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

Authors:
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, Carl Weidinger
Year of publication:
2019
Volume:
10
Issue:
1
Issn:
2041-1723
Journal title abbreviated:
NAT COMMUN
Journal title long:
Nature communications
Impact factor:
12.121
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.