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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

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