Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle

Claire Laurens (1) , Virginie Bourlier (1) , Aline Mairal (1) , Katie Louche (1) , Pierre-Marie Badin (1) , Etienne Mouisel (1) , Alexandra Montagner (2) , André Marette (3, 4) , Angelo Tremblay (4, 5) , John S. Weisnagel (6) , Hervé Guillou (7) , Dominique Langin (8) , Denis R. Joanisse (4, 5) , Cédric Moro (1)

1 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
2 ToxAlim - ToxAlim
3 Department of Medicine
4 IUCPQ - Institut Universitaire de Cardiologie et de Pneumologie de Québec
5 Department of Kinesiology
6 CHU-CHUQ
7 ToxAlim-TIM - Toxicologie Intégrative & Métabolisme
8 Department of Clinical Biochemistry

Lipid droplets (LD) play a central role in lipid homeostasis by controlling transient fatty acid (FA) storage and release from triacylglycerols stores, while preventing high levels of cellular toxic lipids. This crucial function in oxidative tissues is altered in obesity and type 2 diabetes. Perilipin 5 (PLIN5) is a LD protein whose mechanistic and causal link with lipotoxicity and insulin resistance has raised controversies. We investigated here the physiological role of PLIN5 in skeletal muscle upon various metabolic challenges. We show that PLIN5 protein is elevated in endurance-trained (ET) subjects and correlates with muscle oxidative capacity and whole-body insulin sensitivity. When overexpressed in human skeletal muscle cells to recapitulate the ET phenotype, PLIN5 diminishes lipolysis and FA oxidation under basal condition, but paradoxically enhances FA oxidation during forskolin-and contraction-mediated lipolysis. Moreover, PLIN5 partly protects muscle cells against lipid-induced lipotoxicity. In addition, we demonstrate that down-regulation of PLIN5 in skeletal muscle inhibits insulin-mediated glucose uptake under normal chow feeding condition, while paradoxically improving insulin sensitivity upon high-fat feeding. These data highlight a key role of PLIN5 in LD function, first by finely adjusting LD FA supply to mitochondrial oxidation, and second acting as a protective factor against lipotoxicity in skeletal muscle.

Mots clés: human health; voluntary muscle; fatty acid; type ii diabetes; obesity

Mots clés: santé humaine; muscle squelettique; homéostasie lipidique; acide gras; diabète de type 2; obésité; métabolisme

Domaines: Sciences du Vivant [q-bio]

Claire Laurens, Virginie Bourlier, Aline Mairal, Katie Louche, Pierre-Marie Badin, et al.. Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle. Scientific Reports, 2016, 6, ⟨10.1038/srep38310⟩. ⟨hal-01605047⟩