Plucinska, K.; Chen, Z.-Z.; Xiang, R.; Zaman, S.; Yan, L.; Hurson, C.; Peterson, C.; Fredrickson, K.; Farrell, L.; Walker, J.; Kars, M. E.; Tiwari, G.; Pourquie, O.; Itan, Y.; Carroll, T.; Chen, K. Y.; Cypess, A. M.; Gerszten, R. E.; Cohen, P.

Cold exposure has been proposed to provide a constellation of salutary effects, yet its molecular correlates remain largely unknown. Brown adipose tissue (BAT) is the main site of adaptive thermogenesis, and its prevalence is linked with cardiometabolic health. Since the benefits of BAT activation and cold exposure more generally may be mediated through blood-borne factors, we conducted an extensive analysis of the circulating proteome linked with an acute cold challenge in healthy adults. Our goal was to uncover early molecular changes triggered by cooling and establish their specific relationships with the human brown adipocyte secretome as well as various phenotypic traits. Based on comprehensive inter-cohort validations, we provide the first reproducible proteomic signature of cold exposure in humans. Our data demonstrate that cooling favorably modulates circulating mediators linked with chronological aging, as well as metabolic and cardiovascular diseases, providing new potential biochemical transducers of the benefits associated with cold therapy.