ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation. To better understand the role of intracellular ANGPTL8 in adipocytes and assess whether it may play a role in adipocyte differentiation, we knocked down its expression in normal mouse subcutaneous preadipocytes. ANGPTL8 knockdown reduced adipocyte differentiation, cellular TG accumulation and also isoproterenol-stimulated lipolysis at day 7 of differentiation. RNA-Seq analysis of ANGPTL8 siRNA or control siRNA transfected SC preadipocytes on days 0, 2, 4 and 7 of differentiation showed that ANGPTL8 knockdown impeded the early (day 2) expression of adipogenic and insulin signaling genes, PPARγ, as well as genes related to extracellular matrix and NF-κB signaling. Insulin mediated Akt phosphorylation was reduced at an early stage during adipocyte differentiation. This study based on normal primary cells shows that ANGPTL8 has intracellular actions in addition to effects in the extracellular space, like modulating LPL activity. Preadipocyte ANGPTL8 expression modulates their differentiation possibly via changes in insulin signaling gene expression.

ANGPTL8主要在肝脏和脂肪组织中表达，通过与ANGPTL3和ANGPTL4的相互作用调节细胞外空间中存在的脂蛋白脂肪酶（LPL）的活性和甘油三酯（TG）代谢。细胞内 ANGPTL8 是否也能在其表达的组织中发挥作用尚不确定。ANGPTL8 表达在前脂肪细胞中较低，并且在分化过程中显着增加。为了更好地了解细胞内 ANGPTL8 在脂肪细胞中的作用并评估它是否在脂肪细胞分化中发挥作用，我们敲低了其在正常小鼠皮下前脂肪细胞中的表达。ANGPTL8 敲低减少了脂肪细胞分化、细胞 TG 积累以及分化第 7 天异丙肾上腺素刺激的脂肪分解。在分化第 0、2、4 和 7 天对 ANGPTL8 siRNA 或对照 siRNA 转染的 SC 前脂肪细胞进行 RNA-Seq 分析表明，ANGPTL8 敲低阻碍了脂肪形成和胰岛素信号基因、PPARγ 以及相关基因的早期（第 2 天）表达。细胞外基质和 NF-κB 信号传导。胰岛素介导的 Akt 磷酸化在脂肪细胞分化的早期阶段减少。这项基于正常原代细胞的研究表明，ANGPTL8 除了在细胞外空间中发挥作用外，还具有细胞内作用，例如调节 LPL 活性。前脂肪细胞 ANGPTL8 表达可能通过胰岛素信号基因表达的变化来调节其分化。