Mast cells are essential effector cells in the elicitation of the allergic responses by releasing cytoplasmic granules. Our recent studies suggest that mast cells participate in human pathobiology beyond allergic inflammation. Mast cell deficiency or pharmacological stabilization of mast cells reduces significantly the incidences of experimental atherosclerosis and abdominal aortic aneurysms in mice. As a close associated metabolic disorder of atherosclerosis and aortic aneurysms, obesity becomes not just an important scientific topic, but also a serious social problem worldwide. For the first time, we revealed accumulation of mast cells in adipose tissues from obese humans and mice. Using mast cell-deficient mouse model or anti-allergy mast cell stabilizer cromolyn, we demonstrated that mast cells are important player in obesity. Mast cell-deficient mice or those treated with cromolyn are significantly leaner than the control mice and show significant increase of glucose tolerance. Along with reduced body weight gain and increased glucose tolerance, serum levels of leptin, chemokine MCP-1, cytokine TNF-a, and obesity pertinent protease cathepsin S are also reduced in mast cell-deficient mice or those received cromolyn treatment. Although a mechanism by which mast cells contribute to obesity remains to be investigated, in vitro differentiated mast cells promote mouse pre-adipocyte differentiation. Thus, our central hypothesis is that mast cells produce pro-inflammatory cytokines and proteases to modulate the biology of adipose tissue and the extracellular matrix, thereby contributing to obesity, glucose tolerance and insulin sensitivity.
Two specific aims are proposed: 1). To study the role of mast cells in body weight gain and glucose metabolism and to examine whether we can control the progression of obesity and/or reverse the phenotypes of pre-formed obesity in mice by regulating mast cell activations. 2). To identify which chemokine receptors that mast cells use for homing to the adipose tissues and to identify which of those common mast cell mediators contributes to obesity. Together, these lines of experiments should provide strong evidence of whether mast cells are required for obesity and mechanistic explanations of how mast cells might influence this common metabolic disorder.

Public Health Relevance

Obesity is a serious public health problem that affects 30% of adults in the US. Although physical exercise and open surgery are used in the clinic to reduce the body weight, effective non-invasive therapy of obesity lacks. This proposal tests the hypothesis that pro-inflammatory mast cells are important participants of obesity, and examines thoroughly whether we can manage body weight gain by regulating mast cell activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060942-13
Application #
8257536
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
2009-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
13
Fiscal Year
2012
Total Cost
$421,970
Indirect Cost
$174,470
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Bot, Ilze; Shi, Guo-Ping; Kovanen, Petri T (2015) Mast cells as effectors in atherosclerosis. Arterioscler Thromb Vasc Biol 35:265-71
Xu, Junyan; Shi, Guo-Ping (2014) Vascular wall extracellular matrix proteins and vascular diseases. Biochim Biophys Acta 1842:2106-2119
Lafarge, Jean-Charles; Pini, Maria; Pelloux, Véronique et al. (2014) Cathepsin S inhibition lowers blood glucose levels in mice. Diabetologia 57:1674-83
Wang, Jing; Sjöberg, Sara; Tang, Ting-Ting et al. (2014) Cathepsin G activity lowers plasma LDL and reduces atherosclerosis. Biochim Biophys Acta 1842:2174-83
Xu, Na; Zhang, Yuan-Yuan; Lin, Yan et al. (2014) Increased levels of lysosomal cysteinyl cathepsins in human varicose veins: a histology study. Thromb Haemost 111:333-44
Wang, Jing; Lindholt, Jes S; Sukhova, Galina K et al. (2014) IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms. EMBO Mol Med 6:952-69
Hu, Lina; Cheng, Xian Wu; Song, Haizhen et al. (2014) Cathepsin K activity controls injury-related vascular repair in mice. Hypertension 63:607-15
Wang, Jing; Sjoberg, Sara; Tia, Viviane et al. (2013) Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice. Atherosclerosis 229:304-9
Lv, Bing-Jie; Lindholt, Jes S; Wang, Jing et al. (2013) Plasma levels of cathepsins L, K, and V and risks of abdominal aortic aneurysms: a randomized population-based study. Atherosclerosis 230:100-5

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