GLP-1受体激动剂通过FGF21/FGFR1/β-Klotho途径调节肥胖小鼠脂肪组织神经酰胺代谢异常的机制研究

Fibroblast growth factor 21 (FGF21) is a newly discovered metabolic regulatory factor. FGF-21 initiates its biological functions by binding to β-klotho and fibroblast growth factor receptor (FGFR). Recent studies have showed that FGF21 reduces ceramide content and alleviates insulin resistance of white adipose tissue. In animal models of obesity and insulin resistance, the expressions of FGFR1 and β-Klotho in white adipose tissue are markedly decreased. Our previous studies showed that glucagon like peptide-1 (GLP-1) receptor agonist significantly increased the expressions of FGFR1 and β-Klotho, and enhanced insulin sensitivity. Based on the findings, we hypothesize that GLP-1 receptor agonist regulates ceramide metabolism of white adipose tissue in high-fat diet-induced obese mice in a FGF21/FGFR1/β-Klotho-dependent pathway. This study firstly used the high-fat diet-induced obese mice, transgenic mice with ceramidase or β-Klotho knockout within adipose tissue to confirm the effect of GLP-1 receptor agonist on the FGF21/FGFR1/β-Klotho pathway and insulin resistance in white adipose tissue by histology and molecular biology technology; secondly, by using gene manipulation, we explored whether GLP-1 receptor agonist increases the expression of FGFR1 and β-Klotho in adipocytes and reduces ceramide content of white adipose tissue in high-fat diet-induced obese mice in a FGF21/FGFR1/β-Klotho-dependent pathway. The study findings will provide new ideas for the treatment of obesity-associated metabolic disorders.

成纤维细胞生长因子21（FGF21）降低脂肪组织神经酰胺、改善胰岛素抵抗，肥胖时其受体FGFR/β-Klotho表达下降、信号异常。我们前期发现GLP-1受体激动剂改善肥胖2型糖尿病患者FGF21信号通路。预实验示GLP-1降低脂肪细胞神经酰胺、增加FGFR1/β-Klotho表达及激活、改善胰岛素抵抗。据此我们假设：GLP-1受体激动剂通过激活FGF21/FGFR1/β-Klotho调节肥胖小鼠脂肪组织神经酰胺代谢、改善胰岛素抵抗。课题首先在高脂诱导肥胖小鼠、脂肪组织特异性神经酰胺酶敲除及β-Klotho敲除转基因小鼠模型，通过组织学、分子生物学等手段明确GLP-1受体激动剂对FGF21、神经酰胺代谢及胰岛素信号影响；其次在脂肪细胞应用慢病毒敲低或过表达FGFR1、β-Klotho等手段，初步阐明GLP-1受体激动剂改善脂肪组织胰岛素抵抗具体机制。本研究为改善肥胖相关代谢异常提供新的思路

课题研究发现GLP-1受体激动剂利拉鲁肽改善高脂饮食诱导肥胖小鼠肥胖和胰岛素抵抗，改善糖脂代谢指标，抑制内脏脂肪神经酰胺合成酶CerS6的表达，CerS6可能是GLP-1受体激动剂改善胰岛素抵抗、肥胖和2型糖尿病的潜在靶点。脂质组学研究结果表明GLP-1受体激动剂改善肥胖、2型糖尿病患者血清脂代谢紊乱，特别是鞘磷脂、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺代谢，这些改变的脂质可能是GLP-1受体激动剂的治疗潜在的新机制。研究还发现GLP1受体激动剂降低合并非酒精性脂肪性肝病的肥胖2型糖尿病患者血清FGF21水平及肝脏脂肪含量。血清Adropin可能是预测代谢功能障碍相关脂肪肝患者2型糖尿病发展的潜在生物标志物。本研究为GLP-1受体激动剂改善肥胖相关代谢异常提供新的思路。