FGF21
| Category | Compounds |
|---|---|
| Also known as | Fibroblast Growth Factor 21 |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | metabolicgrowth-factorlongevitypeptideresearch |
Overview
Fibroblast Growth Factor 21 (FGF21) is an endocrine member of the FGF family secreted mainly by the liver. Unlike classical FGFs that act locally, FGF21 circulates and acts on distant tissues to regulate glucose and lipid metabolism, thermogenesis, and macronutrient preference. It is induced by fasting, ketogenic diets, protein restriction, and stress on the integrated stress response.
FGF21 has been studied extensively as a biomarker and therapeutic candidate for metabolic disease, including obesity, type 2 diabetes, and nonalcoholic steatohepatitis. Recombinant FGF21 and long-acting analogs (often built on Fc-fusion scaffolds) have advanced through clinical trials for fibrotic liver disease and metabolic dysfunction. It is commonly discussed alongside Klotho, which is required as a co-receptor for FGF21 signaling.
FGF21 also attracts attention in longevity research because elevated endogenous levels are observed in calorie-restricted and ketogenic states, and transgenic mice overexpressing FGF21 show extended lifespan. In peptide research contexts, FGF21 is often grouped with MOTS-c, GDF-15, and NAD precursors.
Structure / Chemistry
FGF21 is a ~209-residue protein (mature form ~181 residues) in the FGF19 subfamily. It lacks the heparin-binding domain of classical FGFs, which allows it to diffuse into circulation. Native FGF21 has a very short half-life, so therapeutic programs use engineered variants with stabilized termini and Fc or albumin fusion.
Mechanism of Action
FGF21 signals through FGF receptor 1c in complex with β-Klotho, a co-receptor restricted to metabolic tissues such as liver, adipose, and specific brain regions. Engaged pathways include MAPK and PI3K/AKT signaling. Downstream effects include increased glucose uptake, brown adipose thermogenesis, hepatic fatty-acid oxidation, and central alterations in macronutrient preference (notably reduced sugar and alcohol intake in animal models).
Research Summary
| Area | Finding | Reference |
|---|---|---|
| Discovery | Identified as PPARα target, metabolic hormone | Kharitonenkov et al., J Clin Invest 2005 |
| Longevity | FGF21-transgenic mice showed lifespan extension | Zhang et al., eLife 2012 |
| NASH | FGF21 analogs reduced liver fat in clinical trials | Harrison et al., Lancet 2018 |
| Macronutrient | FGF21 modulated sweet/alcohol preference | Talukdar et al., Cell Metab 2016 |
| Human biology | Elevated FGF21 in fasting and ketogenic states | Gälman et al., Cell Metab 2008 |
Pharmacokinetics
Native FGF21 has a half-life measured in hours, too short for therapeutic use. Fc-fused or PEGylated long-acting variants used in trials have half-lives supporting weekly or biweekly dosing. Administration is subcutaneous. Human research doses vary widely across programs; specific values are referenced only as trial parameters.
Common Discussion Topics
- Relationship between FGF21 and Klotho co-receptor biology.
- Role in ketogenic and fasting states.
- NASH/MASH therapeutic development.
- Overlap with incretin agents like Semaglutide and Retatrutide.
- Longevity implications from transgenic models.
Related Compounds
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Related entries
- 5-Amino-1MQ— 5-Amino-1MQ is a small-molecule NNMT inhibitor studied for its effects on adipose metabolism, NAD+ preservation, and methylation balance.
- FGL— FGL is a short peptide mimetic of NCAM's FGFR-binding site, studied for neurotrophic, cognitive, and neuroprotective activity.
- GDF-15— GDF-15 is a stress-responsive cytokine that signals through the hindbrain GFRAL receptor to suppress appetite, studied in cachexia, obesity, and chemotherapy-induced nausea.
- Klotho— Klotho is an anti-aging protein that functions both as a membrane co-receptor and as a circulating hormone, with roles in phosphate handling, cognition, and longevity.
- MOTS-c— A 16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA gene of mitochondrial DNA, identified as an exercise mimetic that activates AMPK signaling and regulates metabolic homeostasis.