Maria-jesus Obregon - Academia.edu (original) (raw)

Papers by Maria-jesus Obregon

Redox Biology, 2021

Therapeutic potential of metformin in obese/diabetic patients has been associated to its ability ... more Therapeutic potential of metformin in obese/diabetic patients has been associated to its ability to combat insulin resistance. However, it remains largely unknown the signaling pathways involved and whether some cell types are particularly relevant for its beneficial effects. M1-activation of macrophages by bacterial lipopolysaccharide (LPS) promotes a paracrine activation of hypoxia-inducible factor-1α (HIF1α) in brown adipocytes which reduces insulin signaling and glucose uptake, as well as β-adrenergic sensitivity. Addition of metformin to M1-polarized macrophages blunted these signs of brown adipocyte dysfunction. At the molecular level, metformin inhibits an inflammatory program executed by HIF1α in macrophages by inducing its degradation through the inhibition of mitochondrial complex I activity, thereby reducing oxygen consumption in a reactive oxygen species (ROS)-independent manner. In obese mice, metformin reduced inflammatory features in brown adipose tissue (BAT) such as macrophage infiltration, proinflammatory signaling and gene expression, and restored the response to cold exposure. In conclusion, the impact of metformin on macrophages by suppressing a HIF1α-dependent proinflammatory program is likely responsible for a secondary beneficial effect on insulin-mediated glucose uptake and β-adrenergic responses in brown adipocytes.

To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in co... more To study the protective effects of maternal thyroxine (T4) and 3,5,3'-triiodothyronine (T3) in congenital hypothyroidism, we gave pregnant rats methimazole (MMI), an antithyroid drug that crosses the placenta, and infused them with three different doses of T4 or T3. The concentrations of both T4 and T3 were determined in maternal and fetal plasma and tissues (obtained near term) by specific RIAs. Several thyroid hormone-dependent biological end-points were also measured. MMI treatment resulted in marked fetal T4 and T3 deficiency. Infusion of T4 into the mothers increased both these pools in a dose-dependent fashion. There was a preferential increase of T3 in the fetal brain. Thus, with a T4 dose maintaining maternal euthyroidism, fetal brain T3 reached normal values, although fetal plasma T4 was 40% of normal and plasma TSH was high. The infusion of T3 into the mothers increased the total fetal extrathyroidal T3 pool in a dose-dependent fashion. The fetal T4 pools were not increased, however, and this deprived the fetal brain (and possibly the pituitary) of local generation of T3 from T4. As a consequence, fetal brain T3 deficiency was not mitigated even when dams were infused with a toxic dose of T3. The results show that (a) there is a preferential protection of the brain of the hypothyroid fetus from T3 deficiency; (b) maternal T4, but not T3, plays a crucial role in this protection, and (c) any condition which lowers maternal T4 (including treatment with T3) is potentially harmful for the brain of a hypothyroid fetus. Recent confirmation of transplacental passage of T4 in women at term suggests that present results are relevant for human fetuses with impairment of thyroid function. Finding signs of hypothyroidism at birth does not necessarily mean that the brain was unprotected in utero, provided maternal T4 is normal. It is crucial to realize that maintainance of maternal "euthyroidism" is not sufficient, as despite hypothyroxinemia, the mothers may be clinically euthyroid if their T3 levels are normal.

The Thoracic and Cardiovascular Surgeon, 2015

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Resumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebra... more Resumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (Espana) del 6 al 10 de septiembre de 2014.-- et al.

