Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue

Zeyda, Maximilian; Wernly, Bernhard; Demyanets, Svitlana; Kaun, Christoph; Hämmerle, Mariana Beiral; Hantusch, Brigitte; Schranz, M. Eric; Neuhofer, Angelika; Itariu, Bianca; Keck, Maike; Prager, Gerhard; Wojta, Johann; Stulnig, Thomas M.

doi:10.1038/ijo.2012.118

Cited by 145 publications

(137 citation statements)

References 40 publications

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“…Some macrophages respond to . Taken together, IL-33 may directly activate AAM.It has been reported that IL-33 is produced in the adipose tissue [28,29]. In our study, however, we failed to clearly detect il33 expression in GAT from untreated normal mice (Fig.…”

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confidence: 53%

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

et al. 2015

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Eosinophils are multifunctional leukocytes involved in allergic reactions as well as adipose tissue regulation. IL-5 is required for eosinophil survival; however, the in vivo mechanisms of eosinophil regulation are not fully understood. A tg mouse model with il5 promoter-driven EGFP expression was established for detecting the IL-5-producing cells in vivo. Il5-egfp tg mice expressed high levels of EGFP in gonadal adipose tissue (GAT) cells. EGFP + cells in GAT were mainly group 2 innate lymphoid cells (ILCs). IL-33 preferentially expanded EGFP + cells and eosinophils in GAT in vivo. EGFP + ILCs were found to upregulate prg2 mRNA expression in GAT eosinophils. These results demonstrate that ILCs activate eosinophils in GAT. The blockage of IL-33Rα, on the other hand, did not impair EGFP + ILC numbers but did impair eosinophil numbers in vivo. GAT eosinophils expressed IL-33Rα and IL-33 expanded eosinophil numbers in CD90 + cell-depleted mice. IL-33 was further observed to induce the expression of retnla and epx mRNA in eosinophils. These findings demonstrate that IL-33 directly activates eosinophils in GAT, and together with our other findings described above, our findings show that IL-33 has dual pathways via which it activates eosinophils in vivo: a direct activation pathway and a group 2 ILCmediated pathway. Keywords: Eosinophils r IL-33 r Innate lymphoid cells r IL-5Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionEosinophils are multifunctional leukocytes involved in the elimination of parasites and the initiation of allergic reactions [1]. Eosinophils secrete major basic protein (MBP, prg2), eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin, which damage parasites, and in some cases, damage healthy tissues as well [1]. Eosinophils also play critical roles in metabolic homeostasis relating to obesity [2]. GATA-1 is critical to eosinophil development, and dblGATA mice, in which the GATA binding sites in the Gata1 promoter are mutated, are prone to obesity when fed a high-fat diet [2,3]. Eosinophils are located Correspondence: Associate Prof. Masaaki Hashiguchi e-mail: mhashi@dokkyomed.ac.jp in visceral adipose tissue, and the loss of eosinophils leads to a decrease in alternatively activated macrophage (AAM) accumulation [2]. AAMs in gonadal adipose tissue (GAT) are maintained by . The activation of eosinophils critically depends on IL-5: studies using il5-tg mice or il5-deficient mice and anti-IL-5 Ab have demonstrated that the expansion of eosinophils is largely regulated by . Il5-deficient mice show higher body weight and visceral adipose weight in response to a highfat diet [2]. Deficiency of il5 or eosinophils impairs glucose consumption and promotes obesity [2] and adipose tissue metabolism is thus regulated by eosinophils through the activation of AAMs [2,3,9].Innate lymphoid cells (ILCs) play a protective role against foreign pathogens [10]. ILCs are classified into at least three groups, de...

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confidence: 53%

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

et al. 2015

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“…On one hand, IL-33 has been considered to prevent adipose tissue inflammation and thus reduce metabolic complications (38,41). However, other studies have linked increased Il-33 levels to morbid obesity and the development of diabetes (40,41). Since IL-33 has been mainly implicated in immune cell function, our findings might provide a link between inflammation and adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 47%

“…Conflicting data exist with regard to the role of the IL-33/Il1rl1/ ST2 axis in metabolism. On one hand, IL-33 has been considered to prevent adipose tissue inflammation and thus reduce metabolic complications (38,41). However, other studies have linked increased Il-33 levels to morbid obesity and the development of diabetes (40,41).…”

