Maternal thyroid hormone receptor ß activation in mice sparks brown fat thermogenesis in the offspring.

It is well established that maternal thyroid hormones play an important role for the developing fetus; however, the consequences of maternal hyperthyroidism for the offspring remain poorly understood. Here we show in mice that maternal 3,3',5-triiodothyronine (T3) treatment during pregnancy leads to improved glucose tolerance in the adult male offspring and hyperactivity of brown adipose tissue (BAT) thermogenesis in both sexes starting early after birth. The activated BAT provides advantages upon cold exposure, reducing the strain on other thermogenic organs like muscle. This maternal BAT programming requires intact maternal thyroid hormone receptor ß (TRß) signaling, as offspring of mothers lacking this receptor display the opposite phenotype. On the molecular level, we identify distinct T3 induced alterations in maternal serum metabolites, including choline, a key metabolite for healthy pregnancy. Taken together, our results connect maternal TRß activation to the fetal programming of a thermoregulatory phenotype in the offspring.

Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control. Transcriptomic analyses show preserved, thyroid hormone (T3)-dependent upregulation of pacemaker channels (Hcn2, Hcn4), but irreversibly reduced expression of several ion channel genes controlling heart rate. Exposure of TRα1 mutant male mice to higher maternal T3 concentrations in utero, restores altered expression and DNA methylation of ion channels, including Ryr2. Our findings indicate that target genes other than Hcn2 and Hcn4 mediate T3-induced tachycardia and suggest that treatment of RTHα patients with thyroxine in high dosage without concomitant tachycardia, is possible.

Maternal Thyroid Hormone Programs Cardiovascular Functions in the Offspring.

Background: Maternal thyroid hormone (TH) plays an essential role for fetal development, especially for the cardiovascular system and its central control. However, the precise consequences of altered TH action during the different periods in pregnancy remain poorly understood. Methods: To address this question, we used mice heterozygous for a mutant thyroid hormone receptor α1 (TRα1) and wild-type controls that were born to wild-type mothers treated with 3,3',5-triiodothyronine (T3) during the first or the second half of pregnancy. We then phenotyped the offspring animals as adults by in vivo measurements and postmortem tissue analyses. Results: Maternal T3 treatment in either half of the pregnancy did not affect postnatal growth development. Serum thyroxine and hypophyseal thyrotropin subunit beta or deiodinase type II expression was also not affected in any group, only TRα1 mutant males exhibited a reduction in serum T3 levels after the treatment. Likewise, hepatic deiodinase type I was not altered, but serum selenium levels were reduced by the maternal treatment in wild-type offspring of both genders. Most interestingly, a significant increase in heart weight was found in adult wild-types born to mothers that received T3 during the first or second half of pregnancy, while TRα1 mutant males were protected from this effect. Moreover, we detected a significant increase in heart rate selectively in male mice that were exposed to elevated maternal T3 in the second half of the pregnancy. Conclusion: Taken together, our findings demonstrate that maternal TH is of particular relevance during the second half of pregnancy for establishing cardiac properties, with specific effects depending on TRα1 or gender. The data advocate routinely monitoring TH levels during pregnancy to avoid adverse cardiac effects in the offspring.

Identification of 12/15-lipoxygenase as a regulator of axon degeneration through high-content screening.

Axon degeneration is a programed process that takes place during development, in response to neuronal injury, and as a component of neurodegenerative disease pathology, yet the molecular mechanisms that drive this process remain poorly defined. In this study, we have developed a semi-automated, 384-well format axon degeneration assay in rat dorsal root ganglion (DRG) neurons using a trophic factor withdrawal paradigm. Using this setup, we have screened a library of known drugs and bioactives to identify several previously unappreciated regulators of axon degeneration, including lipoxygenases. Multiple structurally distinct lipoxygenase inhibitors as well as mouse DRG neurons lacking expression of 12/15-lipoxygenase display protection of axons in this context. Retinal ganglion cell axons from 12/15-lipoxygenase-null mice were similarly protected from degeneration following nerve crush injury. Through additional mechanistic studies, we demonstrate that lipoxygenases act cell autonomously within neurons to regulate degeneration, and are required for mitochondrial permeabilization and caspase activation in the axon. These findings suggest that these enzymes may represent an attractive target for treatment of neuropathies and provide a potential mechanism for the neuroprotection observed in various settings following lipoxygenase inhibitor treatment.