Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice

Liu, Jian; Divoux, Adeline; Sun, Jiusong; Zhang, Jie; Clément, Karine; Glickman, Jonathan N.; Sukhova, Galina K.; Wolters, Paul J.; Du, Juan; Görgün, Cem Z.; Doria, Alessandro; Libby, Peter; Blumberg, Richard S.; Kahn, Barbara B.; Hotamışlıgil, Gökhan S.; Shi, Guo‐Ping

doi:10.1038/nm.1994

Cited by 678 publications

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“…In normal physiological states, adipose tissue contains only a few mature mast cells. However, their number is increased in metabolic syndrome and obesity [8,33], suggesting that their production and/or homing may be altered, leading to their accumulation in adipose tissue. Mast cells produce a large panel of multifunctional molecules including cytokines, growth factors, or enzymes [10,11].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the presence of numerous mature immune cells has been described including macrophages and lymphocytes that have been largely involved in the inflammatory process linked to the onset of obesity and type II diabetes [4][5][6][7]. More recently, mast cells were described in WAT and were shown to contribute to diet-induced obesity and glucose intolerance [8].…”

Section: Introductionmentioning

confidence: 99%

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Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors

et al. 2010

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White adipose tissue (WAT) is a heterogeneous tissue, found in various locations throughout the body, containing mature adipocytes and the stroma‐vascular fraction (SVF). The SVF includes a large proportion of immune hematopoietic cells, among which, mast cells that contribute to diet‐induced obesity. In this study, we asked whether mast cells present in mice adipose tissue could derive from hematopoietic stem/progenitor cells (HSPC) identified in the tissue. We therefore performed both in vitro and in vivo experiments dedicated to monitoring the progeny of WAT‐derived HSPC. The entire study was conducted in parallel with bone marrow‐derived cells, considered the gold standard for hematopoietic‐lineage studies. Here, we demonstrate that adipose‐derived HSPC contain a precursor‐cell population committed to the mast cell lineage, and able to efficiently home to peripheral organs such as intestine and skin, where it acquires properties of functional tissue mast cells. Additionally, WAT contains a significant mast cell progenitor population, suggesting that the entire mast cell lineage process take place in WAT. Considering the quantitative importance of WAT in the adult organism and the increasing roles recently assigned to mast cells in physiopathology, WAT may represent an important source of mast cells in physiological and pathological situations. STEM CELLS 2010;28:2065–2072

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors

et al. 2010

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“…In db/db obese mice, epididymal AT morphological changes occur concomitantly to up‐regulation of various types of collagens, such as I, IV and VI 25. The former is related with increased adipocyte size 26. This feature is generally followed by persistent inflammatory stimulus in AT that may underline excessive synthesis of ECM components.…”

Section: Introductionmentioning

confidence: 99%

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

Batista

Henriques

Neves

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

106

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Background and aimsCachexia is a syndrome characterized by marked involuntary loss of body weight. Recently, adipose tissue (AT) wasting has been shown to occur before the appearance of other classical cachexia markers. We investigated the composition and rearrangement of the extracellular matrix, adipocyte morphology and inflammation in the subcutaneous AT (scAT) pad of gastrointestinal cancer patients.MethodsSurgical biopsies for scAT were obtained from gastrointestinal cancer patients, who were signed up into the following groups: cancer cachexia (CC, n = 11), weight‐stable cancer (WSC, n = 9) and weight‐stable control (non‐cancer) (control, n = 7). The stable weight groups were considered as those with no important weight change during the last year and body mass index <25 kg/m2. Subcutaneous AT fibrosis was quantified and characterized by quantitative PCR, histological analysis and immunohistochemistry.ResultsThe degree of fibrosis and the distribution and collagen types (I and III) were different in WSC and CC patients. CC patients showed more pronounced fibrosis in comparison with WSC. Infiltrating macrophages surrounding adipocytes and CD3 Ly were found in the fibrotic areas of scAT. Subcutaneous AT fibrotic areas demonstrated increased monocyte chemotactic protein 1 (MCP‐1) and Cluster of Differentiation (CD)68 gene expression in cancer patients.ConclusionsOur data indicate architectural modification consisting of fibrosis and inflammatory cell infiltration in scAT as induced by cachexia in gastrointestinal cancer patients. The latter was characterized by the presence of macrophages and lymphocytes, more evident in the fibrotic areas. In addition, increased MCP‐1 and CD68 gene expression in scAT from cancer patients may indicate an important role of these markers in the early phases of cancer.

