Adult Mice Lacking Mct8 and Dio2 Proteins Present Alterations in Peripheral Thyroid Hormone Levels and Severe Brain and Motor Skill Impairments

Bárez-López, Soledad; Grijota-Martínez, Carmen; Ausó, Eva; Frutos, Mario Fernández-de; Montero-Pedrazuela, Ana; Guadaño-Ferraz, Ana

doi:10.1089/thy.2019.0068

Cited by 43 publications

(38 citation statements)

References 62 publications

(43 reference statements)

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“…In the saline-treated group, T3 and T4 levels in plasma reflected the characteristic thyroid function test in MCT8 deficiency with high T3 (3-fold increase) and low T4 (1.6-fold decrease) in Mct8/Dio2KO animals in comparison to Wt (Fig 2) [22,23]. In the cerebral cortex, Mct8/ Dio2KO mice displayed a 5-fold decrease in T3 content and a 1.6-fold decrease in T4 content, as previously described (Fig 2) [53,54].…”

Section: Intranasal T3 Treatment Does Not Increase Brain T3 Content Asupporting

confidence: 79%

“…To determine if intranasal administration of THs can directly access the brain, we decided to execute an intranasal treatment with L-T3, which does not cross the BBB through OATP1C1, in double Mct8/Dio2KO mice, which present further reduced T3 content in the brain in comparison to single Mct8KO mice [53,54] and therefore present higher sensitivity to detect increases in T3 brain content. For this, Wt and Mct8/Dio2KO mice were treated with either saline or L-T3 by intranasal administration and plasma and cerebral cortex samples were collected 15 minutes after for TH determinations.…”

Section: Intranasal T3 Treatment Does Not Increase Brain T3 Content Amentioning

confidence: 99%

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Intranasal delivery of Thyroid hormones in MCT8 deficiency

et al. 2020

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Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.

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Section: Intranasal T3 Treatment Does Not Increase Brain T3 Content Asupporting

confidence: 79%

Section: Intranasal T3 Treatment Does Not Increase Brain T3 Content Amentioning

confidence: 99%

Intranasal delivery of Thyroid hormones in MCT8 deficiency

et al. 2020

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“…Extraction of T 3 and T 4 from plasma or BAT tissue as well as T 3 and T 4 determinations in plasma was conducted as previously described [ 40 ]. (3–5)-T 2 (D0629, Sigma–Aldrich) and T 3 (T2877, Sigma–Aldrich) were used as substrates to obtain high specific activity (3000 μCi/μg) 125 I-T 3 and 125 I-T 4 , respectively, using 125 I (NEZ033A, PerkinElmer) as previously described [ 41 , 42 ] with minor modifications [ 43 ]. THs from plasma were extracted with methanol (1:6), subjected to evaporation, and resuspended in radioimmunoassay (RIA) buffer (0.04 M of phosphate buffer and pH 8), with 0.2% bovine serum albumin (BSA) and 0.6 mM of merthiolate (T-5125, Sigma–Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Escalona-Garrido

Vázquez

Mera³

et al. 2020

Molecular Metabolism

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Objective Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is necessary to find strategies to protect BAT against the effects of inflammation in energy balance. In this study, we explored the impact of moderate sirtuin 1 (SIRT1) overexpression on insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods The effect of inflammation on BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1 Tg+ ) injected with a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies on differentiated BA (BA-WT and BA-SIRT1 Tg+ ) exposed to a macrophage-derived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), and norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results BAT from the db/db mice was susceptible to metabolic inflammation manifested by the activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance, and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in the lean WT mice upon LPS injection. In contrast, BAT from the mice with moderate overexpression of SIRT1 (SIRT1 Tg+ ) was protected against LPS-induced activation of pro-inflammatory signaling, insulin resistance, and defective thermogenic-related responses upon cold exposure. Importantly, the decline in triiodothyronine (T 3 ) levels in the circulation and intra-BAT after exposure of the WT mice to LPS and cold was markedly attenuated in the SIRT1 Tg+ mice. In vitro BA experiments in the two genotypes revealed that upon differentiation with a T 3 -enriched medium and subsequent exposure to a macrophage-derived pro-inflammatory CM, only BA-SIRT1 Tg+ fully recovered insulin and noradrenergic responses. Conclusions This study has ascertained the benefit of the moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by BAT inflammation. Our results have potential therapeutic value in combinatorial therapies for BAT-specific thyromimetics and SIRT1 activators to combat metainflammation in this tissue.

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“…For this reason, two alternative models are currently being used; MCT8 and DIO2 (Mct8/Dio2KO) or MCT8 and OATP1C1 (Mct8/Slc1c1KO) -deficient mice, in which this compensatory mechanism is suppressed. These models present a thyroid profile similar to that of the patients in addition to several neuromotor alterations, offering a more suitable model (Mayerl et al, 2014;Bárez-López et al, 2019a). In addition, other alternative models currently available include the use of pluripotent stem cells induced from human patients (Vatine et al, 2017) or the use of other organisms such as zebrafish (Vatine et al, 2013), chicken (Delbaere et al, 2017) or even Xenopus (Mughal et al, 2017).…”

Section: Murine Models Of the Diseasementioning

confidence: 99%

MCT8 Deficiency: The Road to Therapies for a Rare Disease

et al. 2020

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Allan-Herndon-Dudley syndrome is a rare disease caused by inactivating mutations in the SLC16A2 gene, which encodes the monocarboxylate transporter 8 (MCT8), a transmembrane transporter specific for thyroid hormones (T3 and T4). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development resulting in severe brain hypothyroidism. Patients also suffer from thyrotoxicity in other organs due to the presence of a high concentration of T3 in the serum. An effective therapeutic strategy should restore thyroid hormone serum levels (both T3 and T4) and should address MCT8 transporter deficiency in brain barriers and neural cells, to enable the access of thyroid hormones to target neural cells. Unfortunately, targeted therapeutic options are currently scarce and their effect is limited to an improvement in the thyrotoxic state, with no sign of any neurological improvement. The use of thyroid hormone analogs such as TRIAC, DITPA, or sobetirome, that do not require MCT8 to cross cell membranes and whose controlled thyromimetic activity could potentially restore the normal function of the affected organs, are being explored to improve the cerebral availability of these analogs. Other strategies aiming to restore the transport of THs through MCT8 at the brain barriers and the cellular membranes include gene replacement therapy and the use of pharmacological chaperones. The design of an appropriate therapeutic strategy in combination with an early diagnosis (at prenatal stages), will be key aspects to improve the devastating alterations present in these patients.

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Adult Mice Lacking Mct8 and Dio2 Proteins Present Alterations in Peripheral Thyroid Hormone Levels and Severe Brain and Motor Skill Impairments

Cited by 43 publications

References 62 publications

Intranasal delivery of Thyroid hormones in MCT8 deficiency

Intranasal delivery of Thyroid hormones in MCT8 deficiency

Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

MCT8 Deficiency: The Road to Therapies for a Rare Disease

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