Although Liraglutide (Lira) increases serum irisin levels in type 2 diabetes mellitus (T2DM), it is unclear whether it induces expression of uncoupling protein 1 (UCP1) of adipocytes via promoting irisin secretion from skeletal muscle. Male T2DM rats were treated with 0.4 mg/kg/d Lira twice a day for 8 weeks, and the protein expression of phosphorylated AMP kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase 1 (p-ACC1) and UCP1 in white adipose tissues were detected. Differentiated C2C12 cells were treated with palmitic acid (PA) and Lira to detect the secretion of irisin. Differentiated 3T3-L1 cells were treated with irisin, supernatant from Lira-treated C2C12 cells, Compound C or siAMPKα1, the triglyceride (TG) content and the related gene expression were measured. The transcriptome in irisin-treated differentiated 3T3-L1 cells was analyzed. Lira elevated serum irisin levels, decreased the adipocyte size and increased the protein expression of UCP1, p-AMPK and p-ACC1 in WAT. Moreover, it promoted the expression of PGC1α and FNDC5, the secretion of irisin in PA-treated differentiated C2C12 cells. The irisin and supernatant decreased TG synthesis and promoted the expression of browning- and lipolysis-related genes in differentiated 3T3-L1 cells. While Compound C and siAMPKα1 blocked AMPK activities and expression, irisin partly reversed the pathway. Finally, the transcriptome analysis indicated that differently expressed genes are mainly involved in browning and lipid metabolism. Overall, our findings showed that Lira modulated muscle-to-adipose signaling pathways in diabetes via irisin-mediated AMPKα/ACC1/UCP1/PPARα pathway. Our results suggest a new mechanism for the treatment of T2DM by Lira.

中文翻译：

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利拉鲁肽通过促进骨骼肌细胞分泌鸢尾素来促进UCP1表达和脂肪细胞的脂肪分解

尽管利拉鲁肽 (Lira) 会增加 2 型糖尿病 (T2DM) 患者的血清鸢尾素水平，但尚不清楚它是否通过促进骨骼肌分泌鸢尾素来诱导脂肪细胞解偶联蛋白 1 (UCP1) 的表达。雄性T2DM大鼠给予0.4 mg/kg/d Lira治疗，每天两次，连续8周，观察白色脂肪中磷酸化AMP激酶（p-AMPK）、磷酸化乙酰辅酶A羧化酶1（p-ACC1）和UCP1的蛋白表达检测到组织。用棕榈酸（PA）和Lira处理分化的C2C12细胞，检测鸢尾素的分泌。用irisin、Lira处理的C2C12细胞上清液、Compound C或siAMPKα1处理分化的3T3-L1细胞，测量甘油三酯（TG）含量和相关基因表达。分析了鸢尾素处理的分化 3T3-L1 细胞的转录组。 Lira 提高了 WAT 中血清鸢尾素水平，减少了脂肪细胞大小，并增加了 UCP1、p-AMPK 和 p-ACC1 的蛋白表达。此外，它还促进PA处理的分化C2C12细胞中PGC1α和FNDC5的表达以及鸢尾素的分泌。鸢尾素和上清液减少了 TG 合成，并促进分化的 3T3-L1 细胞中褐变和脂肪分解相关基因的表达。虽然化合物 C 和 siAMPKα1 阻断 AMPK 活性和表达，但鸢尾素部分逆转了该途径。最后，转录组分析表明差异表达的基因主要涉及褐变和脂质代谢。总体而言，我们的研究结果表明，Lira 通过鸢尾素介导的 AMPKα/ACC1/UCP1/PPARα 通路调节糖尿病中的肌肉到脂肪信号通路。我们的结果提出了 Lira 治疗 T2DM 的新机制。