Muscarinic receptor activation of AMP-activated protein kinase inhibits orexigenic neuropeptide mRNA expression

Abstract

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 AMPKα1-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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.