Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 15 (8), 940-5

Genetic Deficiency and Pharmacological Stabilization of Mast Cells Reduce Diet-Induced Obesity and Diabetes in Mice

Affiliations

Genetic Deficiency and Pharmacological Stabilization of Mast Cells Reduce Diet-Induced Obesity and Diabetes in Mice

Jian Liu et al. Nat Med.

Abstract

Although mast cell functions have classically been related to allergic responses, recent studies indicate that these cells contribute to other common diseases such as multiple sclerosis, rheumatoid arthritis, atherosclerosis, aortic aneurysm and cancer. This study presents evidence that mast cells also contribute to diet-induced obesity and diabetes. For example, white adipose tissue (WAT) from obese humans and mice contain more mast cells than WAT from their lean counterparts. Furthermore, in the context of mice on a Western diet, genetically induced deficiency of mast cells, or their pharmacological stabilization, reduces body weight gain and levels of inflammatory cytokines, chemokines and proteases in serum and WAT, in concert with improved glucose homeostasis and energy expenditure. Mechanistic studies reveal that mast cells contribute to WAT and muscle angiogenesis and associated cell apoptosis and cathepsin activity. Adoptive transfer experiments of cytokine-deficient mast cells show that these cells, by producing interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), contribute to mouse adipose tissue cysteine protease cathepsin expression, apoptosis and angiogenesis, thereby promoting diet-induced obesity and glucose intolerance. Our results showing reduced obesity and diabetes in mice treated with clinically available mast cell-stabilizing agents suggest the potential of developing new therapies for these common human metabolic disorders.

