Adrenergic regulation of proliferation and differentiation in brown adipose tissue

Sammanfattning: Brown adipose tissue constitutes an interesting model for studies of cell proliferation and cellular differentiation. Cold exposure of an animal induces recruitment of the tissue; this is accompanied by a marked increase in the mitogenic activity within the tissue and an increased expression of the genes coding for lipoprotein lipase and the uncoupling protein thermogenin. Stimulation of DNA synthesis in mouse brown adipose tissue invivo is here suggested to be a ß-adrenergically mediated process.In-vitro studies of the lipoprotein lipase gene in brown fat cell cultures revealed that the expression of this gene was under control of ß-adrenergic receptors of the ß3-receptor subtype. The increased gene expression was apparently not mediated through elevations of the cytosolic cAMP level. A localized cAMP signal is proposed.The brown fat cell culture system was further developed, to allow precursor cells to differentiate to the degree that functional resemblance to brown adipose tissue was obtained; especially, the only biochemical parameter which qualitatively distinguishes brown adipose tissue from white adipose tissue (i.e. the presence of thermogenin) was induced. It was found that thermogenin gene expression was under the control of both a)- and ßadrenergic receptors. A synergism between the adrenergic signal, thyroxine and insulin was also observed. Thermogenin itself was synthesized and targeted to the mitochondrial inner membrane, demonstrating the functional competence of these cultured cells.In-vivo studies of thermogenin gene expression in cold-exposed rats revealed that while there was only a transient increase in the transcription rate of the gene, the level of thermogenin mRNA was maintained at an elevated level for at least four days in cold. A prolongation of thermogenin mRNA half-life during sustained cold stimulation is suggested.It was concluded that the adrenergic signalling pathway allows for a multitude of cellular responses, either alone or through interaction with different signal transduction systems, and maybe also through specific localization of the signal in space.