Leptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease

Jörn F. Ziegler, Chotima Böttcher, Marilena Letizia, Cansu Yerinde, Hao Wu, Inka Freise, Yasmina Rodriguez-Sillke, Ani K. Stoyanova, Martin E. Kreis, Patrick Asbach, Desiree Kunkel, Josef Priller, Ioannis Anagnostopoulos, Anja A. Kühl, Konstanze Miehle, Michael Stumvoll, Florian Tran, Broder Fredrich, Michael Forster, Andre Franke, Christian Bojarski, Rainer Glauben, Britt-Sabina Löscher, Britta Siegmund () and Carl Weidinger ()
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Jörn F. Ziegler: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Chotima Böttcher: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Marilena Letizia: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Cansu Yerinde: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Hao Wu: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Inka Freise: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Yasmina Rodriguez-Sillke: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Ani K. Stoyanova: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Martin E. Kreis: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Patrick Asbach: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Desiree Kunkel: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Josef Priller: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Ioannis Anagnostopoulos: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Anja A. Kühl: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Konstanze Miehle: University of Leipzig Medical Center
Michael Stumvoll: University of Leipzig Medical Center
Florian Tran: Christian-Albrechts-University of Kiel
Broder Fredrich: Christian-Albrechts-University of Kiel
Michael Forster: Christian-Albrechts-University of Kiel
Andre Franke: Christian-Albrechts-University of Kiel
Christian Bojarski: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Rainer Glauben: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Britt-Sabina Löscher: Christian-Albrechts-University of Kiel
Britta Siegmund: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Carl Weidinger: Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Leptin has been shown to modulate intestinal inflammation in mice. However, clinical evidence regarding its immune-stimulatory potential in human Crohn’s disease remains sparse. We here describe a patient with the unique combination of acquired generalized lipodystrophy and Crohn’s disease (AGLCD) featuring a lack of adipose tissue, leptin deficiency and intestinal inflammation. Using mass and flow cytometry, immunohistochemistry and functional metabolic analyses, the AGLCD patient was compared to healthy individuals and Crohn’s disease patients regarding immune cell composition, function and metabolism and the effects of recombinant N-methionylleptin (rLeptin) were evaluated. We provide evidence that rLeptin exerts diverse pro-inflammatory effects on immune cell differentiation and function, including the metabolic reprogramming of immune cells and the induction of TNFα, ultimately aggravating Crohn’s disease in the AGLCD patient, which can be reversed by anti-TNFα therapy. Our results indicate that leptin is required for human immune homeostasis and contributes to autoimmunity in a TNFα-dependent manner.

Date: 2019
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DOI: 10.1038/s41467-019-13559-7

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