Patel Vishal J, Joharapurkar Amit A, Kshirsagar Samadhan G, Sutariya Brijesh K, Patel Maulik S, Bahekar Rajesh H, Jain Mukul R
Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H.No.8A, Moraiya, Ahmedabad, 382210, India.
Curr Mol Pharmacol. 2019;12(2):139-146. doi: 10.2174/1874467212666190212112402.
Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism.
We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH).
Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH.
Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.
胰高血糖素样肽-1（GLP-1）和胰高血糖素受体的平衡激动剂正逐渐成为治疗肥胖症和糖尿病的疗法。此类激动剂还可调节脂质代谢，且与其降低体重的作用无关。除胆汁稳态外，激动剂的许多作用部分由成纤维细胞生长因子21（FGF21）信号介导。由于甲状腺激素是胆汁稳态的重要调节因子，我们研究了甲状腺激素在激动剂诱导的脂质和胆汁代谢变化中的作用。
我们评估了单剂量150至10000μg/kg的激动剂Aib2 C24嵌合体2对高脂饮食诱导的肥胖（DIO）小鼠和正常饮食小鼠中四碘甲状腺原氨酸（T4）和三碘甲状腺原氨酸（T3）的影响。在四个小鼠模型中评估了激动剂的重复剂量治疗（150μg/kg，皮下注射），即对DIO小鼠、丙硫氧嘧啶（PTU）治疗的DIO小鼠、甲巯咪唑（MTM）治疗的DIO小鼠以及胆碱缺乏、L-氨基酸限定、高脂饮食（CDAHFD）诱导的非酒精性脂肪性肝炎（NASH）模型的脂质和胆汁稳态的影响。
单剂量激动剂治疗未改变正常饮食小鼠和DIO小鼠的血清T3和T4。激动剂治疗改善了脂质代谢和胆汁胆固醇排泄。GLP-1和胰高血糖素激动剂的长期治疗未改变甲状腺功能减退的DIO小鼠和CDAHFD诱导的NASH小鼠的血清T3。治疗4周和40周后，激动剂使DIO小鼠的血清T4升高，不过甲状腺功能减退小鼠或NASH小鼠的T4水平未观察到变化。
我们的数据表明，GLP-1和胰高血糖素受体的激动剂不会通过甲状腺信号调节胆汁稳态。
