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Activation of Mitogen-Activated Protein Kinase by Norepinephrine in Brown Adipocytes from Rats¹

Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Ehime 791–02, Japan

Address all correspondence and requests for reprints to: Yasutake Shimizu, Ph.D., Ehime University School of Medicine, Department of Medical Biochemistry, Shigenobu, Ehime 791–02, Japan. E-mail: yshimizu{at}m.ehime-u.ac.jp

We have investigated the adrenergic control of mitogen-activated protein kinase (MAPK) activity in brown adipocytes. Cold exposure in rats led to an activation of MAPK in brown adipose tissue, as determined by the gel mobility shift assay and in-gel kinase assay. In contrast, no activation was seen after surgical sympathetic denervation of the tissue. The neurotransmitter, norepinephrine (NE), directly activated MAPK of brown adipocytes in primary cultures in the absence of insulin and serum. NE-induced activation of MAPK was mimicked by ß-adrenergic agonists, including a ß₃-agonist, BRL37344. Activation of MAPK also was observed by an -agonist, phenylephrine, the extent of which being much lower than that by ß-agonists. The effect of NE was attenuated by the ß-adrenergic antagonist, propranolol. Dibutyryl cAMP also mimicked the effect of NE. The phorbol ester, phorbol-12-myristate, 13-acetate (PMA), could induce activation of MAPK, but pretreatment of the cultured cells with PMA to down-regulate protein kinase C did not abolish the ability of NE in activating MAPK. Furthermore, a selective inhibitor of phosphatidylinositol-3 kinase, wortmannin, did not inhibit the effect of NE, whereas insulin-induced activation of MAPK was totally suppressed. These results demonstrate that NE activates MAPK directly in brown adipocytes and that the effect of NE is not mediated by PMA-sensitive protein kinase C or wortmannin-sensitive phosphatidylinositol-3 kinase but rather is likely to be dependent on ß-receptor-mediated increase in cAMP with a minor contribution of -receptor-mediated signals.

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