Activation of AMP-activated protein kinase stimulates proopiomelanocortin gene transcription in AtT20 corticotroph cells

1 Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku; and Departments of 2 Medicine and 3 Clinical Pathophysiology, Nagoya University Graduate School of Medicine and Hospital, Nagoya, Japan Submitted 12 March 2006 ; accepted in final form 21 Febr...

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Published in:American journal of physiology: endocrinology and metabolism 2007-06, Vol.292 (6), p.E1899-E1905
Main Authors: Iwasaki, Yasumasa, Nishiyama, Mitsuru, Taguchi, Takafumi, Kambayashi, Machiko, Asai, Masato, Yoshida, Masanori, Nigawara, Takeshi, Hashimoto, Kozo
Format: Article
Language:English
Subjects:
Adrenocorticotropic Hormone - secretion
Aminoimidazole Carboxamide - administration & dosage
Aminoimidazole Carboxamide - analogs & derivatives
Aminoimidazole Carboxamide - pharmacology
AMP-Activated Protein Kinases
Animals
Cell Line
Cellular biology
Corticotrophs - metabolism
Corticotropin-Releasing Hormone - genetics
Dose-Response Relationship, Drug
Enzyme Activation - physiology
Gene expression
Gene Expression - drug effects
Gene Expression Regulation
Kinases
Metabolism
Multienzyme Complexes - metabolism
Phosphorylation - drug effects
Pro-Opiomelanocortin - genetics
Promoter Regions, Genetic - drug effects
Protein-Serine-Threonine Kinases - metabolism
Ribonucleotides - administration & dosage
Ribonucleotides - pharmacology
RNA, Messenger - metabolism
Signal Transduction - physiology
Transcription Factor AP-1 - physiology
Transcription, Genetic - drug effects
Transcription, Genetic - physiology
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Summary:1 Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Nankoku; and Departments of 2 Medicine and 3 Clinical Pathophysiology, Nagoya University Graduate School of Medicine and Hospital, Nagoya, Japan Submitted 12 March 2006 ; accepted in final form 21 February 2007 Starvation is known to activate the hypothalamo-pituitary-adrenal (HPA) axis, a representative antistress system in the living organism. In this study, we investigated in vitro whether activation of the AMP-activated protein kinase (AMPK), which is known to occur in intracellular energy depletion, influences the expression of POMC gene that encodes adrenocorticotropin. We first confirmed that each subunit of AMPK was expressed in the AtT20 corticotroph cell line. We then found that AICAR, a cell-permeable AMP analog and an activator of AMPK, potently stimulated the 5'-promoter activity of POMC gene in a dose-dependent manner. The effects were promoter specific because AICAR enhanced the AP1-mediated POMC promoter activities but did not influence other transcription factor-induced transcription. The effect of AICAR on POMC gene transcription was completely eliminated by specific AMPK inhibitor compound C or by dominant negative AMPK, whereas overexpression of constitutively active AMPK mimicked the effect of AICAR. Finally, experiments using specific kinase inhibitors suggested that the PI 3-kinase-mediated signaling pathway is at least partly involved in the effect. Our results suggest that intracellular energy depletion with the resultant activation of AMPK directly stimulates the HPA axis at the pituitary level by increasing the expression of POMC gene. adenosine 5'-monophosphate; adrenocorticotropin; energy homeostasis; pituitary; starvation Address for reprint requests and other correspondence: Y. Iwasaki, Dept. of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku 783-8505, Japan (e-mail: iwasaki{at}kochi-u.ac.jp )
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00116.2006