Figures

Figure 1
Figure 1
Macrophages and mast cells in human WAT. a. Human HAM56 immunostaining of WAT from obese and lean subjects. b. HAM56+ macrophages near the microvessels in obese WAT. c. Human mast cell tryptase immunostaining of WAT from obese and lean subjects. d. Tryptase+ mast cells close to microvessels in obese WAT. e. Many more macrophages than mast cells were detected in WAT, and both cell types were significantly higher in obese WAT than in lean WAT (Mann-Whitney test). Mast cell number per mm2 in obese WAT vs. lean WAT increased independently of gender (P > 0.05) or diabetic status (P > 0.05) (Mann-Whitney test) and did not correlate with age (P > 0.05, Spearman’s correlation test). Arrows indicate HAM56+ macrophages or tryptase+ mast cells; V: microvessel; scale bars: 100 µm in a and c and 25 µm in b and d. f. ELISA analysis revealed significantly higher levels of serum mast cell tryptase in obese subjects than in lean donors (P = 0.01, unpaired t-test). This significance remained after adjusting for gender (P = 0.01), but disappeared after adjusting for fasting glucose, insulin, and homeostasis model assessment (HOMA) (P > 0.05, multivariate analysis). This suggests that the association between serum tryptase and obesity depends on blood glucose homeostasis, consistent with significant positive correlations between serum tryptase and fasting glycemia (R = 0.19, P < 0.05), insulin (R = 0.21, P < 0.04), and HOMA (R = 0.24, P < 0.02) (non-parametric Spearman’s correlation). P < 0.05 was considered statistically significant.
Figure 2
Figure 2
Mast cell deficiency and stabilization reduced diet-induced obesity and diabetes in male mice. a. Body weight gain and visceral and subcutaneous fat weight in WT and KitW-sh/W-sh mice (C57BL/6). bc. CD117 immunostaining and CD117+ mast cells in WAT from WT mice with different treatments. Arrows indicate CD117+ mast cells; V: WAT microvessels, scale bars: 100 µm. d. Mac-2+ macrophage numbers in WAT from different groups of mice as indicated. e. Glucose tolerance assay in WT and KitW-sh/W-sh mice that consumed a Western diet for 12 weeks with and without DSCG treatments. f. Immunoblot analysis for UCP1 (32 kDa) in brown fat from WT, KitW-sh/W-sh and DSCG-treated WT mice that consumed a Western diet for 12 weeks. Actin (42 kDa) immunoblot was used for protein loading control. g. DSCG reduced pre-formed obesity and diabetes. Arrow indicates where pre-formed obese mice were divided into four groups. Mouse glucose tolerance assays for all four groups of mice after the treatments are shown to the right. h. Body weight gain and glucose tolerance assay in WT mice treated with or without ketotifen. i. Ketotifen reduced pre-formed obesity and diabetes in a similar protocol as in g. j. Reduced body weight and improved glucose tolerance in KitWv/Wv and WT mice (WBB6F1/J) treated with DSCG or ketotifen. The number of mice for each group is indicated in the bars or the parentheses. *Each time point was compared to Western diet-fed WT mice. P < 0.05 was considered statistically significant; Mann-Whitney test. NS: no significant difference.
Figure 3
Figure 3
Mast cell functions in angiogenesis, apoptosis, and protease expression. a. CD31 immunostaining of WAT and muscle from WT and KitW-sh/W-sh mice that consumed a Western diet for 12 weeks with or without receiving DSCG. Arrows indicate CD31+ microvessels in the WAT or muscle. Scale bars: 100 µm. b. Quantification (mean ± SEM) of CD31-positive areas in WAT and muscle. c. Quantification (mean ± SEM) of apoptotic cells in WAT and muscle. d. Cysteine protease cathepsin active site JPM labeling using WAT extracts from different groups of mice that consumed 12 weeks of a Western or chow diet. Arrowheads indicate active cathepsins. Actin immunoblot assured equal protein loading. e. Serum cathepsin S ELISA from different groups of mice. f. WAT extract cathepsin S ELISA from different groups of mice. In b, c, e, and fP < 0.05 was considered statistically significant, non-parametric Mann-Whitney test. The number of mice in each group is indicated in each bar. NS: no significant differences.
Figure 4
Figure 4
Mast cell reconstitution in KitW-sh/W-sh mice. Reconstitution of KitW-sh/W-sh mice with BMMC from WT and Tnf–/– mice, but not from Ifng–/–and Il6–/– mice, partially restored body weight gain (a), serum leptin (b), serum insulin (c), serum glucose (d), and glucose tolerance (e). f. CD117+ mast cell numbers in WAT from WT, KitW-sh/W-sh and different reconstituted mice. g. Immunoblot analysis for UCP1 (32 kDa) in brown fat from WT, KitW-sh/W-sh and KitW-sh/W-sh mice received WT BMMC followed by 13 weeks of Western diet consumption. h. Cathepsin active site JPM labeling of cell lysate from 3T3-L1 cells treated with different BMMC. Active CatB and CatS are indicated. i. WAT extract JPM labeling to detect active cathepsins as indicated by arrowheads. Immunoblot analysis for GAPDH (37 kDa) was used for protein loading control. j. Quantification of CD31-positive areas in WAT and muscle from different groups of mice. All data in a–f and j are mean ± SEM. The number of mice for each group is indicated in the bars or in the parentheses. P < 0.05 was considered statistically significant, non-parametric Mann-Whitney test.

Similar articles

See all similar articles

Cited by 254 PubMed Central articles

See all "Cited by" articles

References

    1. Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nat. Immunol. 2005;6:135–142. - PubMed
    1. Bingham CO, Austen KF., 3rd Mast-cell responses in the development of asthma. J. Allergy Clin. Immunol. 2000;105:S527–S534. - PubMed
    1. Robbie-Ryan M, Brown M. The role of mast cells in allergy and autoimmunity. Curr. Opin. Immunol. 2002;14:728–733. - PubMed
    1. Secor VH, Secor WE, Gutekunst CA, Brown MA. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 2000;191:813–822. - PMC - PubMed
    1. Lee DM, et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002;297:1689–1692. - PubMed

Publication types

MeSH terms

Substances

Feedback