Adipose Tissue and Mast Cells
4. PARACRINE EFFECTS OF ADIPOSE TISSUE
The possibility that the endocrine secretory activity of large adipose depots may directly contribute to the altered blood plasma levels of certain adipokines has recently gained considerable attention (1–11). Further, the paracrine secretory activity of the small adipose depots has, at long last, become a focus in the biology of disease.
Similarly to endocrine products of large adipose depots reaching many organs through the bloodstream, paracrine products of organ-associated adipose depots can affect their neighboring tissues by a variety of adipokines (see subheading 4.1.3).
4.1. Perivascular Adipose Tissue and Cardiovascular Disease
In our previous papers (4,41), we emphasized the importance of investigating the mole- cular composition of artery-associated adipose tissue, as it may yield clues to a possible
paracrine transmission of protective and pathogenic signals derived from the perivascular adipose tissue toward the adjacent artery wall. Such an outside-to-inside signaling (30,42), recently dubbed vasocrine signaling (31), is implicated in the obesity-related insulin resist- ance phenotype (31) and various vascular disorders (32). Moreover, inflammatory bio- markers measured in blood plasma may not adequately reflect local vascular inflammation.
An intriguing example of perivascular adipose tissue is the (sub)epicardial adipose tissue (EAT) that is conjunctioned to the adventitia of the most atherosclerosis-prone portions of the coronary artery—that is, the most proximal part of its left anterior descend- ing branch. The possible involvement of EAT in coronary atherosclerosis and other cardiac pathologies has recently been addressed. Epicardial adipose tissue is a visceral fat depot around the heart, especially the right-ventricular free wall and left-ventricular apex. This neglected tissue is now recognized as a potent producer of various inflammation-related adipokines (43–48). Specifically, recent findings demonstrate that the portion of the left anterior descending coronary artery running in the EAT develops atherosclerotic lesions, whereas the portion running in the myocardium is free of atherosclerotic lesions (ref. 41 and references therein). Further, the “atherosclerotic” EAT exhibits (1) reduced levels of adiponectin, an anti-inflammatory and antiatherosclerotic adipokine (45), (2) elevated levels of monocyte chemoattractant protein-1, IL-1G, IL-6, tumor necrosis factor (TNF)-F (44,46,47), and NGF (43,49), and (3) the presence of inflammatory cell infiltrates, includ- ing mast cells (43), lymphocytes (44), and macrophages (47) (reviewed in refs. 32,48,49).
4.2. Orbital Adipose Tissue and Thyroid-Associated Ophthalmopathy
Thyroid-associated (Graves’) ophthalmopathy (TAO) has an autoimmune patho- genesis possibly related to the thyrotropin receptor (50–53). The symptoms of TAO result from inflammation, fibrosis, and accumulation of orbital adipose tissues.
Immunohistochemical analysis of orbital tissue biopsies from patients with TAO demonstrates that the thyrotropin receptor is expressed in fibroblast-like cells, accom- panied by mast cell infiltrates (50,51). Whether these mast cells, via their fibrogenic (34–36) and/or angiogenic (37) potential, may contribute to TAO-associated fibrosis and orbital adipose tissue hypertrophy, respectively, remains to be evaluated. Further, transforming growth factor-G inhibits, whereas IL-6 stimulates, thyrotropin receptor expression (52), suggesting that the pathogenesis of TAO may be influenced by com- peting inhibitory (yin) and stimulatory (yang) adipokine effects within the orbit. One study examined 2686 genes, of which 25 known genes were upregulated in TAO orbital tissues, whereas 11 genes were downregulated (53). Upregulated genes included secreted frizzled-related protein (sFRP)-1 and several adipocyte-related genes, includ- ing peroxisome proliferator-activated receptor (PPAR)Land adiponectin. Treatment of TAO orbital preadipocytes in vitro with recombinant sFRP-1 significantly increased their adiponectin and leptin secretion (53).
4.3. Mammary Adipose Tissue and Breast Cancer
It is known that inflammation can promote tumorigenesis. There is compelling evidence indicating that both normal mammary gland development and breast cancer growth depend, in part, on microenvironment, of which adipose tissue is a key component (ref. 28and references therein). Interestingly, the mammary gland microenvironment during postlactational involution shares similarities with inflammation, which may be
promotional for breast cancer development associated with pregnancy (54). Recently, an elegant study by Celis et al. (28) provided the most extensive proteomic analysis of the mammary adipose secretome in high-risk breast cancer patients.
