Department of Human Biology, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
Diabetes. 2012 Nov;61(11):2679-90. doi: 10.2337/db11-1402. Epub 2012 Jul 17.
Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid (IMCL) storage exceeds intracellular needs and induces lipotoxic events, ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/adipose differentiation-related protein [ADRP]) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol (TAG) storage, marginally increased fatty-acid (FA) oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase in protein content of the subunits of the oxidative phosphorylation (OXPHOS) chain. Diacylglycerol levels were unchanged, whereas ceramide levels were increased. Despite the increased IMCL accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs toward TAG storage in LDs, thereby blunting lipotoxicity-associated insulin resistance.
2 型糖尿病的特征是骨骼肌中脂质过度储存。过多的肌内脂滴（IMCL）储存超过细胞内的需求，并诱导脂毒性事件，最终导致胰岛素抵抗的发展。脂滴（LD）包被蛋白可能控制骨骼肌中适当的脂质储存。 perilipin 2（PLIN2/脂肪分化相关蛋白[ADRP]）是骨骼肌中表达最丰富的 LD 包被蛋白之一。在这里，我们通过研究体外 PLIN2 敲低和体外及体内过表达的影响，研究了 PLIN2 在肌内脂质处理和胰岛素敏感性中的作用。PLIN2 敲低减少了 LD 形成和三酰基甘油（TAG）储存，轻微增加了脂肪酸（FA）氧化，并增加了棕榈酸掺入二酰基甘油和磷脂。体外 PLIN2 过表达增加了肌内 TAG 储存，同时改善了胰岛素敏感性。体内肌肉特异性 PLIN2 过表达导致 LD 积累增加，并减弱了高脂肪饮食诱导的氧化磷酸化（OXPHOS）链亚基蛋白含量增加。二酰基甘油水平不变，而神经酰胺水平增加。尽管 IMCL 积累增加，但 PLIN2 过表达改善了骨骼肌胰岛素敏感性。我们的结论是，PLIN2 通过将多余的 FA 向 LD 中的 TAG 储存分配来增强脂质在骨骼肌中的储存，从而减轻与脂毒性相关的胰岛素抵抗，因此对脂质储存是必不可少的。
