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J. Biol. Chem., Vol. 283, Issue 25, 17116-17122, June 20, 2008

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Muscarinic Receptor Activation of AMP-activated Protein Kinase Inhibits Orexigenic Neuropeptide mRNA Expression^*

From the Medical Research Council (MRC) Cellular Stress Group, MRC Clinical Sciences Centre, Du Cane Road, London W12 0NN, United Kingdom

AMP-activated protein kinase (AMPK) plays a crucial role in both cellular and whole body energy homeostasis. Here we demonstrate that the muscarinic receptor agonist carbachol activates AMPK1-containing complexes in the human SH-SY5Y cell line via a mechanism specific for the AMPK upstream kinase, Ca²⁺/calmodulin-dependent protein kinase kinase β. Activation of AMPK inhibits mRNA expression of the orexigenic neuropeptides Agouti-related peptide and melanin-concentrating hormone but surprisingly has no effect on neuropeptide Y mRNA, a neuropeptide previously shown to be regulated by AMPK. Rather than restoring mRNA levels to baseline, pharmacological inhibition of Ca²⁺/calmodulin-dependent protein kinase kinase β or AMPK greatly increases Agouti-related peptide and melanin-concentrating hormone mRNA expression. These data support a hypothesis that modulating basal AMPK activity in the hypothalamus is essential for maintaining tight regulation of pathways contributing to food intake.

Received for publication, November 1, 2007 , and in revised form, March 26, 2008.

^* This work was supported by the Medical Research Council (to D. C. and A. S.) and a Wellcome Trust/Imperial College Value in People Award (to C. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-20-8383-2097; Fax: 44-20-8383-8514; E-mail: claire.thornton{at}imperial.ac.uk.

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