walder-leptinsmetabolic-2015.pdf (1.27 MB)
Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level.
journal contribution
posted on 2015-02-01, 00:00 authored by L Zabeau, C J Jensen, S Seeuws, K Venken, A Verhee, D Catteeuw, G van Loo, H Chen, Ken WalderKen Walder, J Hollis, S Foote, M J Morris, J Van der Heyden, F Peelman, B J Oldfield, J P Rubio, D Elewaut, J TavernierThe adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. We here provide genetic and biochemical evidence that the metabolic and immune functions of leptin can be uncoupled at the receptor level. First, homozygous mutant fatt/fatt mice carry a spontaneous splice mutation causing deletion of the leptin receptor (LR) immunoglobulin-like domain (IGD) in all LR isoforms. These mice are hyperphagic and morbidly obese, but display only minimal changes in size and cellularity of the thymus, and cellular immune responses are unaffected. These animals also displayed liver damage in response to concavalin A comparable to wild-type and heterozygous littermates. Second, treatment of healthy mice with a neutralizing nanobody targeting IGD induced weight gain and hyperinsulinaemia, but completely failed to block development of experimentally induced autoimmune diseases. These data indicate that leptin receptor deficiency or antagonism profoundly affects metabolism, with little concomitant effects on immune functions.
History
Journal
Cellular and Molecular Life SciencesVolume
72Issue
3Pagination
629 - 644Publisher
Springer VerlagLocation
SwitzerlandPublisher DOI
Link to full text
ISSN
1420-9071eISSN
1420-9071Language
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2015, Springer VerlagUsage metrics
Keywords
Analysis of VarianceAnimalsArthritis, ExperimentalBase SequenceBlotting, WesternDNA PrimersDrug-Induced Liver InjuryEncephalomyelitis, Autoimmune, ExperimentalFlow CytometryHEK293 CellsHumansLeptinMCF-7 CellsMaleMiceMice, Mutant StrainsMolecular Sequence DataMyelin-Oligodendrocyte GlycoproteinProtein Structure, TertiaryReceptors, LeptinReverse Transcriptase Polymerase Chain ReactionSequence Analysis, DNASequence DeletionAntagonistAutoimmune diseaseGenetic modelLeptin receptorMetabolismNanobodyObesityScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyCell BiologyJANUS KINASE\/SIGNAL TRANSDUCERDB\/DB MICEOB\/OB MICEAUTOIMMUNE ENCEPHALOMYELITISPROTECTS MICEOB-RRECEPTORDEFICIENCYACTIVATIONMUTATIONPhysiology
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