Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo

2008 ◽  
Vol 104 (1) ◽  
pp. 178-185 ◽  
Author(s):  
Isabella Irrcher ◽  
Donald R. Walkinshaw ◽  
Treacey E. Sheehan ◽  
David A. Hood

Thyroid hormone (T3) regulates the function of many tissues within the body. The effects of T3 have largely been attributed to the modulation of thyroid hormone receptor-dependent gene transcription. However, nongenomic actions of T3 via the initiation of signaling events are emerging in a number of cell types. This study investigated the ability of short-term T3 treatment to phosphorylate and, therefore, activate signaling proteins in rat tissues in vivo. The kinases investigated included p38, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) 1/2. Following 2 h of T3 treatment, p38 and AMPK phosphorylation was increased in both the slow-twitch soleus and the fast-twitch plantaris muscles. In contrast, ERK1/2 was not activated in either muscle type. Neither p38 nor AMPK was affected in heart. However, AMPK activation was decreased by T3 in liver. ERK1/2 activation was decreased by T3 in heart, but increased in liver. Possible downstream consequences of T3-induced kinase phosphorylation were investigated by measuring cAMP response element binding protein (CREB) and thyroid hormone receptor DNA binding, as well as peroxisome proliferator-activated receptor-α coactivator-1 mRNA levels. Protein DNA binding to the cAMP or thyroid hormone response elements was unaltered by T3. However, peroxisome proliferator-activated receptor-α coactivator-1 mRNA expression was increased following 12 h of T3 treatment in soleus. These data are the first to characterize the effects of T3 treatment on kinase phosphorylation in vivo. We show that T3 rapidly modifies kinase activity in a tissue-specific fashion. Moreover, the T3-induced phosphorylation of p38 and AMPK in both slow- and fast-twitch skeletal muscles suggests that these events may be important in mediating hormone-induced increases in mitochondrial biogenesis in skeletal muscle.

2002 ◽  
Vol 22 (16) ◽  
pp. 5782-5792 ◽  
Author(s):  
Dangsheng Li ◽  
Tong Li ◽  
Fang Wang ◽  
Heather Tian ◽  
Herbert H. Samuels

ABSTRACT Many members of the thyroid hormone/retinoid receptor subfamily (type II nuclear receptors) function as heterodimers with the retinoid X receptor (RXR). In heterodimers which are referred to as permissive, such as peroxisome proliferator activated receptor/RXR, both partners can bind cognate ligands and elicit ligand-dependent transactivation. In contrast, the thyroid hormone receptor (TR)/RXR heterodimer is believed to be nonpermissive, where RXR is thought to be incapable of ligand binding and is often referred to as a silent partner. In this report, we used a sensitive derepression assay system that we developed previously to reexamine the TR/RXR interrelationship. We provide functional evidence suggesting that in a TR/RXR heterodimer, the RXR component can bind its ligand in vivo. Ligand binding by RXR does not appear to directly activate the TR/RXR heterodimer; instead, it leads to a (at least transient or dynamic) dissociation of a cellular inhibitor(s)/corepressor(s) from its TR partner and thus may serve to modulate unliganded TR-mediated repression and/or liganded TR-mediated activation. Our results argue against the current silent-partner model for RXR in the TR/RXR heterodimer and reveal an unexpected aspect of cross regulation between TR and RXR.


2003 ◽  
Vol 112 (4) ◽  
pp. 588-597 ◽  
Author(s):  
Nobuyuki Shibusawa ◽  
Koshi Hashimoto ◽  
Amisra A. Nikrodhanond ◽  
M. Charles Liberman ◽  
Meredithe L. Applebury ◽  
...  

2007 ◽  
Vol 27 (6) ◽  
pp. 2359-2371 ◽  
Author(s):  
Hao Ying ◽  
Osamu Araki ◽  
Fumihiko Furuya ◽  
Yasuhito Kato ◽  
Sheue-Yann Cheng

ABSTRACT Thyroid hormone (T3) is critical for growth, differentiation, and maintenance of metabolic homeostasis. Mice with a knock-in mutation in the thyroid hormone receptor α gene (TRα1PV) were created previously to explore the roles of mutated TRα1 in vivo. TRα1PV is a dominant negative mutant with a frameshift mutation in the carboxyl-terminal 14 amino acids that results in the loss of T3 binding and transcription capacity. Homozygous knock-in TRα1PV/PV mice are embryonic lethal, and heterozygous TRα1PV/+ mice display the striking phenotype of dwarfism. These mutant mice provide a valuable tool for identifying the defects that contribute to dwarfism. Here we show that white adipose tissue (WAT) mass was markedly reduced in TRα1PV/+ mice. The expression of peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipogenesis, was repressed at both mRNA and protein levels in WAT of TRα1PV/+ mice. Moreover, TRα1PV acted to inhibit the transcription activity of PPARγ by competition with PPARγ for binding to PPARγ response elements and for heterodimerization with the retinoid X receptors. The expression of TRα1PV blocked the T3-dependent adipogenesis of 3T3-L1 cells and repressed the expression of PPARγ. Thus, mutations of TRα1 severely affect adipogenesis via cross talk with PPARγ signaling. The present study suggests that defects in adipogenesis could contribute to the phenotypic manifestation of reduced body weight in TRα1PV/+ mice.


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