Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis

Glia play a dynamic role in central nutrient sensing and appetite regulation yet represent underexplored targets in treating dysregulated energy balance. Glia within the dorsal vagal complex of the hindbrain synthesize the anorexigenic peptide octadecaneuropeptide (ODN), the influence and therapeutic potential of which remain to be explored. We demonstrate that hindbrain-targeted ODN induced weight loss, counteracted glucoprivation, and improved glucose clearance in rats. Furthermore, blocking central ODN signaling attenuated the anorectic response to GLP-1R agonists in rats. Peripheral administration of an ODN derivative, TDN, improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp in obese mice and induced weight loss without pica behavior, a proxy for nausea in rats, or emesis in the musk shrew, a vomiting mammalian model. Central ODN and TDN treatment in rats was not accompanied by changes in core body temperature, physical activity, or heart rate. This work highlights hindbrain ODN signaling as an important modulator of energy balance and demonstrates the potential for targeting this gliopeptide system to treat dysregulated feeding and metabolic activity without side effects.. Publication Link

Central TDN in rats and peripheral TDN in mice improves weight and glycemic control.

Cumulative HFD intake (A) and 24-hour body weight change (B) in rats injected at the lateral ventricle with TDN (200 μg/2 μl) or vehicle. OGTT (C), OGTT AUC (D), glucose-stimulated insulin (E), ITT (F), and ITT AUC (G) in HFD-fed rats 4V injected with TND (200 μg/2 μl) or vehicle.