T Induces Both Markers of Maturation and Aging in Pancreatic β-Cells.

Previously, we showed that thyroid hormone (TH) triiodothyronine (T) enhanced β-cell functional maturation through induction of High levels of T have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T increased (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of and induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements.

Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production.

Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (HS) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries.

Liganded Thyroid Hormone Receptors Transactivate the DNA Methyltransferase 3a Gene in Mouse Neuronal Cells.

Thyroid hormone (T3) is essential for proper neurological development. The hormone, bound to its receptors, regulates gene transcription in part by modulating posttranslational modifications of histones. Methylation of DNA, which is established by the de novo DNA methyltransferase (DNMT)3a and DNMT3b, and maintained by DNMT1 is another epigenetic modification influencing gene transcription.

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway.

Transcriptional coregulators are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoRΔID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoRΔID in mouse liver improves dietary cholesterol tolerance in an LXRα-independent manner.

Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors.

Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TRβ) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1(-/-) mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TRβ, termed NCoRΔID, have low TH levels and normal TSH.

Novel mechanism of positive versus negative regulation by thyroid hormone receptor β1 (TRβ1) identified by genome-wide profiling of binding sites in mouse liver.

Triiodothyronine (T3) regulates key metabolic processes in the liver through the thyroid hormone receptor, TRβ1. However, the number of known target genes directly regulated by TRβ1 is limited, and the mechanisms by which positive and especially negative transcriptional regulation occur are not well understood. To characterize the TRβ1 cistrome in vivo, we expressed a biotinylated TRβ1 in hypo- and hyperthyroid mouse livers, used ChIP-seq to identify genomic TRβ1 targets, and correlated these data with gene expression changes.

Family members CREB and CREM control thyrotropin-releasing hormone (TRH) expression in the hypothalamus.

Thyrotropin-releasing hormone (TRH) in the paraventricular nucleus (PVN) of the hypothalamus is regulated by thyroid hormone (TH). cAMP response element binding protein (CREB) has also been postulated to regulate TRH expression but its interaction with TH signaling in vivo is not known. To evaluate the role of CREB in TRH regulation in vivo, we deleted CREB from PVN neurons to generate the CREB1(ΔSIM1) mouse.

NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways.

Fasting-induced suppression of the hypothalamic-pituitary-thyroid (HPT) axis is an adaptive response to decrease energy expenditure during food deprivation. Previous studies demonstrate that leptin communicates nutritional status to the HPT axis through thyrotropin-releasing hormone (TRH) in the paraventricular nucleus (PVN) of the hypothalamus. Leptin targets TRH neurons either directly or indirectly via the arcuate nucleus through pro-opiomelanocortin (POMC) and agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons.

The nuclear receptor corepressor (NCoR) controls thyroid hormone sensitivity and the set point of the hypothalamic-pituitary-thyroid axis.

The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoRΔID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T(4) and T(3) concentrations accompanied by normal TSH levels, suggesting central hypothyroidism.

Regulation of hepatic six transmembrane epithelial antigen of prostate 4 (STEAP4) expression by STAT3 and CCAAT/enhancer-binding protein alpha.

STEAP4 is a plasma membrane metalloreductase involved in the transport of iron and copper. Recently, STEAP4 was implicated in promoting insulin sensitivity by acting in white adipose tissue to control the production of inflammatory cytokines such as interleukin 6. Indeed, the loss of STEAP4 expression in mice leads to increased production of inflammatory cytokines in visceral white adipose tissue and systemic insulin resistance.

STAT3 targets the regulatory regions of gluconeogenic genes in vivo.

The regulation of expression of gluconeogenic genes including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver plays an important role in glucose homeostasis, because aberrant expression of these genes contributes to the development of type 2 diabetes. Previous reports demonstrate that signal transducer and activator of transcription 3 (STAT3) plays a key role in regulating gluconeogenic gene expression, but the mechanism remains unclear. Herein we demonstrate that phosphorylated STAT3 is required for repression of G6Pase expression by IL-6 in both HepG2 cells and mouse liver.

Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells.

The pleiotropic cytokine interleukin 6 (IL-6) is involved in immune cell homeostasis. Additionally, IL-6 expression and signaling in tumor cells have been shown to elicit both protumor and antitumor properties. There is a plethora of mechanistic knowledge regarding how IL-6 signal transduction translates to biological responses.

Role of the aryl hydrocarbon receptor in drug metabolism.

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates the transcription of certain key enzymes involved in the metabolism of xenobiotic substances including some drugs. The AhR can be activated by a wide range of classes of compounds (e.g.

Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity.

The aryl hydrocarbon receptor (AhR) mediates the biological activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Whether the AhR can mediate enhanced transcriptional activity in the absence of ligand binding has not been established. Hepatocytes from AhR-null (AhR-KO) and wild-type (AhR-WT) neonatal mice were immortalized with Simian virus 40.

The transactivation domain of the Ah receptor is a key determinant of cellular localization and ligand-independent nucleocytoplasmic shuttling properties.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates transcription of a number of target genes upon binding ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Large intra- and interspecies variations exist with respect to sensitivity to TCDD, and this could, at least in part, be due to a considerable variation in the AhR amino acid sequence between species. The N-terminal half of the AhR is well-conserved across species, whereas the C-terminal half exhibits a considerable degree of degeneracy.

Use of 2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin as a probe to determine the relative ligand affinity of human versus mouse aryl hydrocarbon receptor in cultured cells.

The aryl hydrocarbon receptor (AhR) is a ligand-induced transcription factor that is activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other related compounds, leading to toxicity. There is considerable variation in the response to TCDD among different species, and this may be correlated to differences in the AhR. Variations in the structure of the AhR could result in altered biochemical properties of the receptor, such as ligand affinity or transactivation potential.

Divergent roles of hepatitis B virus X-associated protein 2 (XAP2) in human versus mouse Ah receptor complexes.

The aryl hydrocarbon receptor (AhR) mediates the toxicologic and carcinogenic properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin. In the cytoplasm, the AhR is complexed with a dimer of hsp90, and the hepatitis B virus X-associated protein 2 (XAP2). Most studies that have examined the ability of XAP2 to modulate the AhR have characterized the mouse receptor (mAhR).

The hsp90 Co-chaperone XAP2 alters importin beta recognition of the bipartite nuclear localization signal of the Ah receptor and represses transcriptional activity.

The mouse aryl hydrocarbon receptor (mAhR) is a ligand-activated transcription factor that exists in a tetrameric, core complex with a dimer of the 90-kDa heat shock protein, and the hepatitis B virus X-associated protein 2 (XAP2). Transiently expressed mAhR-YFP (yellow fluorescent protein fused with the mAhR) localizes throughout cells, with a majority occupying nuclei. Co-expression of XAP2 with mAhR-YFP results in a distinct redistribution to the cytoplasm.