FGF21 Acts as a Stress Hormone by Boosting Cellular Repair via Hydrogen Sulfide
New research reveals FGF21 has a physiological role in reducing ER stress by amplifying the unfolded protein response through sulfide signaling.
Summary
FGF21 is a hormone long known for its metabolic effects at high doses, but its normal physiological role has been unclear. This study from Helmholtz Center Munich reveals that FGF21 acts as an endocrine stress hormone, helping cells manage a common form of cellular damage called endoplasmic reticulum (ER) stress. When proteins in cells misfold, the unfolded protein response (UPR) kicks in to restore order. Researchers found that FGF21 amplifies this repair process by increasing the production of hydrogen sulfide (H2S), a signaling gas. This mechanism requires the FGF21 receptor beta-klotho and works even at normal, physiological hormone levels. The discovery opens new avenues for understanding metabolic disease and potentially harnessing FGF21 or H2S-based therapies to protect cells from stress-related damage.
Detailed Summary
Endoplasmic reticulum (ER) stress is a fundamental cellular challenge in which the ER becomes overwhelmed with misfolded proteins, triggering the unfolded protein response (UPR). Chronic, unresolved ER stress is implicated in obesity, type 2 diabetes, fatty liver disease, and aging. Understanding what naturally regulates this process could unlock new therapeutic strategies.
Researchers at the Helmholtz Center Munich used proximity labeling — a cutting-edge technique that maps a protein's immediate molecular neighborhood inside living cells — to investigate how FGF21 interacts with its receptor beta-klotho (KLB) at the intracellular level. They discovered unexpected associations between FGF21 signaling and protein folding machinery, ER stress pathways, and hydrogen sulfide (H2S) production.
The key finding is that FGF21 enhances, but does not independently initiate, the UPR by stimulating enzymatic production of H2S, a gasotransmitter with known cytoprotective properties. When sulfide signaling was blocked — either genetically or pharmacologically — FGF21's ability to modulate the UPR was abolished. Conversely, administering an H2S donor in vivo reproduced FGF21's effects, confirming H2S as the critical intermediate. Importantly, even physiological (not just suprapharmacological) concentrations of FGF21 were sufficient to regulate the UPR through increased hepatic H2S production.
These results reframe FGF21 from a pharmacological metabolic regulator into a physiological stress hormone with a defined molecular mechanism. The FGF21–H2S–UPR axis may represent an endogenous cellular protection system activated during metabolic stress states such as fasting or overnutrition.
Clinically, this work supports FGF21 analogs currently in development for NASH, obesity, and metabolic syndrome as having a plausible stress-protective mechanism beyond their known effects on lipid and glucose metabolism. However, full interpretation is constrained by abstract-only access, and the translational implications to human physiology require confirmation in clinical studies.
Key Findings
- FGF21 acts as an endocrine stress hormone that amplifies the unfolded protein response to reduce ER stress.
- FGF21 increases enzymatic hydrogen sulfide (H2S) production, which mediates its enhancement of the UPR.
- Blocking sulfide signaling eliminates FGF21's protective effect on ER stress, confirming H2S as the key mediator.
- Even physiological FGF21 levels — not just high pharmacological doses — activate UPR modulation via hepatic H2S.
- An H2S donor drug reproduced FGF21's effects in vivo, suggesting a potential therapeutic avenue.
Methodology
The study used proximity labeling to map intracellular interactions of FGF21 at its receptor beta-klotho, combined with genetic and pharmacological inhibition of sulfide signaling and in vivo H2S donor experiments. Both loss-of-function (gene knockout, inhibitors) and gain-of-function (H2S donor administration) approaches were used to establish causality. The research was conducted at the Helmholtz Center Munich with collaborators at the University of Alabama at Birmingham and Novo Nordisk.
Study Limitations
This summary is based on the abstract only, as the full paper is not open access, limiting assessment of sample sizes, model systems, and detailed methodology. It is unclear how directly these findings translate to human physiology without clinical validation studies. Some authors have financial ties to Novo Nordisk and Eli Lilly, which should be noted when interpreting the findings.
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