Cold-induced nonshivering thermogenesis : tissue origin, activation, recruitment

Abstract: Two types of heat production, shivering and nonshivering thermogenesis, are activated in mammals in the cold. In small mammals, nonshivering thermogenesis becomes the main source of heat upon long-term cold exposure. Cold-induced nonshivering thermogenesis is adrenergically mediated, and the accepted measure of the development of this type of thermogenesis is the thermogenic response of the animal placed in a thermoneutral environment to the injection or infusion of norepinephrine. Brown adipose tissue is regarded as the main source of cold-induced, adrenergically-mediated nonshivering thermogenesis. However, other tissues (e.g. muscle or liver) have also been suggested to contribute to the process. Heat produced in brown adipose tissue is the result of the functioning of a specific protein, uncoupling protein-1 (UCP1). Several proteins structurally related to UCP1 (UCP2, UCP3 and others) have been described. The tissue distribution of the expression of these proteins is broader than that of UCP1 (found only in brown adipocytes), and one of the potential functions ascribed to these proteins was mediation of nonshivering thermogenesis in tissues and organs different from brown adipose tissue.In the present thesis, the sites and mechanisms of nonshivering thermogenesis are discussed. Using UCP1-ablated mice as a model system, we have shown that UCP1-dependent, brown adipose tissue-derived nonshivering thermogenesis is the one and only type of nonshivering thermogenesis induced in the cold. No substitution of a thermogenic process by UCP2, UCP3 or any other protein occurs in the cold-acclimated UCP1-ablated mice.The thermogenic response to injected norepinephrine was shown here to consist of two components: a pharmacological (non-inducible by cold-acclimation) and a physiological (developing as a result of cold exposure) component, and this response therefore cannot, per se, be used as a measure of available adaptive nonshivering thermogenesis. It is, however, a relevant measure of cold-inducible nonshivering thermogenesis, if the comparison is made between warm- and cold-acclimated animals.The processes leading to an increase of the thermogenic capacity of brown adipose tissue (recruitment) are discussed, and the mechanisms behind the acute thermogenic response to several substances (benidipine, carteolol and arotinolol in particular) are analysed.An attempt is also made to clarify the mechanisms underlying the cold intolerance observed in hypothyroidism, an effect possibly dependent on inadequate function of brown adipose tissue and UCP1 expression. Absence of nuclear thyroid hormone receptors also resulted in cold intolerance, but the reason for this was not a lack of UCP1 expression or function, but rather the inability to activate this function. Our results provide new insights into the regulation of UCP1 expression by thyroid hormones and into the reasons for the development of cold sensitivity in the hypothyroid state.