Melanocortin-Induced PKA Activation Inhibits AMPK Activity Via ERK-1/2 and LKB-1 in Hypothalamic GT1-7 Cells
Melanocortin-Induced PKA Activation Inhibits AMPK Activity Via ERK-1/2 and LKB-1 in Hypothalamic GT1-7 Cells
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DOI：
10.1210/me.2011-1218
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发表时间：
2012-04-01
影响因子：
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通讯作者：
Breit, Andreas
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文献类型：
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作者：
Damm, Ellen;Buech, Thomas R. H.;Breit, Andreas
alpha-Melanocyte-stimulating hormone (alpha-MSH)-induced activation of the melanocortin-4 receptor in hypothalamic neurons increases energy expenditure and inhibits food intake. Active hypothalamic AMP-activated protein kinase (AMPK) has recently been reported to enhance food intake, and in vivo experiments suggested that intrahypothalamic injection of melanocortins decreased food intake due to the inhibition of AMPK activity. However, it is not clear whether alpha-MSH affects AMPK via direct intracellular signaling cascades or if the release of paracrine factors is involved. Here, we used a murine, hypothalamic cell line (GT1-7 cells) and monitored AMPK phosphorylation at Thr(172), which has been suggested to increase AMPK activity. We found that alpha-MSH dephosphorylated AMPK at Thr(172) and consequently decreased phosphorylation of the established AMPK substrate acetyl-coenzyme A-carboxylase at Ser(79). Inhibitory effects of alpha-MSH on AMPK were blocked by specific inhibitors of protein kinase A (PKA) or ERK-1/2, pointing to an important role of both kinases in this process. Because alpha-MSH-induced activation of ERK-1/2 was blunted by PKA inhibitors, we propose that ERK-1/2 serves as a link between PKA and AMPK in GT1-7 cells. Furthermore, down-regulation of liver kinase B-1, but not inhibition of calcium-calmodulin-dependent kinase kinase-beta or TGF beta-activated kinase-1 decreased basal phosphorylation of AMPK and its dephosphorylation induced by alpha-MSH. Thus, we propose that alpha-MSH inhibits AMPK activity via a linear pathway, including PKA, ERK-1/2, and liver kinase B-1 in GT1-7 cells. Given the importance of the melanocortin system in the formation of adipositas, detailed knowledge about this pathway might help to develop drugs targeting obesity. (Molecular Endocrinology 26: 643-654, 2012)
