caa a22 4500 606175911 CHVBK 20210128100745.0 cr unu---uuuuu 210128e20150201xx s 000 0 eng 10.1007/s00018-014-1697-x doi (NATIONALLICENCE)springer-10.1007/s00018-014-1697-x Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level [Elektronische Daten] [Lennart Zabeau, Cathy Jensen, Sylvie Seeuws, Koen Venken, Annick Verhee, Dominiek Catteeuw, Geert van Loo, Hui Chen, Ken Walder, Jacob Hollis, Simon Foote, Margaret Morris, José Van der Heyden, Frank Peelman, Brian Oldfield, Justin Rubio, Dirk Elewaut, Jan Tavernier] 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. The Author(s), 2014 Leptin receptor nationallicence Antagonist nationallicence Genetic model nationallicence Nanobody nationallicence Obesity nationallicence Metabolism nationallicence Autoimmune disease nationallicence ALT : Alanine aminotransferase nationallicence AST : Aspartate aminotransferase nationallicence CIA : Collagen induced arthritis nationallicence COMP : Cartilage oligomeric matrix protein nationallicence CRH : Cytokine receptor homology nationallicence EAE : Autoimmune encephalomyelitis nationallicence FN III : Fibronectin type III nationallicence IGD : Immunoglobulin-like domain nationallicence IL : Interleukin nationallicence INF-γ : Interferon gamma nationallicence JAK : Janus kinase nationallicence LR : Leptin receptor nationallicence SEAP : Secreted alkaline phosphatase nationallicence STAT : Signal transducer and activator of transcription nationallicence TNF-α : Tumour necrosis factor alpha nationallicence TReg : Regulatory T cell nationallicence Zabeau Lennart Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut Jensen Cathy Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia aut Seeuws Sylvie Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium aut Venken Koen Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium aut Verhee Annick Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut Catteeuw Dominiek Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut van Loo Geert Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, Faculty of Sciences, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium aut Chen Hui Department of Pharmacology, University of Melbourne, Melbourne, Australia aut Walder Ken Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia aut Hollis Jacob Department of Physiology, Monash University, Melbourne, Australia aut Foote Simon Menzies Research Institute, Hobart, Australia aut Morris Margaret Department of Pharmacology, University of Melbourne, Melbourne, Australia aut Van der Heyden José Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut Peelman Frank Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut Oldfield Brian Department of Physiology, Monash University, Melbourne, Australia aut Rubio Justin Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia aut Elewaut Dirk Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium aut Tavernier Jan Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut Cellular and Molecular Life Sciences Springer Basel 72/3(2015-02-01), 629-644 1420-682X 72:3<629 2015 72 18 https://doi.org/10.1007/s00018-014-1697-x text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1697-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zabeau Lennart Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Jensen Cathy Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia aut NATIONALLICENCE 700 1- Seeuws Sylvie Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Venken Koen Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Verhee Annick Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Catteeuw Dominiek Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- van Loo Geert Inflammation Research Center, Unit of Molecular Signal Transduction in Inflammation, Faculty of Sciences, Flanders Institute for Biotechnology, Ghent University, Ghent, Belgium aut NATIONALLICENCE 700 1- Chen Hui Department of Pharmacology, University of Melbourne, Melbourne, Australia aut NATIONALLICENCE 700 1- Walder Ken Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia aut NATIONALLICENCE 700 1- Hollis Jacob Department of Physiology, Monash University, Melbourne, Australia aut NATIONALLICENCE 700 1- Foote Simon Menzies Research Institute, Hobart, Australia aut NATIONALLICENCE 700 1- Morris Margaret Department of Pharmacology, University of Melbourne, Melbourne, Australia aut NATIONALLICENCE 700 1- Van der Heyden José Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Peelman Frank Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Oldfield Brian Department of Physiology, Monash University, Melbourne, Australia aut NATIONALLICENCE 700 1- Rubio Justin Neurogenetics Laboratory, Howard Florey Institute, Melbourne, Australia aut NATIONALLICENCE 700 1- Elewaut Dirk Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium aut NATIONALLICENCE 700 1- Tavernier Jan Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Flanders Institute for Biotechnology, Ghent University, A. Baertsoenkaai 3, 9000, Ghent, Belgium aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/3(2015-02-01), 629-644 1420-682X 72:3<629 2015 72 18