Nesfatin-1
A hypothalamic satiety peptide that suppresses food intake completely independently of leptin, which is why it keeps getting revisited as a route into leptin-resistant obesity.
Also known as NUCB2-derived peptide, NEFA/nucleobindin-2 fragment, NUCB2(1-82)
Animal data only — Rodent or other animal studies. Dose translation to humans is genuinely uncertain.
Twenty years of consistent rodent data since the 2006 Nature discovery paper, heavily reliant on intracerebroventricular dosing. Human data are limited to circulating-level associations. No receptor, no human trial, no viable delivery route yet.
How it works
Nesfatin-1 is the N-terminal fragment of nucleobindin-2, produced in the paraventricular and supraoptic nuclei, the arcuate nucleus and the nucleus of the solitary tract, as well as peripherally in gastric mucosa and pancreatic beta cells. Central administration reduces feeding in a dose-dependent way and this effect persists in Zucker rats with defective leptin receptors, which is the key observation driving interest. Downstream it requires intact melanocortin-3/4 receptor signalling and engages oxytocin and CRF pathways. Peripheral nesfatin-1 also enhances glucose-stimulated insulin secretion. Its receptor has still not been cloned, which is a serious limitation — nearly thirty years of hormone biology says an orphan ligand with no identified receptor is hard to drug rationally. It also crosses the blood-brain barrier bidirectionally by a non-saturable mechanism, which is unusual for a peptide this size.
Targets: Melanocortin-3/4 receptor pathway (downstream), Oxytocin neurons, CRF signalling, Unidentified nesfatin-1 receptor
Dosing
| Protocol | Dose | Frequency | Route |
|---|---|---|---|
| No human protocol existsNot applicable. | — | not established | subcutaneous |
- · Almost all convincing rodent work uses intracerebroventricular injection — a route that does not exist outside a laboratory. Peripheral dosing produces much weaker effects. This is the central reason nesfatin-1 has not become a drug despite twenty years of enthusiasm.
Cycling
Not applicable.
Pharmacology
- Half-life
- Short. Circulating half-life has not been formally established in humans.
- Onset
- Anorectic effect within hours of central administration in rodents.
- Routes
- intranasal, subcutaneous, intravenous
- Molecule
- Endogenous 82-amino-acid peptide cleaved from nucleobindin-2
- Sequence length
- 82 amino acids
Handling
- Diluent
- Bacteriostatic water
- Lyophilised
- Freezer at -20 C or below.
- Reconstituted
- Refrigerated, short term; avoid freeze-thaw cycles.
Intranasal — usable, with a caveat
Intranasal dosing appears in rodent studies of appetite and anxiety, and that is the whole evidence base for the route. Nothing in humans.
Mixing
At 82 residues this is a small protein, not a simple synthetic peptide; correct folding matters and cheap material often is not correct.
Side effects
- commonUnknown in humans— No human administration data exist.
- uncommonBlood pressure elevation— Central nesfatin-1 raises blood pressure and sympathetic outflow in rodents — a genuine theoretical concern for any future human use.
Do not use if
- Human use outside research.
- Uncontrolled hypertension - rodent data show sympathoexcitatory and pressor effects.
What to monitor
- · Not applicable outside research.
Legal status
Research reagent. Not approved anywhere.
References
- Oh-I et al. 2006, Nature — identification of nesfatin-1 as a satiety molecule in the hypothalamus (preclinical)
Mechanism in depth
Cleaved from nucleobindin-2, nesfatin-1 reduces food intake in rodents through a leptin-independent central mechanism - which is what made it interesting, since leptin resistance limits leptin-based approaches. Its receptor has never been identified, which is the central gap in the entire literature.
What usually goes wrong
A peptide with no identified receptor cannot have a mechanistically justified dose, and any protocol offered for it is invented. The human literature is entirely observational - circulating levels correlate with metabolic states - with no intervention.
Receptor targets
- Unidentified — No receptor has been cloned or confirmed
Leptin-independent appetite suppression in rodents
Genuinely uncertain
- The receptor is unknown, twenty years after discovery.
- No human interventional trial exists.
- All human data is correlational.