Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, Scotland, UK.
Gene Expression and Regulation, School of Life Sciences, University of Dundee, Dundee, Scotland, UK.
J Endocrinol. 2024 May 20;262(1). doi: 10.1530/JOE-24-0079. Print 2024 Jul 1.
CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.
CD44 是一种细胞表面黏附受体和干细胞标志物，最近被牵连到慢性代谢性疾病中。CD44 的缺失可改善肥胖症中的脂肪组织炎症和胰岛素抵抗。在这里，我们研究了人源和鼠源脂肪组织中细胞类型特异性的 CD44 表达，并进一步研究了前体细胞中的 CD44 如何调节脂肪细胞功能。我们使用 Crispr Cas9 介导的基因缺失和慢病毒介导的基因再表达，发现 CD44 的缺失促进脂肪细胞分化和脂肪生成，而 CD44 的再表达则消除了这种作用，并降低了 3T3-L1 细胞对胰岛素的反应性和脂联素的分泌。从机制上讲，CD44 通过抑制 Pparg 的表达来实现这一点。通过定量蛋白质组学分析，我们进一步发现，细胞周期调控途径主要被 CD44 的缺失所下调。事实上，CD44 的再表达适度恢复了参与细胞周期所有阶段的蛋白质的表达。这些数据进一步得到了 CD44 缺失细胞中前体细胞增殖率增加和 CD44 再表达降低这一效应的支持。我们的数据表明，CD44 在调节脂肪生成和脂肪细胞功能方面起着至关重要的作用，可能是通过调节 PPARγ 和细胞周期相关途径。这项研究首次提供了证据，证明前体细胞中表达的 CD44 在主要表达 CD44 的免疫细胞之外，在调节脂肪细胞功能方面发挥着关键作用。因此，靶向（前）脂肪细胞中的 CD44 可能为治疗肥胖相关代谢并发症提供治疗潜力。
