Alpha₁-adrenergic receptors in brown adipose tissue : thermogenic significance and mode of action

Sammanfattning: The main function of brown adipose tissue (BAT) is to produce heat in response to cold. Norepinephrine (NE), released from sympathetic nerve terminals, activates the tissue via binding to adrenergic receptors. While the role of the classical ß-adrenergic pathways (including cAMP production and lipolysis) in regulation of BAT metabolism is well documented, very little is known about a-adrenergic receptors and responses, which are the scope of the present thesis. The results demonstrate that hamster and rat BAT possess a large number of specific ( H)prazosin binding sites (about 100 000 binding sites per cell) with all the characteristics generally expected of physiologically relevant a^-adrenergic receptors. The stimulation of these receptors results in at least two physiological responses; increased phosphatidylinositol turnover and increased respiration. About 20% of the NE-stimulated oxygen consumption (i.e. heat production) is due to the activation of (as yet unknown) oi^-adrenergic pathways, while 80% originates from ß^-adrenergic responses. Comparison of agonist and antagonist affinities for a.-receptors with their potencies to regulate the above responses indicates that tight coupling exists between a.-receptor occupation and respiration, and that part of the a^-stimulated phosphatidylinositol turnover is closely associated with receptor occupation and may thus be related to the mediation of c^-stimulation. Pa^| of the hormone-stimulated phosphatidylinositol turnover is also Ca -independent. Agoni^t+ affinity o^f a.-receptors is regulated by guanine nucleotides, Mg , and Na . This indicates an involvement of a guanine nucleotide binding protein in the transduction of a^-adrenergic signals. However, -stimulation does not alter cAMP production (instead changes in cellular Ca dynamics have been demonstrated). Cold acclimation of animals increases a^-receptor density in BAT. As the opposite has been shown regarding ß^-receptors, it is concluded that cold acclimation (i.e. chronic agonist treatment in-situ) leads to inverse regulation of a.- and ß^-receptors (the ratio a./B^ increases). These results, together with some recent reports from other laboratories, indicate that the increased oij-receptor density and increased significance of a^-adrenergic pathways are associated with the activated state of the brown fat.