Adipose fibroblasts are another important cellular component of breast cancer microenvironment. These cells, being bona fide steroidogenic cells, are one of the major extragonadal sources of estrogen secretion. Estrogen synthesis is mediated by the enzyme aromatase cytochrome P450 (P450arom), which converts androgens to estrogens (55). In breast cancer, one of the most aggressive human cancers, intratumoral prolifera- tion of breast adipose fibroblasts is accompanied by increased P450arom expression by these cells, leading to proliferation of breast epithelial cells (56). Notably, breast cancer commonly associates with a prominent immune, especially mast cell, response (57–59).
TNF-F and IL-6, which may potentially derive from both adipose cells and mast cells, upregulate aromatase expression (60). Further, mast cell-secreted tryptase is a potent stimulator of fibroblast proliferation (61), and adipocytes also produce tryptase (12).
A novel piece to the puzzle of breast cancer is that NGF, a molecule known to be produced by adipocytes (5,27,28,43,49) and mast cells (34,62), stimulates breast cancer cell proliferation (63,64). Importantly, the antiestrogen drug tamoxifen inhibits NGF- mediated breast cancer cell proliferation through inhibition of the Trk-A receptor (63).
These data suggest a novel, NGF-mediated mechanism in the action of an old drug, tamoxifen, in breast cancer pharmacotherapy. Together these findings open possibilities for an adipose NGF-/mast cell-oriented therapy of breast cancer (1), and pressingly call for studies on pharmacology of this neoplastic disorder.
5. CONCLUSIONS
Adipose tissue is a major source of and target for inflammatory signals. Although adipocyte–macrophage (13,19,20,47) and adipocyte–lymphocyte (29) interactions enjoy the researchers’ appreciation, adipose mast cells have been relatively less studied until now. Nonetheless, adipocytes and mast cells share several biological features: (1) they are bona fide secretory cell types; (2) they cover almost the same spectrum of secretory proteins (seeTable 1); and (3) they are co-implicated in the pathobiology of various inflammatory diseases. Despite these associations, further investigations will be required to illuminate the biology of mast cells in mast cells in health and disease. The following example might be a “role model” for such studies: activated human mast cells synthesize and release large amounts of plasminogen activator inhibitor type 1 through a nonconventional secretory pathway, using multivesicular endosome-mediated secretion of exosomes (65). If this appears to be the case for adipose mast cells, it may further “inflame” adipose tissue. Also, comparing the biological responses of mast cells in wild-type mice with those of genetically engineered knock-in or knockout mice may provide new insights into adipose mast cell biology. Finally, a further suggesiton of a possible relation between mast cells and adipocytes is underscored by the observation that hyperlipidemia develops in mast cell-deficient W/WW mice (66).
Because the actions of adipokines are complex and diverse, we need to design novel studies to determine how these molecules affect various inflammatory processes.
Mechanistically, promotion of anti-inflammatory (yin) and suppression of proinflam- matory (yang) adipokine-mediated signals may result in an improvement of inflammatory
disease therapy (Table 2). The present challenge is thus to cultivate an adipocentric thinking about how we can make adipokines work for the benefits of patients. It is our belief that we should collaborate to more easily (and pleasantly) achieve that goal, as advised by the yin–yang philosophy also named “The Book of Ease.”
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Table 2
Examples of Adipokines as Possible Yin–Yang Modulators of Inflammation
Yin Yang
Anti-inflammatory signals Proinflammatory signals
Adiponectin (1–3,5,6,8,45,67)a TNF-F(5–9,44)
IL-10 (5,13,67) Interleukin-1, -6 (14,18,44)
Nerve growth factor (5,27,43,49) Leptin (8)
Transforming growth factor-G(52) Plasminogen activator inhibitor-1 (5–9)
receptor antagonist (10) IL-18 (71)
Pigment epithelium-derived factor (21,68) Resistin (8,14,46)
Calorie restriction (12) Monocyte chemoattractant protein-1 (20,46) Exercise-induced myokines (70) IL-8 (CXCL8) (8,14,19,44,46)
Adrenomedullin (69) Eotaxin (CCL11) (19,46)
Calcitonin gene-related peptide (72) RANTES (CCL5) (9,14,19,46) Metallothionein-1,-2 (72) Hypoxia-inducible factor-1F(13)
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