Introduction and Objective: PVHMC4R and PBNMC4R neurons are central to the regulation of energy intake and glucose metabolism, yet the neurocircuit mechanisms underlying glycemic control at these neural nodes remain unclear. Here, we investigated whether a PVHMC4R → PBNMC4R neurocircuit contributes to glucoregulation using an intersectional viral mapping approach. Methods: To anatomically define this pathway, we utilized MC4R-Cre;Ai65F mice and delivered a retrograde AAV encoding Flp recombinase (retroAAV-DIO-FLPo) into the PBN, enabling Flp-dependent tdTomato expression selectively in PVHMC4R neurons projecting to the PBN. Robust tdTomato labeling in the PBN and PVH confirmed the correct anatomical specificity of the targeted neurocircuit. To assess circuit functions on energy metabolism, we used MC4R-cre mice to implement an in vivo intersectional (dual) viral strategy by injecting retroAAV-DIO-FLPo into the PBN and a Flp-dependent inhibitory DREADD (AAV-fDIO-hM4Di-mCherry) into the PVH, thereby selectively suppressing the PVHMC4R → PBNMC4R circuit. Results: Acute chemogenetic inhibition with a single dose of CNO increased food intake, demonstrating circuit functionality. Interestingly, blood glucose tended to decrease, indicating a functional role of the neurocircuit to influence glucose metabolism. To determine whether the observed glucoregulatory effects were secondary to changes in caloric intake, we next administered CNO every 8-h to achieve sustained inhibition and conducted pair-feeding. Under pair-fed conditions, constitutive inhibition of the PVHMC4R → PBNMC4R reduced blood glucose by ~20% over 24-h, indicating that this pathway exerts a glucose-lowering effect independent of food intake. Conclusion: These findings expand our understanding of central melanocortin pathways and identify a discrete neurocircuit that links hypothalamic-brainstem communication to glucose homeostasis and suggest the PVHMC4R → PBNMC4R circuit as a potential target for the development of centrally acting anti-diabetic therapies. Disclosure A.A. Uner: None. K. Rodrigues: None. M. Lee: None. W. Yang: None. H. Ozkan: None. J. Young: None. S. Kim: None. J. Hong: None. J. Suh: None. Y. Kim: None. Funding National Institutes of Health (R01DK129946), National Institutes of Health (R01AG080842)
UNER et al. (Fri,) studied this question.