Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.

Indian Ocean hides Global Warming Marine scientists proof additional heat uptake during the past decades May 18, 2015/Miami/Kiel. Why has the global temperature rise paused during the past two decades? A team of scientists from the US and the German GEOMAR Helmholtz Centre for Ocean Research Kiel was able to now show that the heat content of the Indian Ocean has risen substantially since late 1990s although the global temperature showed only little changes.

Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis, and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor (TR) interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors (PPARs), liver X receptor (LXR), and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor (RXR) heterodimer partners, DNA binding sites, and transcriptional co-factors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways, and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity, and diabetes. Thyroid Hormone and MetabolismThyroid hormone is a key metabolic regulator coordinating short-term and long-term energy needs [1]. Significant metabolic changes are seen with variations in thyroid status in humans [2]. Hyperthyroidism, characterized by elevated serum thyroid hormone levels, is associated with accelerated metabolism, increased lipolysis, weight loss, increased hepatic cholesterol biosynthesis and excretion, and reduced serum cholesterol levels. Hypothyroidism, characterized by low serum thyroid hormone levels, is associated with reduced metabolism, reduced lipolysis, weight gain, reduced cholesterol clearance, and elevated serum cholesterol. With low food intake, nutrient and other feedback is integrated centrally to reduce thyroid hormone production, resulting in lower metabolic rate and shifting the body to an energy conservation mode [3]. In fact, body weight in humans is inversely correlated with thyroid hormone levels [4]. Many of the actions of thyroid hormone in metabolic regulation involve modulation of other metabolic signaling pathways (Table 1). Thyroid Hormone ActionThyroid hormone acts predominantly through its nuclear receptors, thyroid hormone receptor (TR) α and β, which are differentially expressed developmentally and in adult tissues [1]. TR isoform-specific metabolic functions have been identified, and selective TR agonists have been developed to stimulate specific metabolic pathways [5,6]. The functional TR complex consists Address Correspondences: Gregory A. Brent, Molecular Endocrinology Laboratory, Building 114, Room 230, VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, CA 90073, Phone 301 268-3735, FAX 310 268-4982, gbrent@ucla.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could a...

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Thyroid hormone has profound effects on metabolic homeostasis, regulating both lipogenesis and lipolysis, primarily by modulating adrenergic activity. We generated mice with a point mutation in the thyroid hormone receptor ␣ (TR␣) gene producing a dominant-negative TR␣ mutant receptor with a proline to histidine substitution (P398H). The heterozygous P398H mutant mice had a 3.4-fold (p < 0.02) increase in serum thyrotropin (TSH) levels. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were slightly elevated compared with wild-type mice. The P398H mice had a 4.4-fold increase in body fat (as a fraction of total body weight) (p < 0.001) and a 5-fold increase in serum leptin levels (p < 0.005) compared with wild-type mice. A 3-fold increase in serum fasting insulin levels (p < 0.002) and a 55% increase in fasting glucose levels (p < 0.01) were observed in P398H compared with wild-type mice. There was a marked reduction in norepinephrine-induced lipolysis, as reflected in reduced glycerol release from white adipose tissue isolated from P398H mice. Heart rate and cold-induced adaptive thermogenesis, mediated by thyroid hormone-catecholamine interaction, were also reduced in P398H mice. In conclusion, the TR␣ P398H mutation is associated with visceral adiposity and insulin resistance primarily due to a marked reduction in catecholamine-stimulated lipolysis. The observed phenotype in the TR␣ P398H mouse is likely due to interference with TR␣ action as well as influence on other metabolic signaling pathways. The physiologic significance of these findings will ultimately depend on understanding the full range of actions of this mutation.Thyroid hormone plays a central role in metabolic homeostasis. Thyroid hormone stimulates basal metabolic rate and adaptive thermogenesis. Hyperthyroidism amplifies catecholamine-stimulated lipolysis and increases thermogenesis and oxygen consumption in adipose tissue (1-3). Hypothyroidism reduces the response to catecholamines and increases energy-saving anabolic activity in adipose tissue (4).Thyroid hormone has long been recognized to augment adrenergic activity, and influences adrenergic signaling at multiple levels. Catecholamines bind at least five subtypes of adrenergic receptors (␣1, ␣2, ␤1, ␤2, and ␤3) that are expressed in fat cells and are coupled with the adenylylcyclase system to activate (via ␤ receptors) or inhibit (via ␣2 receptor) the cAMPactivated hormone-sensitive lipase (HSL) 1 (5-9). Reduced catecholamine-stimulated lipolysis in hypothyroidism is thought to be due to a reduced number of ␤-adrenergic receptors (␤1 and ␤2) in fat cells (4, 10 -13), reduced interaction with G s , and enhanced G i protein interaction via ␣2-adrenergic receptorcoupled stimulation (14). Additionally, hypothyroidism is associated with low intracellular levels of protein kinase, known to phosphorylate and activate HSL (2,12,13). No significant alteration of ␣2-adrenergic receptor number has been found in fat cells isolated from either hypo-or hyperthyroid animals (6).The two majo...

