Cold exposure and human metabolism: A heterogeneous response across tissues and organs

Cold-induced metabolic responses across human organs and tissues vary markedly and do not regulate metabolism uniformly. The magnitude and nature of these responses differ depending on the type of cold exposure, ranging from mild surface cooling and beta-adrenergic stimulation to deep tissue cooling impacting intracellular biophysical and metabolic properties. Upregulating brown adipose tissue (BAT) activity has been proposed to improve whole-body metabolism. Despite its high metabolic activity, BAT mass is typically only 50-100 g and may contribute less than 1% of total heat production during thermogenesis. In contrast, skeletal muscles and white adipocytes may play greater roles in thermogenic and metabolic regulation. Cold exposure triggers a cascade of metabolic responses across tissues, extending beyond fuel partitioning and the regulation of uncoupling proteins. It also alters gene expression, protein synthesis, and metabolic pathways. In response to cold, the body increases sympathetic nervous system activity, leading to peripheral vasoconstriction and energy substrate mobilization. Brown adipocytes increase mitochondrial uncoupling to produce heat, while skeletal muscle contributes through shivering and non-shivering thermogenesis. The liver adjusts glucose production and lipid metabolism, the heart and circulatory system adapt to altered hemodynamic demands, and the kidneys modify fluid balance. Endocrine systems, including the thyroid, amplify thermogenic capacity, and the brain integrates thermal sensing with behavioral responses. Cold exposure also modulates immune function, cytokine profiles and inflammatory pathways across tissues, and shifts in gut microbiome composition influence nutrient absorption, bile acid metabolism and energy homeostasis. These coordinated tissue-specific adaptations enable the maintenance of core temperature during cold stress.