Liu, J.; Cone, A. L.; Ferguson, D.; Breese, A.; Skelton, H. E.; Escobedo, A.; Kravitz, A. V.; Landsness, E. C.; Finck, B. N.; Norris, A. J.

Maintaining energy balance requires coordination between food intake and energy expenditure, yet the neural pathways that regulate energy expenditure remain unclear. This study identifies kappa opioid receptor expressing neurons in the preoptic area of the hypothalamus as a key regulator of whole-body metabolism. Using mouse models combined with fiber photometry, chemogenetic activation and inhibition, and chronic disruption of synaptic output, the results show that activity of these neurons follows daily pattern, are suppressed during feeding, and their inhibition acutely increases energy expenditure, body temperature, and activity levels. Long-term inhibition of this population produces sustained weight loss, selective reduction of white fat, preservation of lean mass and brown fat, and improved glucose tolerance even during high-fat feeding. These findings reveal a previously unrecognized circuit that links metabolic state with daily timing cues and suggest that targeting this neuronal population may offer new strategies for treating obesity and related metabolic disorders.