Medicina, 2021

Hepatocellular carcinoma (HCC) is the most common primary liver tumor. Hexachlorobenzene (HCB) is... more Hepatocellular carcinoma (HCC) is the most common primary liver tumor. Hexachlorobenzene (HCB) is an endocrine disruptor and a liver tumor promoter. Deregulation of thyroid hormone (TH) homeostasis may play a significant role in early neoplastic transformation. The aim of this study was to evaluate the relation between TH metabolism and the regulation of cell growth in an in vivo and in vitro model. We examined the role of transforming growth factor-β1 (TGF-β1) on TH deiodinase expression and hepatocyte proliferation. An initiation (DEN)/promotion (HCB) tumor model from rat liver and HepG2 cells were used. We evaluated PCNA, p21, p27, SMAD2/3, TGF-β1, deiodinase 1 (D1), D3, protein expression levels; D1 and D3 mRNA expression; TH and TGF-β1, D1, D3, and GST-P protein levels in focal/non-focal areas. In vivo, HCB decreased triiodothyronine (T3) and D1 mRNA levels and increased thyroxine (T4) and D3 mRNA levels in liver from DEN+HCB vs. DEN group. HCB increased protein levels from D3,...

Aging Cell, 2019

Age‐related increased adiposity is an important contributory factor in the development of insulin... more Age‐related increased adiposity is an important contributory factor in the development of insulin resistance (IR) and is associated with metabolic defects. Caloric restriction (CR) is known to induce weight loss and to decrease adiposity while preventing metabolic risk factors. Here, we show that moderate 20% CR delays early deleterious effects of aging on white and brown adipose tissue (WAT and BAT, respectively) function and improves peripheral IR. To elucidate the role of CR in delaying early signs of aging, young (3 months), middle‐aged (12 months), and old (20 months) mice fed al libitum and middle‐aged and old mice subjected to early‐onset CR were used. We show that impaired plasticity of subcutaneous WAT (scWAT) contributes to IR, which is already evident in middle‐aged mice. Moreover, alteration of thyroid axis status with age is an important factor contributing to BAT dysfunction in middle‐aged animals. Both defects in WAT and BAT/beige cells are ameliorated by CR. Accordin...

PLOS ONE, 2016

The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduce... more The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders.

Journal of Pediatric Endocrinology and Metabolism, 2007

The association between alterations of thyroid function early after birth and neurodevelopmental ... more The association between alterations of thyroid function early after birth and neurodevelopmental disorders has been recognized for more than a century. There has been, however, less consensus regarding the stage of fetal life during which thyroid hormone is thought to be necessary for normal brain development (for an extensive review see"). This was mainly a consequence of opposing views regarding the importance of maternal thyroid hormones for the fetus. On the one hand, those who had personal field experience concerning iodine deficiency disorders were convinced of its importance on the basis of the severity of the damage to the central nervous system of the progeny which they associated with the degree of maternal thyroxine (T4) deficiency, and assumed could only be prevented when the latter was corrected before mid-gestation. On the other hand, Western-trained physicians generally adhered to the idea that maternal thyroid hormones did not play a role in early neurodevelopment, an idea apparently supported by the good results obtained with prompt treatment of congenital hypothyroidism (CH). This success was interpreted as proof that the fetal brain did not need thyroid hormone until after birth. The idea that the maternal thyroid hormones were of little relevance for the early fetal brain was reinforced by increasing evidence pointing towards the existence of an efficient utero-placental 'barrier' that prevented the transfer of physiologically relevant amounts of maternal thyroid hormones into the fetal compartment. The importance of an adequate provision of thyroid hormones for brain development during later phases of pregnancy became obvious after the transfer of

Springer eBooks, 1988

Discussions concerning the significance of brown adipose tissue for the newborn mammal have becom... more Discussions concerning the significance of brown adipose tissue for the newborn mammal have become facilitated within the last few years by a general agreement on the following basic facts: That in all mammals, newborns as well as adults, facultative non-shivering thermogenesis is brown-fat thermogenesis That the molecular background to the unique ability of brown adipose tissue to function as a heat-producing organ is the existence in this tissue of a large abundance of mitochondria endowed with the uncoupling protein thermogenin, and That the amount of thermogenin in a mammal (under most circumstances) is the rate-limiting factor for thermogenesis.

