Abstract
Aims/hypothesisIn contrast to insulin-resistant individuals, insulin-sensitive athletes possess high intramyocellular lipid content (IMCL), good mitochondrial function and high perilipin 5 (PLIN5) levels, suggesting a role for PLIN5 in benign IMCL storage. We hypothesised a role for PLIN5 in modulating fasting-mediated insulin resistance.MethodsTwelve men were fasted for 60 h, before and after which muscle biopsies were taken and stained for lipid droplets (LDs), PLIN5 and laminin. Confocal microscopy images were analysed for LD size, number, PLIN5 association and subcellular distribution.ResultsFasting elevated IMCL content 2.8-fold and reduced insulin sensitivity (by 55%). Individuals with the most prominent increase in IMCL showed the least reduction in insulin sensitivity (r = 0.657; p = 0.028) and mitochondrial function (r = 0.896; p = 0.006). During fasting, PLIN5 gene expression or PLIN5 protein content in muscle homogenates was unaffected, microscopy analyses revealed that the fraction of PLIN5 associated with LDs (PLIN5+) increased significantly (+26%) upon fasting, suggesting PLIN5 redistribution. The significant increase in LD number (+23%) and size (+23%) upon fasting was entirely accounted for by PLIN5+ LDs, not by LDs devoid of PLIN5. Also the association between IMCL storage capacity and insulin resistance and mitochondrial dysfunction was only apparent for PLIN5+ LDs.Conclusions/interpretationFasting results in subcellular redistribution of PLIN5 and promotes the capacity to store excess fat in larger and more numerous PLIN5-decorated LDs. This associates with blunting of fasting-induced insulin resistance and mitochondrial dysfunction, suggesting a role for PLIN5 in the modulation of fasting-mediated lipotoxicity.Trial registration:trialregister.nl NTR 2042Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3865-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Excess lipid can be stored ectopically as triacylglycerol in lipid droplets (LDs)
The association between intramyocellular lipid (IMCL) storage capacity and insulin resistance and mitochondrial dysfunction was only apparent for perilipin 5 (PLIN5)+ LDs
Muscle lysates were made from sections with equal distribution between type I and type II muscle fibres in the fed and fasted state (50 ± 2% and 52 ± 4% type I fibres in the fed IMCL content and insulin resistance Fasting significantly augmented IMCL content (1.67 ± 0.32 arbitrary units [AU] in the fed state; 4.60 ± 0.72 AU after fasting) [29]
Summary
Excess lipid can be stored ectopically as triacylglycerol in lipid droplets (LDs) (e.g. in skeletal muscle). This is often associated with compromised myocellular insulin sensitivity [1,2,3]. Rodent studies revealed that a high-fat diet increases intramyocellular lipid (IMCL) content and promotes insulin resistance [4]. Acute elevation of lipid availability in humans profoundly augments IMCL storage and insulin resistance [5]. Excess fat in muscle is stored in LDs containing predominantly neutral lipids like triacylglycerol and cholesteryl esters. Endurance-trained athletes have high levels of IMCL while being very sensitive to insulin [15] and are less sensitive to acute lipid-induced insulin resistance upon lipid infusion [5]. In searching for a unifying factor in conditions of maintained insulin sensitivity despite the presence of high levels of IMCL, we noticed that in all conditions when insulin sensitivity was maintained even though IMCL was high or elevated, the gene expression or protein content of perilipin 5 (PLIN5) was increased [13, 16, 17]
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