Raptin, a sleep-induced hypothalamic hormone, suppresses appetite and obesity.

Summary

The authors identify Raptin, a peptide hormone cleaved from RCN2, whose secretion peaks during sleep and is controlled by an SCN–PVN circuit. Raptin binds GRM3 in hypothalamic and gastric neurons to suppress appetite and slow gastric emptying via PI3K-AKT, protecting against obesity; human data link sleep deficiency with impaired Raptin and an RCN2 nonsense variant with night eating and obesity.

Key Findings

• Identified Raptin, a peptide hormone cleaved from RCN2, with sleep-peaking secretion controlled by an SCN (AVP+) to PVN circuit.
• Raptin binds GRM3 in hypothalamic and gastric neurons to reduce appetite and delay gastric emptying via PI3K–AKT signaling.
• Sleep deficiency blunts Raptin release; humans with an RCN2 nonsense variant exhibit night eating syndrome and obesity.

Clinical Implications

Emphasizes sleep health as a metabolic intervention and nominates GRM3–Raptin signaling as a potential target for appetite suppression; Raptin or GRM3 agonists might complement lifestyle therapy, pending safety and efficacy studies.

Limitations

• Predominantly preclinical; causal effects and safety in humans remain to be established.
• Long-term metabolic and cardiovascular consequences of modulating GRM3–Raptin signaling are unknown.

Future Directions

Develop pharmacologic agonists/analogs of Raptin or GRM3 agonists; test efficacy and safety in obesity and sleep-disorder populations; evaluate biomarker utility of circulating Raptin.