UAM Ediciones, Jun 27, 2019

Gabriella Morreale: su vida y su tiempo 106 Gabriella alude aquí a un pasaje bíblico: Jesús entró... more Gabriella Morreale: su vida y su tiempo 106 Gabriella alude aquí a un pasaje bíblico: Jesús entró en cierta ocasión en una aldea y una mujer llamada Marta le recibió en su casa. La hermana de ésta, María, se sentó a los pies de Jesús para escuchar su palabra, mientras que Marta estaba afanada en múltiples quehaceres. El relato ha sido tradicionalmente entendido como expresión de dos formas distintas de vivir el cristianismo y, por extensión, la vida en general: una contemplativa (la de María) y otra activa (la de Marta). Da la impresión de que Gabriella lleva la metáfora hasta el ámbito científico asociando la vía contemplativa con la investigación teórica y la activa con la investigación experimental, con humildad no exenta de una ligera ironía. 107 Algernon es una rata de laboratorio a la que se ha practicado una cirugía experimental para aumentar su inteligencia. Charlie Gordon, que padece desde la infancia retraso mental, se somete a la misma operación. Ambos protagonizan Flores para Algernon, una conmovedora novela publicada por Daniel Keyes en 1966 que está considerada-no sin razón-como una obra maestra de la ciencia ficción. Aborda cuestiones como el papel de los discapacitados en nuestra sociedad y la experimentación con personas y animales.

Resumen del trabajo presentado al MCT8 Symposium: "Current Knowledge, Future Research on Tre... more Resumen del trabajo presentado al MCT8 Symposium: "Current Knowledge, Future Research on Treatment", celebrado en California (USA) del 12 al 14 de enero de 2016.

Resumen del poster presentado al VII Congreso Internacional de Medicamentos Huerfanos y Enfermeda... more Resumen del poster presentado al VII Congreso Internacional de Medicamentos Huerfanos y Enfermedades Raras: "Consolidando esfuerzos: Una responsabilidad compartida”, celebrado en Sevilla (Espana) del 12 al 14 de febrero de 2015.

Resumen del poster presentado al 38th Annual Meeting of the European Thyroid Association celebrad... more Resumen del poster presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (Espana) del 6 al 10 de septiembre de 2014.-- et al.

European Thyroid Journal, 2018

Resumen del trabajo presentado al 17 National Congress of the Spanish Society of Neuroscience (SE... more Resumen del trabajo presentado al 17 National Congress of the Spanish Society of Neuroscience (SENC), celebrado en Alicante (Espana) del 27 al 30 de septiembre de 2017.

Cerebral Cortex, 2017

Thyroid hormones (THs, T4 and the transcriptionally active hormone T3) play an essential role in ... more Thyroid hormones (THs, T4 and the transcriptionally active hormone T3) play an essential role in neurodevelopment; however, the mechanisms underlying T3 brain delivery during mice fetal development are not well known. This work has explored the sources of brain T3 during mice fetal development using biochemical, anatomical, and molecular approaches. The findings revealed that during late gestation, a large amount of fetal brain T4 is of maternal origin. Also, in the developing mouse brain, fetal T3 content is regulated through the conversion of T4 into T3 by type-2 deiodinase (D2) activity, which is present from earlier prenatal stages. Additionally, D2 activity was found to be essential to mediate expression of T3-dependent genes in the cerebral cortex, and also necessary to generate the transient cerebral cortex hyperthyroidism present in mice lacking the TH transporter Monocarboxylate transporter 8. Notably, the gene encoding for D2 (Dio2) was mainly expressed at the bloodcerebrospinal fluid barrier (BCSFB). Overall, these data signify that T4 deiodinated by D2 may be the only source of T3 during neocortical development. We therefore propose that D2 activity at the BCSFB converts the T4 transported across the choroid plexus into T3, thus supplying the brain with active hormone to maintain TH homeostasis