Section: Discussionmentioning

confidence: 99%

Regulation of De Novo Adipocyte Differentiation Through Cross Talk Between Adipocytes and Preadipocytes

et al. 2015

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There are many known adipokines differentially secreted from the different adipose depots; however, their paracrine and autocrine effects on de novo adipocyte formation are not fully understood. By developing a coculture method of preadipocytes with primary subcutaneous and visceral adipocytes or tissue explants, we could show that the total secretome inhibited preadipocyte differentiation. Using a proteomics approach with fractionated secretome samples, we were able to identify a spectrum of factors that either positively or negatively affected adipocyte formation. Among the secreted factors, Slc27a1, Vim, Cp, and Ecm1 promoted adipocyte differentiation, whereas Got2, Cpq, interleukin-1 receptor-like 1/ST2-IL-33, Sparc, and Lgals3bp decreased adipocyte differentiation. In human subcutaneous adipocytes of lean subjects, obese subjects, and obese subjects with type 2 diabetes, Vim and Slc27a1 expression was negatively correlated with adipocyte size and BMI and positively correlated with insulin sensitivity, while Sparc and Got2 showed the opposite trend. Furthermore, we demonstrate that Slc27a1 was increased upon weight loss in morbidly obese patients, while Sparc expression was reduced. Taken together, our findings identify adipokines that regulate adipocyte differentiation through positive or negative paracrine and autocrine feedback loop mechanisms, which could potentially affect whole-body energy metabolism.

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“…IL-33, discovered in 2005 and widely expressed in fibroblasts, epithelial cells and endothelial cells (16), is reported to exert cardioprotective effects (17,18). In fat tissues, IL-33 and ST2 present a paracrine and positive-feedback signaling mechanism (19,20). Further study shows that the IL-33/ST2 pathway enhances the secretion of T-helper 2 (Th2) cytokines of adipocytes, promotes accumulation of Th2 cells in fat tissues and transforms macrophages into a protective M2 type, all presenting anti-inflammation effects, concomitant with reducing fasting blood glucose and improving insulin resistance (8).…”

Section: Discussionmentioning

confidence: 99%

A single-nucleotide polymorphism in the interleukin-1 receptor-associated protein gene is associated with impaired glucose regulation and type 2 diabetes in a case-controlled study

Wen

Yang

et al. 2015

Biomedical Reports

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Abstract. Impaired glucose regulation (IGR), containing prediabetes and diabetes, is an inflammatory disease. The interleukin-33 (IL-33)/IL-1 receptor-like 1 and IL-1/IL-1 receptor (IL-1R) pathways are involved and play opposite roles. While the IL-1R-associated protein (IL-1Rap) is indispensible for the two pathways, the association between the single-nucleotide polymorphisms (SNPs) of the IL-1Rap gene and IGR has not been determined. TaqMan probe quantitative polymerase chain reaction was used to genotype 11 SNPs in the regions of the IL-1Rap gene selected on the basis of linkage disequilibrium using the HapMap database in a study of 889 individuals (156 IGR patients in the case group and 733 non-diabetic patients in the control group). Logistic regression was applied to control the potential confounders in the multivariate analysis. Among 11 SNPs, IL-1Rap rs3773958 was associated with IGR. Further analysis showed that the odds ratios for GT and GT + GG carriers vs. TT carriers were 1.686 and 1.669, respectively, adjusted for gender, age, weight, waist, drinking, smoking, hypertension, alanine aminotransferase, total cholesterol and triglycerides. For rs3773958 in the non-smoking subgroup, GT and GT + GG carriers had a significantly higher risk of IGR compared to the TT carriers. The same conclusions were drawn using data from non-drinking and non-overweight subgroups. However, interactions between rs3773958 and smoking, drinking or being overweight were not significant. In conclusion, rs3773958 in the IL-1Rap gene region was associated with IGR.

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Severe obesity increases adipose tissue expression of interleukin-33 and its receptor ST2, both predominantly detectable in endothelial cells of human adipose tissue

Cited by 145 publications

References 40 publications

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

IL‐33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells

Regulation of De Novo Adipocyte Differentiation Through Cross Talk Between Adipocytes and Preadipocytes

A single-nucleotide polymorphism in the interleukin-1 receptor-associated protein gene is associated with impaired glucose regulation and type 2 diabetes in a case-controlled study

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