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

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.

Reduced Incorporation of Fatty Acids Into Triacylglycerol in Myotubes From Obese Individuals With Type 2 Diabetes

“…These relationships support our previous findings that highlight the role of PGC1a in the regulation of intramuscular lipid droplet programming in mice and humans (23). Finally, we focused on expression levels of the lipid droplet coat proteins PLIN5, PLIN3, and PLIN2 as well as the lipolytic protein ATGL in both muscle tissue and myotubes because we have previously shown in animal studies that overexpressing PLIN2 or PLIN5 increases TAG storage capacity and results in the prevention of high-fat-induced insulin resistance (40,46). In the current study, we found that PLIN5 was elevated in the muscle tissue of the T2D individuals but not in their myotubes.…”

“…IMCL content inversely correlates with peripheral insulin sensitivity (34-37), suggesting that fat accumulation (38,39). Other studies have even suggested that increasing the TAG storage capacity, specifically in skeletal muscle, may be beneficial (40)(41)(42). Although these studies used different methods (i.e., genetic manipulations, exercise), they clearly demonstrated a beneficial effect of increased TAG storage on skeletal muscle insulin sensitivity.…”

Adaptação Do Músculo Esquelético Ao Exercício Físico: Considerações Moleculares E Energéticas

“…Os fatores NRF1 e 2 são requeridos para a biogênese mitocondrial e os receptores nucleares alfa relacionados ao estrogênio (EERα) induzem a expressão de genes que regulam a fosforilação oxidativa, biogênese mitocondrial e a síntese de ATP. Ambos, fatores NRF1, NRF2 e receptores EERα, mostraram-se elevados no tecido muscular em resposta a oxidação de ácidos graxos 49 54 . A proteína PLIN2 é essencial para o estoque de triglicérides intramusculares e inibição da lipólise 54 .…”

“…Ambos, fatores NRF1, NRF2 e receptores EERα, mostraram-se elevados no tecido muscular em resposta a oxidação de ácidos graxos 49 54 . A proteína PLIN2 é essencial para o estoque de triglicérides intramusculares e inibição da lipólise 54 . Sendo, portanto, a expressão das proteínas PLIN2 e PLIN5 altamente reguladas no exercício aeróbico.…”

“…Sendo, portanto, a expressão das proteínas PLIN2 e PLIN5 altamente reguladas no exercício aeróbico. Foi demonstrado que indivíduos idosos exercitados tiveram maior expressão de PLIN5 em comparação com sedentários 51 e que jovens atletas possuíam elevada expressão de PLIN2 e PLIN5 quando comparados aos controles 54 . Mais recentemente, o músculo esquelético tem ganhado o status de órgão endócrino, acumulando evidências de que durante o exercício, este tecido tem produzido e secretado citocinas e peptídeos ativos (miocinas) na circulação 55 .…”