A hypothalamic neuronal population coordinates metabolic adaptations to cold.

Cold exposure increases feeding, thermogenesis, and energy expenditure to maintain body temperature and energy balance, but the underlying neural mechanisms remain unclear. Here, we identify cold-responsive neurons in the dorsal posterior periventricular hypothalamus that coordinate these adaptations. Activation of GABAergic or cold-activated neurons increased food intake, body temperature, and brown adipose tissue thermogenesis, whereas their inhibition attenuated cold-induced hyperphagia and thermogenesis. Single-nucleus RNA sequencing identified Lef1 as a marker of cold-activated neurons in this region. Activation of Lef1+ neurons recapitulated key cold responses, whereas silencing attenuated them. Lef1 positively regulated Kcnk2, which encodes the cold-sensitive potassium channel TREK-1. Cold reduced Kcnk2 expression and potassium currents, while pharmacological or genetic Kcnk2 inhibition increased feeding and body temperature. Conversely, Kcnk2 gain-of-function blunted cold responses. Together, these findings identify Lef1+ hypothalamic neurons and Kcnk2 modulation as a mechanism linking environmental temperature to neuronal activity and systemic metabolic adaptation.