Perilipin 5 (PLIN5) is a lipid-droplet associated protein that is highly expressed in oxidative tissues, such as skeletal muscle and heart, and plays a major role in regulating lipid metabolism in most tissues. The aim of this study was to delineate the role of PLIN5 in regulating substrate metabolism in muscle. Lipid and glucose metabolism were assessed by radiometric techniques in primary myotubes produced from wild type and whole body PLIN5 null mice. Mice with conditional targeted deletion of PLIN5 in skeletal and cardiac muscle were generated by Cre-Lox approaches (MCK-Cre) and used to examine metabolism in muscle in vivo. Wild-type (Wt) and PLIN5 muscle-specific knockout (Plin5MKO) mice were fed either a chow or a high fat diet (HFD) for 12 weeks before experiments. PLIN5 deletion increased lipolysis of intramyocellular triacylglycerol and the oxidation of the liberated fatty acids in vitro. PLIN5 deletion did not affect the oxidation or storage of extracellular-derived fatty acids, glucose oxidation or glycogen synthesis but did remodel the intracellular lipid pool, resulting in increased ceramide content. Plin5MKO mice had normal body weight, food intake and energy expenditure. The respiratory exchange ratio (RER) was reduced in Plin5MKO mice, demonstrating an increase in whole-body fatty acid oxidation and reciprocal decrease in carbohydrate oxidation. Intriguingly, fatty acid and glucose oxidation were not different between genotypes when assessed in skeletal muscle ex vivo. In mice fed a HFD, glucose tolerance was markedly better in Plin5MKO compared with Wt mice and this was associated with increased glucose clearance without changes in endogenous glucose production. 

The conclusion from these studies is that PLIN5 ablation increases intracellular lipolysis and remodels the skeletal muscle lipidome, without marked effects on glucose metabolism in vitro. In contrast, PLIN5 ablation enhances glucose disposal in the setting of rodent obesity in vivo. This mismatch in glucose metabolism and the discrepancy between whole-body and skeletal muscle fatty acid oxidation suggests that PLIN5 ablation may alter endocrine signalling to modulate whole body metabolism. Alternatively, altered metabolism in another tissue, most likely the heart, may be driving the in vivo phenotype.