Guo-Ping Shi, DSc.

Inflammation in obesity and diabetes

 

Accumulating evidence suggests that inflammatory cells, including macrophages, different subtypes of T cells, neutrophils, eosinophils, and mast cells all contribute to the development and progression of obesity and diabetes (1-7). We demonstrate that mast cells contribute to diet-induced obesity and diabetes by inducing vascular cell protease production, angiogenesis, and possibly inflammatory cell infiltration (7, 8). These activities of mast cells are mediated by their inflammatory cytokines IFN-g, IL-6, TNF-a, and chemokine MCP-1 after activation. Therefore, stabilization of mast cells prevents mice from obesity and diabetes (7). Although there are multiple pathways to activate mast cells, IgE binding to mast cell surface high affinity receptor FceR1 is one of the most common mechanisms of mast cell activation (9). We show that, in addition to mast cells, IgE also activates macrophages (10), CD4+ T cells, CD8+ T cells, and even vascular cells. In a population study, plasma IgE appears as a risk factor of human pre-diabetes and glucose tolerance (11, 12). Therefore, IgE may also participate in the pathogenesis of obesity and diabetes. Inactivation of IgE activity by genetic mutation of the ligand IgE or its receptor FceR1 or by treating subjects with an anti-IgE antibody may prevent or reduce both genetic and diet-induced obesity and diabetes. We also show that IgE activates macrophages, and probably other inflammatory cells by enhancing the activity of a sodium-proton exchanging protein Nhe-1. We hypothesize that inactivation of this proton pump may also ameliorate obesity and diabetes. To our surprise, in genetically modified leptin-deficient ob/ob mice, however, mast cell-deficiency enhances both obesity and type-2 diabetes. We demonstrate that mast cells from these mice have anti-inflammatory activity. In vitro, leptin-deficient mast cells promote macrophage polarization towards M2 phenotypes. In both diet-induced and genetic obese mice, repopulation of leptin-deficient mast cells reduces both obesity and diabetes by polarizing macrophages towards M2 phenotypes, providing the first evidence that mast cells change phenotypes from pro-inflammatory to anti-inflammatory depending on their expression of leptin.

 

References.

1. Liu J, Divoux A, Sun J, et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med. 2009;15:940-945. PMCID:PMC2736875

 

2. Zhang J, Chen H, Liu L, et al. Chemokine (C-C motif) receptor 2 mediates mast cell migration to abdominal aortic aneurysm lesions in mice. Cardiovasc Res. 2012;96:543-551. PMCID:PMC3500042

 

3. Xu JM, Shi GP. Emerging role of mast cells and macrophages in cardiovascular and metabolic diseases. Endocr Rev. 2012;33:71-108. PMCID:PMC3365842

 

4. Wang J, Cheng X, Xiang MX, et al. IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice. J Clin Invest. 2011;121:3564-3577. PMCID:PMC3163955

 

5. Wang Z, Zhang H, Shen XH, et al. Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus. PLoS one. 2011;6:e28962. PMCID:PMC3241693

 

6. Wang Z, Zhang H, Shen XH, et al. Immunoglobulin E and mast cell proteases are potential risk factors of impaired fasting glucose and impaired glucose tolerance in humans. Ann Med. 2013;45:220-229. PMCID:PMC3934348

 

 

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