The rapid switch on of the transient short-term responses involved in adjustment of homeostasis plays a key role in human adaptation to low temperatures that is essential for adjustment to low-temperature environment. The network of signaling pathways together with metabolic regulators provide sufficient plasticity of the cells of immune system, the normal function of which is extremely important for successful human adaptation. Sufficient energy supply to immunocompetent cells makes it possible to form an adequate immune response to any negative factor and to ensure adaptive functional rearrangements. The study was aimed to assess the variants of the immunocompetent cell metabolic pathways involved in acquiring individual cold sensitivity. A total of 180 people aged 25–55 (130 females, 50 males) were assessed before and after the short-term whole body cooling. Enzyme immunoassay was used to define the levels of IL10, IL6, TNFα, irisin, transferrin, sTfR, HIF-1α, Sirt3 in peripheral blood and cell lysate. The levels of glycogen (cytochemical methods) and ATP (luciferin-luciferase assay) in lymphocytes were defined. The decrease in peripheral blood lymphocyte levels after cooling was indicative of the formation of immediate adaptive response and activation of glycolysis amid less intense inflammatory response. The increase in the levels of circulating lymphocytes after the cold esposure was associated with activation of inflammatory responses. The lower ratio of HIF-1α/SIRT3 metabolic regulators was found in the surveyed volunteers who showed no changes in the levels of lymphocytes. This indicated predominance of mitochondrial activity in adaptation to low temperatures.