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

在肥胖的发展过程中，WAT内的脂肪细胞前体（AP）细胞分化产生新的成熟脂肪细胞，脂肪组织的细胞外基质（ECM）经历重塑。2组先天淋巴样细胞（ILC2s）在内脏WAT中最丰富，据报道对维持脂肪组织稳态很重要。我们假设ILC2s可能对调节内脏脂肪组织的AP激活和分化很重要。我们发现来自ILC2s的可溶性因子抑制了APs在分化过程中的脂质积累，并增加了成纤维细胞表型的脂肪细胞的外观，增加了胶原和ECM蛋白的产生。利用新一代蛋白质组学分析，我们发现了一些参与脂肪生成的蛋白被下调，而参与细胞-细胞粘附、ECM稳定性和重塑的蛋白被ilc2衍生因子显著上调。在体内，高热量饲料诱导的早期AP激活与参与ECM产生的通路上调有关。与缺乏适应性淋巴样细胞但具有先天淋巴样细胞（包括ILC2）的Rag2-/-小鼠相比，缺乏适应性淋巴样细胞的Il2rg-/-Rag2-/-小鼠早期AP激活明显减弱。这些数据表明，激活的脂肪组织驻留ILC2s可能抑制细胞生物能量途径，以防止早期暴露于高脂肪饮食时过度的脂质积累，也可能参与细胞外基质的重塑以容纳多余的能量。

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.