cAMP-Regulated Cell Proliferation in Brown Preadipocytes

Abstract: As a prototypical second messenger, cAMP is involved in the regulation of multiple cell functions. cAMP has a well established inhibitory effect on cell proliferation in smooth muscle and epithelial cell types. However, there is accumulating evidence also for stimulatory effect on proliferation, mainly in endocrine cell types.Mechanisms mediating the cAMP stimulatory effect are not well studied. cAMP, produced via ?1-adrenoceptor activation, promotes cell proliferation in brown preadipocytes. Due to the importance of brown adipose tissue in energy metabolism and its implication in the treatment of obesity and type II diabetes, understanding the mechanisms of tissue recruitment has clinical implication for the treatment of these metabolic syndromes.We found that the Erk1/2 family of MAPK, often involved in regulation of cell proliferation, can be activated in response to the stimulation of G protein-coupled receptors, including adrenergic receptors (?1-, ?2-, ?1- and ?3-Adrenoceptors) and mitogenic lysophosphatidic acid (LPA) in primary cultured brown adipocytes. In contrast to the case e.g. in many immortalized cell lines and various primary cultured cells, EGF receptor transactivation is not employed in Erk1/2 activation by any G protein-coupled receptor tested in brown adipocytes. This suggests that EGF receptor transactivation is not an universal mediation process for GPCR activation of MAPK.cAMP-activated cell proliferation in brown preadipocytes is mediated through PKA rather than Epac under serum-free conditions. This effect is independent of PI3K/Akt, mTOR or Erk1/2 MAPK pathways. Differential responses to two different MEK inhibitors PD98059 and U0126 suggested the involvement of a pathway sensitive to PD98059, but independent of the Erk1/2 family of MAPK. At the transcriptional level, by combining microarray and RT-qPCR, we have identified eight genes, under the regulation of cAMP, that may be involved in the further mediation of the cAMP effect on cell proliferation.An understanding of cAMP-induced cell proliferation may be of importance both in metabolic and cancer research.