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“…Mast cells may be relevant to these studies because they have been implicated in regulation of adipogenesis (Liu et al, 2009). Pronounced species differences in the distribution of mast cells among tissues have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Tissue area, adipocyte number and area, and mast cell number were measured. Mast cells were measured because they have been implicated in regulation of adipocyte and osteoblast differentiation (Liu et al, 2009) and Kit W/W-m and Kit Sl/Sl-d mice are mast cell deficient. The data are expressed as adipocyte density (number/mm 2 ) and size (lm 2 ) and mast cell density (number/mm 2 ).…”

Section: Study In Ratsmentioning

confidence: 99%

Effect of Reduced c‐Kit Signaling on Bone Marrow Adiposity

Turner

Wong

Iwaniec

2011

The Anatomical Record

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c-Kit (CD117) is required for normal differentiation of osteoblasts from bone marrow stromal cells and for normal bone formation. Osteoblasts and adipocytes originate from a common progenitor cell, and a reciprocal relationship in differentiation of the two lineages is often observed. Therefore, the effects of abnormal c-kit signaling on bone marrow adiposity and adipocyte precursor pool size were evaluated in mouse strains with loss of function mutations in kit receptor or kit ligand. Additionally, to determine whether short-duration pharmacological disruption of kit signaling influences bone marrow adiposity, we administered the kit receptor antagonist gleevec (imatinib mesilate) for 1 week to middle aged (13-month-old) male rats known to have high levels of bone marrow fat. Compared to wild-type littermates, adipocytes were absent and adipocyte precursors greatly reduced in bone marrow from kit receptor-deficient Kit W/W-m mice. Administration of secreted kit ligand to membrane-associated kit ligand-deficient Kit Sl/Sl-d mice was ineffective in inducing bone marrow adipogenesis. These findings suggest that activation of kit receptor by the membrane-associated form of kit ligand is required for kit signaling to promote bone marrow adipogenesis in mice. Rats treated with gleevec had lower adipocyte density compared to age-matched controls, suggesting that kit signaling is required to maintain normal bone marrow adiposity. Taken together, our results indicate that c-Kit signaling plays an important but previously unsuspected role in regulating bone marrow adiposity. Anat Rec, 294:1126Rec, 294: -1134Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.Key words: hematopoietic stem cell; mesenchymal stem cell; adipocyte; mast cell; receptor tyrosine kinase; gleevec (imatinib mesilate)Osteoblasts and adipocytes are derived from a common bone marrow progenitor (Prockop, 1997;Vaananen, 2005;Valtieri and Sorrentino, 2008). The primary function of osteoblasts is well defined. Osteoblasts generate bone matrix to support bone growth, turnover, and remodeling. Additionally, osteoblasts have been reported to participate in hematopoietic stem cell mobilization from their bone marrow niche and to support hematopoiesis (Nagayoshi et al., 2006;Mayack and Wagers, 2008). In contrast, the physiological significance of adipocytes residing within bone marrow is less well defined.Most fat depots act as dynamic energy reservoirs to maintain circulating triglyceride and free fatty acid levels (Caserta et al., 2001). During severe caloric restriction, fat catabolism becomes an important source of energy and peripheral fat depots decline in mass. In contrast, severe caloric restriction is associated with increased bone marrow adiposity (Batista et al., 1988;Bohm, 2000;Cui et al., 2006;Duque, 2008;Bredella et al., 2009). Bone marrow adipocytes sequester and esterify fatty acids during starvation, a finding which has fostered the belief that the bone marrow fat depot does not function as an important energy reservoir for peripheral tissu...

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Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice

Cited by 678 publications

References 34 publications

Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors

Adipose Tissue as a Dedicated Reservoir of Functional Mast Cell Progenitors

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

Effect of Reduced c‐Kit Signaling on Bone Marrow Adiposity

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