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Role of group 2 innate lymphoid cells in regulation of adipocyte development and function in steady state and in obesity

第 2 组先天淋巴细胞在稳定状态和肥胖中脂肪细胞发育和功能调节中的作用

基本信息

批准号：
18K15202
负责人：
EALEY KAFI
金额：
$ 2.66万
依托单位：
Institute of Physical and Chemical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Early-Career Scientists
财政年份：
2018
资助国家：
日本
起止时间：
2018-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18K15202/
关键词：
ILC2 adipose tissue adipocyte precursor adipogenesis obesity immunometabolism homeostasis

项目摘要

During obesity development, new mature adipocytes arise from the differentiation of adipocyte precursor (AP) cells within WAT and the extracellular matrix (ECM) of adipose tissues undergoes remodeling. Group 2 innate lymphoid cells (ILC2s) are most abundant in visceral WAT and have been reported to be important for maintaining adipose tissue homeostasis. We hypothesized that ILC2s may be important for regulating AP activation and differentiation in visceral adipose tissue.We found that soluble factors from ILC2s inhibited lipid accumulation in APs during differentiation and increased appearance of adipocytes with a fibroblastic phenotype, with increased production of collagens and ECM proteins. Using next-generation proteomics analysis, we identified several proteins involved in lipogenesis that were downregulated and proteins involved in cell-cell adhesion and ECM stability and remodeling significantly upregulated by ILC2-derived factors. In vivo, early AP activation induced by HFD feeding, was associated with upregulation of pathways involved in ECM production. Early AP activation was significantly blunted in Il2rg-/-Rag2-/- mice that lack adaptive and innate lymphoid cells, compared to Rag2-/- mice that lack adaptive lymphoid cells but have innate lymphoid cells, including ILC2. These data suggest that activated adipose-tissue resident ILC2s may inhibit cellular bioenergetic pathways to prevent excessive lipid accumulation upon early exposure to a high fat diet and may also be involved in remodeling of the extracellular matrix to accommodate excess energy.

在肥胖发展过程中，新的成熟脂肪细胞由 WAT 内的脂肪细胞前体 (AP) 细胞分化产生，并且脂肪组织的细胞外基质 (ECM) 发生重塑。第 2 组先天淋巴细胞 (ILC2) 在内脏 WAT 中最为丰富，据报道对于维持脂肪组织稳态非常重要。我们假设ILC2可能对于调节内脏脂肪组织中的AP激活和分化很重要。我们发现ILC2的可溶性因子在分化过程中抑制AP中的脂质积累，并增加具有成纤维细胞表型的脂肪细胞的出现，同时增加胶原蛋白和ECM蛋白的产生。通过下一代蛋白质组学分析，我们发现了几种参与脂肪生成的蛋白质被下调，以及参与细胞间粘附、ECM 稳定性和重塑的蛋白质被 ILC2 衍生因子显着上调。在体内，HFD 喂养诱导的早期 AP 激活与 ECM 产生相关途径的上调有关。与缺乏适应性淋巴细胞但具有先天性淋巴细胞（包括 ILC2）的 Rag2-/- 小鼠相比，缺乏适应性和先天性淋巴细胞的 Il2rg-/-Rag2-/- 小鼠的早期 AP 激活显着减弱。这些数据表明，活化的脂肪组织驻留ILC2可能会抑制细胞生物能量途径，以防止早期暴露于高脂肪饮食时脂质过度积累，并且还可能参与细胞外基质的重塑以容纳多余的能量。