The accumulation of heat shock proteins (HSPs) after the exposure of cells or organisms to elevated temperatures is well established. It is also known that a variety of other environmental and cellular metabolic stressors can induce HSP synthesis. However, few studies have investigated the effect of cold temperature on HSP expression. Here we report that exposure of Institute of Cancer Research (ICR) mice to cold ambient temperatures results in a tissue-selective induction of HSPs in brown adipose tissue (BAT) coincident with the induction of mitochondrial uncoupling protein synthesis. Cold-induced HSP expression is associated with enhanced binding of heat shock transcription factors to DNA, similar to that which occurs after exposure of cells or tissues to heat and other metabolic stresses. Adrenergic receptor antagonists were found to block cold-induced HSP70 expression in BAT, whereas adrenergic agonists induced BAT HSP expression in the absence of cold exposure. These findings suggest that norepinephrine, released in response to cold exposure, induces HSP expression in BAT. Norepinephrine appears to initiate transcription of HSP genes after binding to BAT adrenergic receptors through, as yet, undetermined signal transduction pathways. Thermogenesis results from an increase in activity and synthesis of several metabolic enzymes in BAT of animals exposed to cold challenge. The concomitant increase in HSPs may function to facilitate the translocation and activity of the enzymes involved in this process.

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Adult and aged male C57BL/6J mice were subjected to three consecutive 3-hour cold stress tests (partial physical restraint at 6 degrees C), repeated 2 weeks apart. Body mass and colonic temperature were measured before each test, and colonic temperature, O2 consumption, and CO2 production were measured during cold exposure. The slopes of colonic temperature and heat production and the mean metabolic heat production were calculated for each animal. Adult mice showed stronger cold tolerance compared to aged mice and also exhibited habituation to cold exposure (improvement of cold tolerance with repeated tests). Mean metabolic heat production during cold exposure was greater in adult mice, and only adults demonstrated significant increases across tests in both metabolic heat production and slope of metabolic heat production over time. We hypothesize that reduced cold tolerance in aged mice is related mainly to a decrease in metabolic heat production. Increased metabolic heat production in subsequent tests in adults is a probable mechanism for habituation to repeated cold exposure.

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