FGF21 signaling activation: Treating obesity at the expense of cardiac hypertrophy?
Left ventricular hypertrophy (LVH) can occur as a physiological adaptation to transient stressors such as exercise or pregnancy, or as a pathological response to chronic strain. Pathological LVH contributes substantially to heart failure with preserved or reduced ejection fraction (HFpEF, HFrEF). While intracellular drivers have been well studied, the role of interorgan signaling remains less defined.
Our recent published work in humans and mice revealed a liver–brain–heart axis mediated by fibroblast growth factor 21 (FGF21). Although FGF21 analogs show metabolic benefits and are in clinical development, we found that under sustained cardiac stress, FGF21 can promote pathological hypertrophy. In pressure overload (transverse aortic constriction, TAC), hepatic FGF21 production rises before cardiac dysfunction, inducing FGF21 expression in cardiomyocytes (CMs). Subsequently, CM-derived FGF21 disrupts hypothalamic oxytocin signaling, driving pathological LVH. Deleting FGF21 from hepatocytes or CMs restored oxytocin signaling and reduced LVH, identifying CM-derived FGF21 as a direct mediator of cardiomyopathy.
On the other hand, in HFpEF, the effects diverged: hepatocyte-specific FGF21 deletion, which was protective in TAC, accelerated progression to HFrEF, suggesting an early adaptive role for liver-derived FGF21. Conversely, CM-specific deletion delayed HFpEF development.
These findings constitute the basis of our ongoing research aiming to address how liver-derived FGF21 promotes adaptive hypertrophy, whereas CM-derived FGF21 drives maladaptive remodeling. This work has important implications for ongoing clinical use of FGF21 analogs in metabolic disease, underscoring the need to evaluate cardiac risk and highlighting the potential of targeting the FGF21–oxytocin pathway for heart failure prevention and treatment.
SPEAKER BIOGRAPHY
Konstantinos Drosatos received his undergraduate degree in Biology from the Aristotle University of Thessaloniki in 2000. He pursued graduate studies in Molecular Biology and Biomedicine at the University of Crete, Greece, and Boston University, USA. From 2007 to 2012, he conducted postdoctoral research at Columbia University, where he was later promoted to Associate Research Scientist. In 2014, he joined the Temple University School of Medicine as a tenure-track Assistant Professor and was promoted to Associate Professor with tenure in 2020. In 2021, he was appointed Ohio Eminent Scholar and Professor of Pharmacology & Systems Physiology at the University of Cincinnati College of Medicine.
Date:
21 November 2025, 13:00
Venue:
Sherrington Library, off Parks Road OX1 3PT
Venue Details:
Sherrington Building
Speaker:
Professor Konstantinos Drosatos (University of Cincinnati College of Medicine)
Organising department:
Department of Physiology, Anatomy and Genetics (DPAG)
Organisers:
Dr Thomas Keeley (DPAG, University of Oxford),
Dr Mootaz Salman (DPAG, University of Oxford)
Organiser contact email address:
events@dpag.ox.ac.uk
Host:
Associate Professor Lisa Heather (DPAG, University of Oxford)
Part of:
DPAG Head of Department Seminar Series
Booking required?:
Not required
Audience:
Members of the University only
Editor:
Hannah Simm
