title: Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level.
abstract: The 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.
authors.affiliation: Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
authors.forename: Lennart
authors.initials: L
authors.lastname: Zabeau
authors.affiliation: Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia.|Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Cathy J
authors.initials: CJ
authors.lastname: Jensen
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Seeuws
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Venken
authors.affiliation: Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: Verhee
authors.affiliation: Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
authors.forename: Dominiek
authors.initials: D
authors.lastname: Catteeuw
authors.affiliation: Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, Faculty of Sciences, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Australia.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.affiliation: Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hollis
authors.affiliation: Menzies Research Institute, Hobart, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Foote
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
authors.forename: José
authors.initials: J
authors.lastname: Van der Heyden
authors.affiliation: Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.affiliation: Department of Physiology, Monash University, Melbourne, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Oldfield
authors.affiliation: Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.affiliation: Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium. jan.tavernier@vib-ugent.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology; D001483:Base Sequence; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D020738:Leptin / Q000276:immunology* / Q000378:metabolism*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D017931:DNA Primers; D020738:Leptin; D063308:Myelin-Oligodendrocyte Glycoprotein; D054411:Receptors, Leptin
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