Perilipin 2 Improves Insulin Sensitivity in Skeletal Muscle Despite Elevated Intramuscular Lipid Levels

  1. Patrick Schrauwen1
  1. 1Department of Human Biology, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
  2. 2Department of Human Movement Sciences, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre, Maastricht, the Netherlands
  3. 3Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands
  4. 4Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands
  5. 5Department of Neuroscience, School of Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands
  6. 6Department of Molecular Cell Biology, Maastricht University Medical Centre, Maastricht, the Netherlands
  1. Corresponding author: Patrick Schrauwen, p.schrauwen{at}maastrichtuniversity.nl.

Abstract

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.

  • Received October 7, 2011.
  • Accepted April 20, 2012.

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