Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome
- Ximena Hildebrandt
- Önay Veli
- Armel Hyoubi
- Julia Zinngrebe
- Ali T. Abdallah
- Julian Rodefeld
- Anne Hoffmann
- Liane Gardeweg
- Öykü Kaya
- Elena Wagner
- Andreas Lindhorst
- Matea Poggenberg
- Yuan Wang
- Joëlle Dimmler
- Jutta Schillings
- Pegi Koci
- Francesca Bonechi
- Lucas Valdez Capuccino
- Christine Kiefer
- Konstantinos Kelepouras
- Adhideb Ghosh
- Falko Noé
- Christian Wolfrum
- Michael Singer
- Gianmaria Liccardi
- Tom Luedde
- Aslihan Yavas
- Ahmed Ghallab
- Jan G. Hengstler
- Philipp Antczak
- Martin Gericke
- Holger Winkels
- Matthias Blüher
- Henning Walczak
- Alessandro Annibaldi
- Pamela Fischer-Posovszky
- Nieves Peltzer
2025-09-17
Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes ( Hoip A-KO ) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8–mediated cell death is sufficient to prevent lipodystrophy and MASLD in Hoip A-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death–driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome.