Characterization of intestinal immune responses in generalized human and murine lipodystrophy

Letizia M, Omar T, Weidner P, Jakob MO, Freise I, Krug SM, Löscher BS, Rosati E, Obermayer B, Gamez-Belmonte R, Hecker J, Ziegler JF, Weixler B, Asbach P, Kunkel D, Stumvoll M, Miehle K, Becker C, Klose CS, Glauben R, Beule D, Kühl AA, Conrad T, Tacke F, Wirtz S, Franke A, Sanders AD, Siegmund B, Weidinger C (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Journal of Clinical Investigation American Society for Clinical Investigation

Book Volume: 136

Journal Issue: 6

DOI: 10.1172/JCI192322

Abstract

Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA-seq, we observed an oligoclonal expansion of T cells in the periphery and inflamed intestine in a patient with AGL and Crohn's disease (AGLCD). To explore if loss of adipose tissue triggers lymphoproliferation, we studied lipodystrophic mice as a model for AGL. Unexpectedly, lipodystrophic mice did not show T cell expansion, were protected from colitis, and displayed a defect in the development of proinflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T cell expansion in AGLCD is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell-intrinsic de novo neuroblastoma RAS viral oncogene homolog (NRAS) mutation, implicating somatic mosaicism as a facilitator of clonal T cell expansion and intestinal inflammation in AGLCD.

Authors with CRIS profile

Maria de los Reyes Gámez Belmonte Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Christoph Becker Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Universität Leipzig DE Germany (DE) Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) DE Germany (DE)

How to cite

APA:

Letizia, M., Omar, T., Weidner, P., Jakob, M.O., Freise, I., Krug, S.M.,... Weidinger, C. (2026). Characterization of intestinal immune responses in generalized human and murine lipodystrophy. Journal of Clinical Investigation, 136(6). https://doi.org/10.1172/JCI192322

MLA:

Letizia, Marilena, et al. "Characterization of intestinal immune responses in generalized human and murine lipodystrophy." Journal of Clinical Investigation 136.6 (2026).

BibTeX: Download