Arachidonic acid stimulates DNA synthesis in brown preadipocytes through the activation of protein kinase C and MAPK

作者：Garcia Bibian; Martinez de Mena Raquel; Obregon Maria Jesus^*

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2012, 1821(10): 1309-1315.

DOI：10.1016/j.bbalip.2012.06.011

• Araquidonic acid
• Proliferation
• Brown adipose tissue
• PKC
• MAPK

Arachidonic acid (AA) is a polyunsaturated fatty acid that stimulates the proliferation of many cellular types. We studied the mitogenic potential of AA in rat brown preadipocytes in culture and the signaling pathways involved. AA is a potent mitogen which induces 4-fold DNA synthesis in brown preadipocytes. The AA mitogenic effect increases by NE addition. AA also increases the mitogenic action of different growth factor combinations. Other unsaturated and saturated fatty acids do not stimulate DNA synthesis to the same extent as AA. We analyzed the role of PKC and MEK/MAPK signaling pathways. PKC inhibition by bisindolilmaleimide I (BIS) abolishes AA and phorbol ester stimulation of DNA synthesis and reduces the mitogenic activity of different growth factors in brown preadipocytes. Brown preadipocytes in culture express PKC alpha, delta, epsilon and zeta isoforms. Pretreatment with high doses of the phorbol ester PDBu, induces downregulation of PKCs epsilon and delta and reproduces the effect of BIS indicating that AA-dependent induction of DNA synthesis requires PKC activity. AA also activates MEK/MAPK pathway and the inhibition of MEK activity inhibits AA stimulation of DNA synthesis and brown adipocyte proliferation. Inhibition of PKC delta by rottlerin abolishes AA-dependent stimulation of DNA synthesis and MAPK activation, whereas PKC epsilon inhibition does not produce any effect. In conclusion, our results identify AA as a potent mitogen for brown adipocytes and demonstrate the involvement of the PDBu-sensitive PKC delta isoform and MEK/MAPK pathway in AA-induced proliferation of brown adipocytes. Increased proliferative activity might increase the thermogenic capacity of brown fat.

• 出版日期2012-10