title: Decoration of intramyocellular lipid droplets with PLIN5 modulates fasting-induced insulin resistance and lipotoxicity in humans.
abstract: OBJECTIVE
  In 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.
  
  
  METHODS
  Twelve 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.
  
  
  RESULTS
  Fasting 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
  Fasting 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.
  
  
  BACKGROUND
  trialregister.nl NTR 2042.
authors: Department of Human Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, 6200MD, Maastricht, the Netherlands.
authors: Anne
authors: A
authors: Gemmink
authors: Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Madeleen
authors: M
authors: Bosma
authors: Department of Genetics and Cell Biology-Molecular Cell Biology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors: Helma J H
authors: HJ
authors: Kuijpers
authors: Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors: Joris
authors: J
authors: Hoeks
authors: Department of Human Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, 6200MD, Maastricht, the Netherlands.
authors: Gert
authors: G
authors: Schaart
authors: Department of Genetics and Cell Biology-Molecular Cell Biology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre+, Maastricht, the Netherlands.|Institute for Molecular Cardiovascular Research IMCAR, Universitätsklinikum Aachen, Aachen, Germany.
authors: Marc A M J
authors: MA
authors: van Zandvoort
authors: Department of Human Biology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Maastricht, the Netherlands.
authors: Patrick
authors: P
authors: Schrauwen
authors: Department of Human Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, 6200MD, Maastricht, the Netherlands. Matthijs.hesselink@maastrichtuniversity.nl.
authors: Matthijs K C
authors: MK
authors: Hesselink
mesh_terms: D000328:Adult; D015153:Blotting, Western; D005215:Fasting / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D007797:Laminin / Q000378:metabolism; D066292:Lipid Droplets; D008297:Male; D000070797:Perilipin-5 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D007797:Laminin; D000070797:Perilipin-5
keywords: Fasting; IMCL; Lipid droplet size; Lipotoxicity; Perilipin 5