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，脂肪细胞前体(AP)细胞在WAT内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。第二组天然淋巴样细胞(ILC2s)在内脏水中含量最丰富，已被报道对维持脂肪组织的动态平衡具有重要作用。我们推测ILC2s可能对调节内脏脂肪组织中AP的激活和分化起重要作用。我们发现ILC2s中的可溶性因子抑制了AP分化过程中的脂质积聚，增加了成纤维细胞表型的脂肪细胞的出现，增加了胶原蛋白和ECM蛋白的产生。利用下一代蛋白质组学分析，我们发现了几个与脂肪形成有关的蛋白质，这些蛋白质在ILC2衍生因子的作用下下调，参与细胞间黏附、ECM稳定性和重塑的蛋白质显著上调。在体内，HFD喂养诱导的AP早期激活与参与ECM产生的途径上调有关。与缺乏适应性淋巴样细胞但具有天然淋巴样细胞(包括ILC2)的Rag2-/-小鼠相比，缺乏适应性和先天淋巴样细胞的IL2RG-/-Rag2-/-小鼠的早期AP激活明显减弱。这些数据表明，激活的脂肪组织驻留的ILC2可能会抑制细胞的生物能量途径，以防止在早期暴露于高脂肪饮食时过度的脂肪积累，并可能参与细胞外基质的重塑，以适应多余的能量。

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.