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Perilipin 5 deletion unmasks an endoplasmic reticulum stress-fibroblast growth factor 21 axis in skeletal muscle
journal contribution
posted on 2018-04-01, 00:00 authored by Magdalene K Montgomery, Ruzaidi Mokhtar, Jacqueline Bayliss, Helena C Parkington, Victor M Suturin, Clinton BruceClinton Bruce, Matthew J WattLipid droplets (LDs) are critical for the regulation of lipid metabolism, and dysregulated lipid metabolism contributes to the pathogenesis of several diseases, including type 2 diabetes. We generated mice with muscle-specific deletion of the LD-associated protein perilipin 5 (PLIN5, Plin5MKO ) and investigated PLIN5's role in regulating skeletal muscle lipid metabolism, intracellular signaling, and whole-body metabolic homeostasis. High-fat feeding induced changes in muscle lipid metabolism of Plin5MKO mice, which included increased fatty acid oxidation and oxidative stress but, surprisingly, a reduction in inflammation and endoplasmic reticulum (ER) stress. These muscle-specific effects were accompanied by whole-body glucose intolerance, adipose tissue insulin resistance, and reduced circulating insulin and C-peptide levels in Plin5MKO mice. This coincided with reduced secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle and liver, resulting in reduced circulating FGF21. Intriguingly, muscle-secreted factors from Plin5MKO , but not wild-type mice, reduced hepatocyte FGF21 secretion. Exogenous correction of FGF21 levels restored glycemic control and insulin secretion in Plin5MKO mice. These results show that changes in lipid metabolism resulting from PLIN5 deletion reduce ER stress in muscle, decrease FGF21 production by muscle and liver, and impair glycemic control. Further, these studies highlight the importance for muscle-liver cross talk in metabolic regulation.
History
Journal
DiabetesVolume
67Issue
4Pagination
594 - 606Publisher
American Diabetes AssociationLocation
Arlington, Va.Publisher DOI
eISSN
1939-327XLanguage
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2018, American Diabetes AssociationUsage metrics
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No categories selectedKeywords
AnimalsBlood GlucoseDiet, High-FatEndoplasmic Reticulum StressEnergy MetabolismFatty AcidsFibroblast Growth FactorsGlucose Tolerance TestHomeostasisIntracellular Signaling Peptides and ProteinsLipid DropletsLipid MetabolismLiverMiceMice, KnockoutMuscle ProteinsMuscle, SkeletalOxidation-ReductionOxidative StressSignal TransductionScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismUNFOLDED PROTEIN RESPONSEINSULIN-RESISTANCEGLUCOSE-HOMEOSTASISFATTY-ACIDFGF21METABOLISMEXPRESSIONEXERCISEPLIN5
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