Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes
Sook Kyung Chang, … , Alexander S. Banks, Michael B. Brenner
Sook Kyung Chang, … , Alexander S. Banks, Michael B. Brenner
Published July 31, 2017
Citation Information: J Clin Invest. 2017;127(9):3300-3312. https://doi.org/10.1172/JCI86881.
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Research Article Inflammation Metabolism

Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes

Abstract

M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function. Cadherin-11–deficient mice displayed increased stromal production of IL-33, with concomitant enhancements in ILC2s and M2 macrophages that helped control adipose tissue inflammation. Higher expression levels of IL-33 in cadherin-11–deficient mice mediated ILC2 activation, resulting in higher IL-13 expression levels and M2 macrophage expansion in adipose tissue. Consistent with reduced adipose tissue inflammation, cadherin-11–deficient mice were protected from obesity-induced glucose intolerance and adipose tissue fibrosis. Importantly, anti–cadherin-11 mAb blockade similarly improved inflammation and glycemic control in obese WT mice. These results suggest that stromal fibroblasts expressing cadherin-11 regulate adipose tissue inflammation and thus highlight cadherin-11 as a potential therapeutic target for the management of obesity.

Authors

Sook Kyung Chang, Ayano C. Kohlgruber, Fumitaka Mizoguchi, Xavier Michelet, Benjamin J. Wolf, Kevin Wei, Pui Y. Lee, Lydia Lynch, Danielle Duquette, Victòria Ceperuelo-Mallafré, Alexander S. Banks, Michael B. Brenner

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Figure 5

Cadherin-11–/– deficiency protects obese mice from poor glycemic control.

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Cadherin-11–/– deficiency protects obese mice from poor glycemic control...
WT and cad-11–/– mice were fed a HFD for 5 weeks, unless otherwise indicated. (A) BW of mice on a HFD (n = 5 HFD-WT and n = 4 HFD-KO). Data are representative of more than 3 independent experiments. EchoMRI analysis for (B) BW and (C) lean and fat mass (n = 7 ND-WT, n = 5 ND-KO, n = 5 HFD-WT, and n = 4 HFD-KO). Data are representative of 2 independent experiments. (D) GTTs and ITTs for WT and cad-11–/– mice fasted overnight for the GTT (n = 9 HFD-WT and n = 8 HFD-KO) and fasted 4 hours for the ITT (n = 4 HFD-WT and n = 5 HFD-KO). Data are representative of more than 3 independent experiments. (E) GTTs for littermates of WT and cad-11–/– mice fed a HFD for 5 weeks (n = 7 HFD-WT, n = 7 HFD-Het, and n = 5 HFD-KO). Het, heterozygous. (F) HOMA-IR index. (G) Serum levels of insulin (n = 5 HFD-WT and n = 5 HFD-KO), adiponectin, and FGF21 (n = 8–9 per group, pooled from 2 independent experiments). (H) Serum levels of FFA (n = 10 per group) and TG (n = 17–18 per group, pooled from 3 independent experiments). Serum factor analyses were done separately with serum samples collected from 3 independent experiments. (I) Representative image of livers and graph showing liver weights for WT and cad-11–/– mice (n = 10 per group, combined from 2 independent experiments). (J) Representative H&E staining of liver sections from WT and cad-11–/– mice fed a HFD for 12 weeks. Scale bars: 100 μm. (K) TLC analyses of nonpolar lipids isolated from livers of obese WT and cad-11–/– mice. Arrow indicates the TG-specific bands as determined by the TG standards (STD) on the TLC plate. Graph shows ImageJ densitometric analysis of TLC-resolved TG (n = 5 HFD-WT and n = 5 HFD-KO). Data are representative of 2 independent experiments. (L) Analysis of ALT activity in serum collected from mice fed a HFD for 12 weeks (n = 7 HFD-WT and n = 6 HFD-KO, combined from 2 independent experiments). Data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired Student’s t test (A–C, F–I, K, and L) and 2-way ANOVA, for WT and cad-11–/– mice (D and E).