Cold exposure and metabolic health: Therapeutic potential for obesity, diabetes, and beyond

Cold exposure, an inducer of brown adipose tissue thermogenesis, has been applied to relieve exercise-induced pain and inflammation, modulate circulation and enhance metabolism. However, its role in managing metabolic diseases and the underlying molecular mechanisms remain inadequately understood. This review provides a comprehensive, updated perspective on the therapeutic potential of cold exposure in obesity, diabetes, inflammation, and cancer. First, we address the physiological effects of cold exposure on adipose tissue thermogenesis and metabolic adaptations. Next, we summarize findings from preclinical and human studies demonstrating that cold exposure reduces serum lipid levels, enhances insulin sensitivity and glucose homeostasis, modulates immune responses, and inhibits tumor growth. Mechanistically, cold sensing is primarily mediated by transient receptor potential channels (TRPM8, TRPA1) in preclinical models, with downstream signaling involving the calcium-protein kinase A-uncoupling protein 1 pathway regulating thermogenesis and metabolism. Despite promising potential, cold exposure is linked to stress and cardiovascular risks, especially in vulnerable populations with metabolic disorders or advanced age. The clinical translation is hindered by unstandardized protocols, flawed cooling devices, and incomplete understanding of human brown adipose tissue function. Further research is necessary to elucidate these risks and develop strategies balancing the benefits and harms of cold exposure for clinical translation.