Department of Neurosurgery, Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
Central Laboratory, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
Front Endocrinol (Lausanne). 2022 Aug 11;13:927763. doi: 10.3389/fendo.2022.927763. eCollection 2022.
Ectopic lipid deposition plays a promoting role in many chronic metabolic diseases. Abnormal adipogenic differentiation of mesenchymal stem cells (MSCs) is an important cause of lipid deposition in organs. Studies have shown that serum angiopoietin-like protein 8 (ANGPTL8) levels are increased in patients with many chronic metabolic diseases (such as type 2 diabetes, obesity, and hepatic steatosis), while the role of ANGPTL8 in ectopic lipid accumulation has not been reported.
We used the Gene Expression Omnibus (GEO) database to analyze the expression of ANGPTL8 in subcutaneous adipose tissue of obese patients and qPCR to analyze the expression of ANGPTL8 in the liver of high-fat diet (HFD)-induced obese mice. To explore the potential roles of ANGPTL8 in the progression of ectopic lipid deposition, ANGPTL8 knockout (KO) mice were constructed, and obesity models were induced by diet and ovariectomy (OVX). We analyzed lipid deposition (TG) in the liver, kidney, and heart tissues of different groups of mice by Oil Red O, Sudan black B staining, and the single reagent GPO-PAP method. We isolated and characterized MSCs to analyze the regulatory effect of ANGPTL8 on Wnt/β-Catenin, a key pathway in adipogenic differentiation. Finally, we used the pathway activator LiCl and a GSK3β inhibitor (i.e., CHIR99021) to analyze the regulatory mechanism of this pathway by ANGPTL8.
ANGPTL8 is highly expressed in the subcutaneous adipose tissue of obese patients and the liver of HFD-induced obese mice. Both normal chow diet (NCD)- and HFD-treated ANGPTL8 KO male mice gained significantly less weight than wild-type (WT) male mice and reduced ectopic lipid deposition in organs. However, the female mice of ANGPTL8 KO, especially the HFD group, did not show differences in body weight or ectopic lipid deposition because HFD could induce estrogen overexpression and then downregulate ANGPTL8 expression, thereby counteracting the reduction in HFD-induced ectopic lipid deposition by ANGPTL8 deletion, and this result was also further proven by the OVX model. Mechanistic studies demonstrated that ANGPTL8 could promote the differentiation of MSCs into adipocytes by inhibiting the Wnt/β-Catenin pathway and upregulating PPARγ and c/EBPα mRNA expression.
ANGPTL8 promotes the differentiation of MSCs into adipocytes, suggesting that ANGPTL8 may be a new target for the prevention and treatment of ectopic lipid deposition in males.
异位脂质沉积在许多慢性代谢性疾病中起着促进作用。间充质干细胞（MSCs）异常的成脂分化是器官内脂质沉积的重要原因。研究表明，许多慢性代谢性疾病（如 2 型糖尿病、肥胖和肝脂肪变性）患者的血清血管生成素样蛋白 8（ANGPTL8）水平升高，而 ANGPTL8 在异位脂质蓄积中的作用尚未报道。
我们使用基因表达综合数据库（GEO）分析肥胖患者皮下脂肪组织中 ANGPTL8 的表达，并用 qPCR 分析高脂肪饮食（HFD）诱导肥胖小鼠肝脏中 ANGPTL8 的表达。为了探讨 ANGPTL8 在异位脂质沉积进展中的潜在作用，构建了 ANGPTL8 敲除（KO）小鼠，并通过饮食和卵巢切除术（OVX）诱导肥胖模型。我们用油红 O、苏丹黑 B 染色和单试剂 GPO-PAP 法分析不同组小鼠肝、肾和心脏组织中的脂质沉积（TG）。我们分离并鉴定了 MSC，以分析 ANGPTL8 对脂肪生成分化的关键途径 Wnt/β-Catenin 的调节作用。最后，我们使用途径激活剂 LiCl 和 GSK3β 抑制剂（即 CHIR99021）分析 ANGPTL8 对该途径的调节机制。
ANGPTL8 在肥胖患者的皮下脂肪组织和 HFD 诱导的肥胖小鼠肝脏中高表达。无论是正常饲料（NCD）喂养还是 HFD 处理的 ANGPTL8 KO 雄性小鼠，其体重明显低于野生型（WT）雄性小鼠，并且器官中的异位脂质沉积减少。然而，ANGPTL8 KO 雌性小鼠，尤其是 HFD 组，体重或异位脂质沉积没有差异，因为 HFD 可诱导雌激素过度表达，然后下调 ANGPTL8 表达，从而抵消 ANGPTL8 缺失对 HFD 诱导的异位脂质沉积的减少，这一结果也进一步通过 OVX 模型得到证实。机制研究表明，ANGPTL8 可通过抑制 Wnt/β-Catenin 通路和上调 PPARγ 和 c/EBPα mRNA 表达来促进 MSC 向脂肪细胞分化。
ANGPTL8 促进 MSC 向脂肪细胞分化，提示 ANGPTL8 可能是男性异位脂质沉积预防和治疗的新靶点。
