GDF-15
| Category | Compounds |
|---|---|
| Also known as | Growth Differentiation Factor 15, MIC-1, NAG-1 |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | metabolicappetitecytokinestress-responseresearch |
Overview
Growth Differentiation Factor 15 (GDF-15), also known as MIC-1 or NAG-1, is a divergent member of the TGF-β superfamily. Its circulating levels rise with cellular stress, mitochondrial dysfunction, pregnancy, infection, and various cancers, where it is an independent biomarker for mortality risk. Over the past decade, the identification of GDF-15's CNS receptor reshaped interest in the molecule as a metabolic signal.
The receptor, GFRAL (GDNF-family receptor α-like), is expressed selectively on a small population of neurons in the hindbrain area postrema and nucleus tractus solitarius. Activation suppresses appetite, induces nausea-like behaviors in animal models, and contributes to the wasting phenotype seen in cancer cachexia. This biology has driven two opposing therapeutic strategies — agonism for obesity, antagonism for cachexia and hyperemesis gravidarum.
GDF-15 is frequently discussed alongside other metabolic peptides such as FGF21, Leptin, and the amylin analog Cagrilintide. It is also of interest in Klotho-related longevity conversations because serum GDF-15 rises with age and mitochondrial stress.
Structure / Chemistry
GDF-15 circulates as a ~25 kDa disulfide-linked homodimer of the mature C-terminal domain (~112 residues per monomer). It is synthesized as a larger precursor that is proteolytically processed. Research reagents include recombinant mature dimer and Fc-fused long-acting variants.
Mechanism of Action
GDF-15 binds GFRAL in the hindbrain, recruiting the co-receptor RET to trigger downstream signaling that modulates appetite and energy balance. The restricted CNS receptor distribution means peripheral GDF-15 acts largely through a defined brainstem circuit rather than broad tissue effects. The molecule has also been implicated in mitochondrial integrated stress response signaling.
Research Summary
| Area | Finding | Reference |
|---|---|---|
| Receptor | GFRAL identified as GDF-15 receptor | Yang et al., Nat Med 2017 |
| Appetite | GDF-15 suppressed food intake via hindbrain | Mullican et al., Nat Med 2017 |
| Cachexia | Elevated GDF-15 drives cancer cachexia in models | Johnen et al., Nat Med 2007 |
| Hyperemesis | GDF-15 implicated in pregnancy nausea | Fejzo et al., Nature 2024 |
| Biomarker | GDF-15 predicts cardiovascular and all-cause mortality | Wollert et al., Clin Chem 2017 |
Pharmacokinetics
Native GDF-15 has a short half-life in circulation. Engineered Fc-fused variants have been used in preclinical studies with half-lives supporting weekly or less frequent administration. Both recombinant dimer and antibody-based antagonists are research tools rather than approved drugs.
Common Discussion Topics
- Dual therapeutic rationale — agonism for obesity vs. antagonism for cachexia.
- Role in pregnancy-related nausea and vomiting.
- Relationship to mitochondrial stress and aging biomarkers.
- Overlap with FGF21 as stress-responsive hormones.
- Potential combination with Semaglutide or Cagrilintide.
Related Compounds
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Related entries
- Cagrilintide— Cagrilintide is a long-acting amylin analog investigated for weight management, often studied in combination with GLP-1 receptor agonists.
- FGF21— FGF21 is a liver-derived metabolic hormone of the fibroblast growth factor family that regulates energy balance, glucose handling, and macronutrient preference.
- 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.
- Leptin— A 167-amino acid adipokine produced by white adipose tissue that signals energy reserve status to the hypothalamus, functioning as the body's primary long-term satiety hormone — with leptin resistance being a central feature of common obesity.
- Semaglutide— A long-acting GLP-1 receptor agonist approved for type 2 diabetes (Ozempic) and chronic weight management (Wegovy), with emerging cardiovascular, renal, and neurological research applications.