight and improved diabetes can all be reversed by the adoptive transfer of bone marrow-derived MCs (BMMCs) from wild-type (WT) mice, but not those from ob/ob mice. FACS analysis and RT-PCR of WAT from KitW-sh/W-sh mice revealed reduced classically activated M1 macrophages and increased alternatively activated M2 macrophages, a profile fully reversible by WT BMMCs but not ob/ob BMMCs. These preliminary results suggest that leptin-deficient MCs polarize M2 macrophages, which produce anti-inflammatory cytokines, associate with lean body mass and metabolic homeostasis, and contribute to insulin sensitivity maintenance. The study of cultured bone marrow-derived macrophages indicated that leptin-deficient BMMCs but not WT BMMCs tipped macrophage towards M2 polarization. Based on our preliminary studies, we hypothesize that deficient leptin expression in MCs may shift cell profiles from pro-inflammatory to anti-inflammatory functions; and that such cells may ameliorate cardiometabolic diseases (e.g. obesity, diabetes, and atherosclerosis) by promoting M2 polarization and probably anti-inflammatory T- cell differentiation in WAT, arteries, or other inflammatory states that involve MCs. We propose three aims to test this hypothesis: to examine whether leptin-deficient mast cells protect mice from obesity and diabetes; to investigate the cellular and molecular mechanisms by which leptin-deficient MCs protect mice from obesity and diabetes and; to examine whether leptin-deficient MCs also exert anti-inflammatory activities in other inflammatory diseases, such as atherosclerosis.
Mast cells (MCs) are commonly considered as pro-inflammatory cells that release inflammatory mediators to exacerbate the pathogenesis of cardiometabolic diseases, such as obesity, diabetes, and atherosclerosis. We discovered that MCs in adipose tissues from lean humans and mice and in healthy human arteries express negligible leptin. Absence of leptin expression converted MCs from pro-inflammatory to anti- inflammatory phenotypes, with the activity to drive macrophage polarization towards alternatively activated M2 cells in cultured bone-marrow-derived macrophages and in white adipose tissues from genetic and diet-induced obese mice. Therefore, we hypothesize that leptin deficiency changes MC inflammatory profile, thereby ameliorating the development and progression of cardiometabolic diseases or any other inflammatory diseases in which MCs are involved.
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