Baranowski Marcin, Zabielski Piotr, Błachnio-Zabielska Agnieszka U, Harasim Ewa, Chabowski Adrian, Górski Jan
Department of Physiology, Medical University of Białystok, Białystok, Poland.
Cell Physiol Biochem. 2014;33(4):1047-57. doi: 10.1159/000358675. Epub 2014 Apr 4.
BACKGROUND/AIM: Liver X receptors (LXRs) are ligand-activated transcription factors that were shown to stimulate hepatic lipogenesis leading to liver steatosis and hypertriglyceridemia. Despite their pro-lipogenic action, LXR activators normalize glycemia and improve insulin sensitivity in rodent models of type 2 diabetes. Antidiabetic action of LXR agonists is thought to result from suppression of hepatic gluconeogenesis. However, it remains unclear whether LXR activation affects muscle insulin sensitivity. In the present study we attempted to answer this question.
The experiments were performed on male Wistar rats fed for 5 weeks on either standard chow or high fat diet. The latter group was further divided into two subgroups receiving either selective LXR agonist - T0901317 (10mg/kg/d) or vehicle during the last week of the experiment. All animals were then anaesthetized and samples of the soleus as well as red and white sections of the gastrocnemius muscle were excised.
As expected, administration of T0901317 to high-fat fed rats augmented diet-induced hyperlipidemia. Nevertheless, it also normalized glucose tolerance and improved insulin-stimulated glucose uptake in isolated soleus muscle. In addition, LXR agonist completely restored glucose transporter 4 expression and insulin-stimulated Akt substrate of 160 kDa phosphorylation in all investigated muscles. Insulin-sensitizing effect of T0901317 was not related to changes in intramuscular level of lipid mediators of insulin resistance, since neither diacylglycerols nor ceramide content was affected by the treatment.
We conclude that improvement in muscle insulin sensitivity is one of the mechanisms underlying the antidiabetic action of LXR activators.
背景/目的：肝脏X受体（LXRs）是配体激活的转录因子，已被证明可刺激肝脏脂肪生成，导致肝脂肪变性和高甘油三酯血症。尽管具有促脂肪生成作用，但在2型糖尿病啮齿动物模型中，LXR激活剂可使血糖正常化并改善胰岛素敏感性。LXR激动剂的抗糖尿病作用被认为是由于抑制肝脏糖异生所致。然而，LXR激活是否影响肌肉胰岛素敏感性仍不清楚。在本研究中，我们试图回答这个问题。
对雄性Wistar大鼠进行实验，分别用标准饲料或高脂饲料喂养5周。在实验的最后一周，后一组进一步分为两个亚组，分别接受选择性LXR激动剂-T0901317（10mg/kg/d）或赋形剂。然后将所有动物麻醉，切除比目鱼肌以及腓肠肌红白肌部分的样本。
正如预期的那样，给高脂喂养的大鼠施用T0901317会加剧饮食诱导的高脂血症。然而，它也使糖耐量正常化，并改善了分离的比目鱼肌中胰岛素刺激的葡萄糖摄取。此外，LXR激动剂完全恢复了所有研究肌肉中葡萄糖转运蛋白4的表达以及胰岛素刺激的160 kDa Akt底物的磷酸化。T0901317的胰岛素增敏作用与肌肉内胰岛素抵抗脂质介质水平的变化无关，因为二酰甘油和神经酰胺含量均未受该治疗影响。
我们得出结论，肌肉胰岛素敏感性的改善是LXR激活剂抗糖尿病作用的潜在机制之一。
