Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels.
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.
Department of Human Biology, NUTRIM School for Nutrition, Toxicology, and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
Madeleen
M
Bosma
Matthijs K C
MK
Hesselink
Lauren M
LM
Sparks
Silvie
S
Timmers
Maria João
MJ
Ferraz
Frits
F
Mattijssen
Denis
D
van Beurden
Gert
G
Schaart
Marc H
MH
de Baets
Fons K
FK
Verheyen
Sander
S
Kersten
Patrick
P
Schrauwen
D000818:Animals; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism* / Q000648:ultrastructure; D059305:Diet, High-Fat / Q000009:adverse effects; D018274:Electroporation; D005260:Female; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D000070780:Perilipin-2; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism
D008565:Membrane Proteins; D009124:Muscle Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; C000602984:Plin2 protein, rat; D034741:RNA, Small Interfering; D011994:Recombinant Proteins