A bioenergetic basis for multiorgan dysfunction in sepsis

Elisa Jentho; Temitope Wilson Ademolue; Hessel Peters Sengers; Joe M. Butler; Linlin Xu; Sharad Rastogi; Jamil Zola Kitoko; Sara Emanuela Pagnotta; Bernhard Drotleff; Pedro Faísca; Valentyna O. Polishchuk; Miguel Mesquita; Paul Horn; Uta Barbara Metzing; Sílvia Cardoso; Gilles Mithieux; Michael W Bauer; Osoul Chouchane; Sebastian Weis; Gianni Panagiotou; Christian von Loeffelholz; Tom van der Poll; Miguel Parreira Soares

doi:10.1101/2025.06.12.659280

PathologybioRxivJun 12, 2025

Preprint

A bioenergetic basis for multiorgan dysfunction in sepsis

Elisa Jentho iD, Temitope Wilson Ademolue iD, Hessel Peters Sengers iD, Joe M. Butler iD, Linlin Xu iD, Sharad Rastogi iD, Jamil Zola Kitoko iD, Sara Emanuela Pagnotta iD, Bernhard Drotleff iD, Pedro Faísca iD, Valentyna O. Polishchuk iD, Miguel Mesquita iD, Paul Horn iD, Uta Barbara Metzing, Sílvia Cardoso iD, Gilles Mithieux iD, Michael W Bauer iD, Osoul Chouchane iD, Sebastian Weis iD, Gianni Panagiotou iD, Christian von Loeffelholz iD, Tom van der Poll iD, Miguel Parreira Soares iD

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Abstract

Sepsis is a life-threatening multiorgan dysfunction that develops from a maladaptive host response to infection1. With an estimated 49 million cases per year and [~]11 million related deaths2, sepsis is a global WHO health priority3. Failure to overcome sepsis morbidity and lethality4,5 calls for alternative therapeutic approaches6-8. Here we report that adipocyte lipolysis is vital to prevent the pathogenesis of sepsis in mice. This protective response is evolutionary conserved, producing a plasma lipidomic profile9,10 that reflects on the severity of clinical sepsis. Mechanistically, adipocyte lipolysis fuels energy metabolism to sustain adaptive thermoregulation to infection, via insulin production and insulin receptor (INSR) signaling in adipocytes. This metabolic-based defense strategy does not impact on bacterial burden, establishing disease tolerance to infection11-14. In conclusion, adipocyte lipolysis induces insulin to rewire energy metabolism and support organ function in response to infection.