This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 22/4/893    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Google Scholar Articles by Yamauchi, M. Articles by Seo, H. PubMed PubMed Citation Articles by Yamauchi, M. Articles by Seo, H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL

Thyroid Hormone Activates Adenosine 5'-Monophosphate-Activated Protein Kinase via Intracellular Calcium Mobilization and Activation of Calcium/Calmodulin-Dependent Protein Kinase Kinase-β

Department of Endocrinology (M.Y., F.K., X.C., X.L., Y.K., H.S.), Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; and Department of Endocrinology and Diabetes (M.Y., Y.O.), Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

Address all correspondence and requests for reprints to: Fukushi Kambe, M.D., Ph.D., Department of Endocrinology, Research Institute of Environmental Medicine (RIEM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. E-mail: kambe{at}riem.nagoya-u.ac.jp.

AMP-activated protein kinase (AMPK) is a key regulator of glucose and fatty acid homeostasis. In muscle cells, AMPK stimulates mitochondrial fatty acid oxidation and ATP production. The thyroid hormone T₃ increases cellular oxygen consumption and is considered to be a major regulator of mitochondrial activities. In this study, we examined the possible involvement of AMPK in the stimulatory action of T₃ on mitochondria. Treatment of C2C12 myoblasts with T₃ rapidly led to phosphorylation of AMPK. Acetyl-coenzyme A carboxylase, a direct target of AMPK, was also phosphorylated after T₃ treatment. Similar results were obtained with 3T3-L1, FRTL-5, and HeLa cells. Stable expression of T₃ receptor (TR)- or TRβ in Neuro2a cells enhanced this effect of T₃, indicating the involvement of TRs. Because HeLa cells express only Ca²⁺/calmodulin-dependent protein kinase kinase-β (CaMKKβ), one of two known AMPK kinases, it was suggested that the effect of T₃ is mediated by CaMKKβ. Indeed, experiments using a CaMKK inhibitor, STO-609, and an isoform-specific small interfering RNA demonstrated the CaMKKβ-dependent phosphorylation of AMPK. Furthermore, T₃ was found to rapidly induce intracellular Ca²⁺ mobilization in HeLa cells, and a Ca²⁺ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), suppressed T₃- as well as ionomycin-dependent phosphorylation of AMPK. In addition, T₃-dependent oxidation of palmitic acids was attenuated by BAPTA, STO-609, and the small interfering RNA for CaMKKβ, indicating that T₃-induced activation of AMPK leads to increased fatty acid oxidation. These results demonstrate that T₃ nontranscriptionally activates AMPK via intracellular Ca²⁺ mobilization and CaMKKβ activation, thereby stimulating mitochondrial fatty acid oxidation.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ

Ligands:   Thyroid hormone