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

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 11; pp. 2679 - 2690
• Main Authors: BOSMA, Madeleen, HESSELINK, Matthijs K. C, KERSTEN, Sander, SCHRAUWEN, Patrick, SPARKS, Lauren M, TIMMERS, Silvie, FERRAZ, Maria Joao, MATTIJSSEN, Frits, BEURDEN, Denis Van, SCHAART, Gert, DE BAETS, Marc H, VERHEYEN, Fons K
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-11-2012
• Subjects: Analysis; Animals; Biological and medical sciences; Body fat; Cell culture; Cell Line; Cellular proteins; Cytoplasmic Granules - metabolism; Cytoplasmic Granules - ultrastructure; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Diet, High-Fat - adverse effects; Electroporation; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Transfer Techniques; Glucose; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Male; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - ultrastructure; Muscles; Musculoskeletal system; Oxidative Phosphorylation; Perilipin-2; Phosphorylation; Physiological aspects; Proteins; Rats; Rats, Wistar; Recombinant Proteins - metabolism; RNA Interference; RNA, Small Interfering; Skeletal muscle; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system; Netherlands; Germany; Endocrinopathy; Pancreatic hormone; Sensitivity; Diabetes mellitus; Lipids; Striated muscle; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-1402

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.