Bosma M, Sparks L M, Hooiveld G J, Jorgensen J A, Houten S M, Schrauwen P, Kersten S, Hesselink M K C
Department of Human Biology, NUTRIM, Maastricht University Medical Centre, The Netherlands.
Biochim Biophys Acta. 2013 Apr;1831(4):844-52. doi: 10.1016/j.bbalip.2013.01.007. Epub 2013 Jan 22.
AIMS/HYPOTHESIS: While lipid deposition in the skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like the skeletal muscle. Here we investigated the effects of PLIN5 overexpression - in comparison with the effects of PLIN2 - on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity.
Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in the skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays.
TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function.
CONCLUSIONS/INTERPRETATION: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in the skeletal muscle promoted expression of a cluster of genes under control of PPARα and PGC1α involved in FA catabolism and mitochondrial oxidation.
目的/假设：虽然骨骼肌中的脂质沉积被认为与肥胖相关的胰岛素抵抗有关，但肌内中性脂质（IMCL）的积累本身并不一定会导致胰岛素抵抗。我们之前证明，脂滴包被蛋白围脂滴蛋白2的过表达会增加肌内脂质含量，同时改善胰岛素敏感性。围脂滴蛋白家族的另一个成员围脂滴蛋白5（PLIN5）主要在骨骼肌等氧化组织中表达。在这里，我们研究了PLIN5过表达对骨骼肌脂质水平、基因表达谱和胰岛素敏感性的影响，并与PLIN2的影响进行了比较。
采用基因电穿孔法使高脂饮食喂养的大鼠胫骨前肌中PLIN5过表达。电穿孔8天后，通过高胰岛素-正常血糖钳夹技术测定骨骼肌中胰岛素介导的葡萄糖摄取。进行电子显微镜、荧光显微镜和脂质提取以研究IMCL的积累。使用微阵列获得基因表达谱。
PLIN5过表达后，三酰甘油（TAG）储存和脂滴大小增加。尽管IMCL含量较高，但胰岛素敏感性未受损，二酰甘油（DAG）和酰基肉碱水平未受影响。与PLIN2过表达的影响相反，微阵列数据分析显示基因表达谱有利于脂肪酸（FA）氧化并改善线粒体功能。
结论/解读：PLIN2和PLIN5均增加中性IMCL含量，且不影响胰岛素介导的葡萄糖摄取。与PLIN2过表达的影响相反，骨骼肌中PLIN5的过表达促进了一组受PPARα和PGC1α控制的基因的表达，这些基因参与FA分解代谢和线粒体氧化。
