Taher Jennifer, Baker Christopher L, Cuizon Carmelle, Masoudpour Hassan, Zhang Rianna, Farr Sarah, Naples Mark, Bourdon Celine, Pausova Zdenka, Adeli Khosrow
Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.
Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
Mol Metab. 2014 Sep 28;3(9):823-33. doi: 10.1016/j.molmet.2014.09.005. eCollection 2014 Dec.
BACKGROUND/OBJECTIVES: Fasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein (VLDL). Recently, the incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production.
The fructose-fed Syrian golden hamster was employed as a model of diet-induced insulin resistance and VLDL overproduction. Hamsters were treated with the GLP-1R agonist exendin-4 by intraperitoneal (ip) injection for peripheral studies or by intracerebroventricular (ICV) administration into the 3rd ventricle for central studies. Peripheral studies were repeated in vagotomised hamsters.
Short term (7-10 day) peripheral exendin-4 enhanced satiety and also prevented fructose-induced fasting dyslipidemia and hyperinsulinemia. These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma. The observed changes in fasting dyslipidemia could be partially explained by reduced respiratory exchange ratio (RER) thereby indicating a switch in energy utilization from carbohydrate to lipid. Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation. Despite these observations, GLP-1R activity could not be detected in primary hamster hepatocytes, thus leading to the investigation of a potential brain-liver axis functioning to regulate lipid metabolism. Short term (4 day) central administration of exendin-4 decreased body weight and food consumption and further prevented fructose-induced hypertriglyceridemia. Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in vagotomised hamsters implicating the involvement of parasympathetic signaling.
Exendin-4 prevents fructose-induced dyslipidemia and hepatic VLDL overproduction in insulin resistance through an indirect mechanism involving altered energy utilization, decreased hepatic lipid synthesis and also requires an intact parasympathetic signaling pathway.
背景/目的：空腹血脂异常在胰岛素抵抗状态中较为常见，其机制与肝脏极低密度脂蛋白（VLDL）过度生成有关。近来，肠促胰岛素激素胰高血糖素样肽-1（GLP-1）被认为与改善胰岛素抵抗相关的血脂异常及减少肝脏脂质储存有关。鉴于肝脏VLDL生成是循环脂质水平的关键决定因素，我们研究了外周和中枢GLP-1受体（GLP-1R）激动作用在调节VLDL生成中的作用。
用果糖喂养的叙利亚金仓鼠作为饮食诱导的胰岛素抵抗和VLDL过度生成模型。仓鼠通过腹腔内（ip）注射GLP-1R激动剂艾塞那肽-4进行外周研究，或通过脑室内（ICV）注入第三脑室进行中枢研究。在外周迷走神经切断的仓鼠中重复外周研究。
短期（7 - 10天）外周给予艾塞那肽-4可增强饱腹感，还可预防果糖诱导的空腹血脂异常和高胰岛素血症。这些变化伴随着空腹血糖水平降低、肝脏脂质含量减少以及血浆中VLDL-TG和-apoB100水平降低。空腹血脂异常的观察到的变化部分可通过呼吸交换率（RER）降低来解释，这表明能量利用从碳水化合物转向脂质。此外，艾塞那肽-4降低了与肝脏从头脂肪生成和炎症相关的mRNA标志物。尽管有这些观察结果，但在原代仓鼠肝细胞中未检测到GLP-1R活性，因此导致对调节脂质代谢的潜在脑-肝轴的研究。短期（4天）中枢给予艾塞那肽-4可降低体重和食物摄入量，并进一步预防果糖诱导的高甘油三酯血症。此外，艾塞那肽-4的外周降脂作用在迷走神经切断的仓鼠中被消除，这表明副交感神经信号参与其中。
艾塞那肽-4通过涉及能量利用改变、肝脏脂质合成减少的间接机制以及完整的副交感神经信号通路，预防胰岛素抵抗中果糖诱导的血脂异常和肝脏VLDL过度生成。