The action of the vitamin D receptor (VDR), 1 like that of other nuclear receptors, is dependent primarily on interaction with its biologically active ligand, 1␣,25-dihydroxyvitamin D 3 (1-3). The binding of ligand to its nuclear receptor leads to conformational changes in the receptor (4 -6), promotes selfdimerization and heterodimerization with the retinoid X receptor (RXR) (7-11), and enhances binding to DNA and transcriptional activities (12-15). It is generally accepted that the transcriptional activities of nuclear receptors are directly correlated with their affinity for their respective ligands (16 -18). There are, however, several exceptions to this rule. For example, the effective dose required to reach 50% saturation (ED 50 ) of the estrogen receptor by its ligand is several orders of magnitude greater than the ED 50 for maximal transcriptional activity (19). A possible explanation for this is that ligand-activated estrogen receptor acts in a cooperative manner with unoccupied estrogen receptor molecules during interaction with its DNA response element or with the transcriptional apparatus, whereas other steroid hormone receptors do not. Another exception is the progesterone antagonist RU486; this synthetic ligand binds tightly to the progesterone receptor, but does not induce transcriptional activity (20). The explanation for this discrepancy is that the analogue/antagonist interacts with the progesterone receptor at a different site from progesterone, thus creating a unique conformational change in the receptor and preventing its normal action (21).Recently, we began to analyze the mechanism of action of analogues of 1␣,25-(OH) 2 D 3 that regulate receptor-mediated transcription more effectively than the natural hormone, although their affinity for VDR is not greater (6). For example, a concentration of 10 Ϫ11 M is required to induce 50% of maximal DNA binding and transcriptional activities of VDR by the 20-epi analogue MC 1288 (1-E; see Fig. 1), but this concentration of 1-E is 200-fold lower than the ED 50 of 2 ϫ 10 Ϫ9 M for saturation of VDR binding sites in equilibrium (6,22). These results suggest that enhanced activation of VDR occurs after binding of the analogue to VDR, but before induction of transcription. Because analogue 1-E induces a unique conformational change in VDR in vitro and enhances dimerization of VDR with RXR in vivo (6), we speculated that the conformation of 20-epi analogue-activated VDR promotes better binding to DNA by stabilizing the VDR heterodimer. The conformational differences between 1␣,25-(OH) 2 D 3 ⅐VDR and 20-epi analogue⅐VDR complexes are probably due to differences in the sites where ligands contact the receptor, as are the differences in the interaction of progesterone and RU486 with the progesterone receptor (21). To test this hypothesis, it is necessary to map the ligand-binding domain of VDR, to identify the amino acids that are required for the binding of 1␣,25-(OH) 2 D 3 to it, and to determine whether the same amino acids are also required for binding of ...

Projections of climate change impacts on coral reefs produced at the coarse resolution (~1°) of Global Climate Models (GCMs) have informed debate but have not helped target local management actions. Here, projections of the onset of annual coral bleaching conditions in the Caribbean under Representative Concentration Pathway (RCP) 8.5 are produced using an ensemble of 33 Coupled Model Intercomparison Project phase‐5 models and via dynamical and statistical downscaling. A high‐resolution (~11 km) regional ocean model (MOM4.1) is used for the dynamical downscaling. For statistical downscaling, sea surface temperature (SST) means and annual cycles in all the GCMs are replaced with observed data from the ~4‐km NOAA Pathfinder SST dataset. Spatial patterns in all three projections are broadly similar; the average year for the onset of annual severe bleaching is 2040–2043 for all projections. However, downscaled projections show many locations where the onset of annual severe bleaching (ASB) varies 10 or more years within a single GCM grid cell. Managers in locations where this applies (e.g., Florida, Turks and Caicos, Puerto Rico, and the Dominican Republic, among others) can identify locations that represent relative albeit temporary refugia. Both downscaled projections are different for the Bahamas compared to the GCM projections. The dynamically downscaled projections suggest an earlier onset of ASB linked to projected changes in regional currents, a feature not resolved in GCMs. This result demonstrates the value of dynamical downscaling for this application and means statistically downscaled projections have to be interpreted with caution. However, aside from west of Andros Island, the projections for the two types of downscaling are mostly aligned; projected onset of ASB is within ±10 years for 72% of the reef locations.

[1] This study examines the potential impact of future anthropogenic global warming on the Gulf of Mexico (GoM) by using a downscaled high-resolution ocean model constrained with the surface forcing fields and initial and boundary conditions obtained from the IPCC-AR4 model simulations under A1B scenario. The simulated volume transport by the Loop Current (LC) is reduced considerably by 20-25% during the 21st century, consistent with a similar rate of reduction in the Atlantic Meridional Overturning Circulation. The effect of the LC in the present climate is to warm the GoM, therefore the reduced LC and the associated weakening of the warm LC eddy have a cooling impact in the GoM, particularly in the northern basin. Due to this cooling influence, the northern GoM is characterized as the region of minimal warming. Low-resolution models, such as the IPCC-AR4 models, underestimate the reduction of the LC and its cooling effect, thus fail to simulate the reduced warming feature in the northern GoM. The potential implications of the reduced warming in the northern GoM on pelagic fish species and their spawning patterns are also discussed.