This study explored the proteomic basis of cold adaptation, quantifying 11,394 proteins across 6 metabolic tissues and plasma. Systems level analysis revealed an enrichment for proteins involved in metabolism. In brown adipose tissue (BAT), cold adaptation was associated with enhanced glucose utilisation, including select remodelling of upper glycolysis to enhance superoxide production and UCP1 activity, and a downregulation of proteins involved in fatty acid oxidation. Strikingly, opposite changes were observed in liver and white adipose tissues, including upregulation of proteins involved in gluconeogenesis and lipolysis, respectively. This suggests that coordinated changes in many organs are required for maximal BAT thermogenesis. This coordination also associated with cold-regulated alterations to the plasma proteome, including elevated Fetuin A that is consistent with enhanced lipolysis in white adipose. Finally, overlapping but inverse changes in cold-exposed and diet-induced obese mice support impaired BAT activity as a driver of obesity.