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Trabajo presentado en Joint Annual Meeting ISMRM-ESMRMB 31st Annual Meeting, celebrado en Londres (Inglaterra) del 07 al 12 de mayo de 2022., Aquaporin-4 (AQP4) is a transmembrane water channel highly expressed in central nervous system, regulating fluid exchange by water transport between two sides of plasmatic membrane, and depending on concentration gradients of solutes, like glucose. On these grounds, we studied AQP4’s role in glucose uptake. AQP4 inhibitor TGN-020 was administrated in adult mice before vehicle and glucose stimulus. Diffusion and T2* images were acquired and apparent diffusion coefficient and T2* were measured. Ex vivo 1H high-resolution magic angle spinning spectra were acquired. Results showed that TGN avoid physiological cerebral response linked to glucose uptake, noting the AQP4 involvement in the process.

Trabajo presentado en el ESMRMB 38th Annual Scientific Meeting, celebrado en modalidad virtual del 07 al 09 de octubre de 2021., Obese patients and male murine models fed on a high fat diet (HFD) are known to experience an inflammatory response of the hypothalamus, the main brain regulator of energy homeostasis [1]. Likewise, this inflammation has been detected in the reward and mesocorticolimbic centres [2]. Preliminary magnetic resonance imaging (MRI) studies have supported evidence of inflammation in male mice brain, produced within only 15 days of HFD [3]. We conducted a study with 18 female mice randomly divided into HFD and control (CTRL) groups. We followed their respective food intake, body weight changes and blood glucose levels during 10 weeks, and performed T2-weighted and magnetization transfer (MT) images (7T Bruker BioSpec) of the brain, 1, 2, 4 and 10 weeks after diet diversification. Mean values of T2 and MT ratios (MTR) were calculated in the hypothalamus, nucleus accumbens, infralimbic area (ILA) and hippocampus. Statistical analysis was performed by a 2-way ANOVA (diet, area) and posthoc T tests. Our results show that weight gain and calorie intake were significantly higher on HFD mice, and no differences were detected in blood glucose levels. MTR and T2 showed a significant diet*area interaction effect at day 7, with lower T2 values and higher MTR in ILA (p

Trabajo presentado en el ESMRMB 38th Annual Scientific Meeting, celebrado en modalidad virtual del 07 al 09 de octubre de 2021., [Introduction]: Obesity is a severe disease, characterized by accumulation of fat in tissues, that induces important alterations in liver, pancreas or brain. It has grown to epidemic proportions, with over 4 million people dying every year as a result of being obese. Besides, obesity is associated with other diseases like diabetes or cancer (1). The influence of overweight in brain tumors, however, is still unclear. On these grounds, an orthotopic glioblastoma mouse model was developed in animals fed with standard diet (SD) and mice submitted to ten weeks of high-fat diet (HFD) feeding prior to intracranial glioma cells injection (2). [Methods]: Two cohorts (n=12) of C57BL6/J male adult mice with HFD (60% fat) and SD feeding were used. Animals were submitted to GL261 glioma cells intracranial injection 10 weeks after diet diversification. They were constantly supervised, and MRI studies were performed 21-24 days post- intracranial tumor cell injection. Anatomical images, magnetization transfer (MT), diffusion tensor Images (DTI), T2, and T2* parametric maps were acquired in a 7T Bruker Biospec horizontal equipment. Parametric maps were generated using an in-house program developed with MatLab which adjusted the MRI signal to the corresponding mathematical equation. Four regions of interest were manually selected, using ImageJ: i) tumor core, ii) tumor periphery, iii) peritumoral region and iv) contralateral healthy brain. Statistical analysis was performed by two-way ANOVA tests with area and diet as factors and post-hoc multiple comparisons with Bonferroni corrections. [Results]: Animals submitted to HFD presented an augmented weight the day of intracranial injection, then, weight tended to decrease till endpoint in both mice cohorts. Obese mice exhibited significantly higher axial diffusivity (Dax) and fractional anisotropy (FA) (p

Trabajo presentado en el 1st ISMRM Iberian Chapter Annual Meeting, celebrado en Portugal del 16 al 17 de junio de 2021., Obesity is a severe disease characterized by accumulation of fat that has grown to epidemic proportions, with over 4 million people dying every year. It induces important alterations in liver, pancreas or brain, and is associated with other diseases like diabetes or cancer (1). However, the influence of overweight in brain tumours is still unclear. On these grounds, an orthotopic glioblastoma (GBM) mouse model was developed in mice fed with standard diet (SD), and mice submitted to high-fat diet (HFD) and investigated the influence of diet in GBM magnetic resonance characterization (2). Two cohorts (n=12) of C57BL6/J male adult mice with HFD and SD feeding were used. Animals were submitted to GL261 glioma cells intracranial injection 10 weeks after diet diversification. MRI studies were performed 21-24 days after. Anatomical images and T2, T2*, MT and DTI maps were acquired in a 7T system. Parametric maps were generated by adjusting the signal to the corresponding equation. Four regions of interest were manually selected: i)tumor core, ii) tumor periphery, iii) peritumoral region and iv) contralateral area. Statistical analysis was performed by two-way ANOVA tests, with area and diet as factors, and post-hoc multiple T-test comparisons with Bonferroni corrections. Data obtained from MRI maps pointed to higher MD, FA, Dax, T2* and MTR values in obese mice, while Drad and T2 were higher for control cohort. The results are consistent with a higher inflammatory state in the brain of obese GBM animals compared to control, agreeing previous results obtained in mice without cancer (3).

Trabajo presentado en el 1st ISMRM Iberian Chapter Annual Meeting, celebrado en Portugal del 16 al 17 de junio de 2021., Aquaporin-4 (AQP4) is a transmembrane water channel highly expressed in central nervous system, regulating fluid exchange [1] by water transport between two sides of plasmatic membrane, and depending on concentration gradients of solutes [2]. Previously, we have shown that functional diffusion MRI can detect cellular swelling associated to glucose uptake [3]. On these grounds, role of APQ4 in this process was studied. AQP4 inhibitor TGN-020 [4] was used to assess cerebral changes after glucose bolus administration in C57BL6/J adult male mice with TGN administration plus glucose, saline administration plus glucose, and saline administration only (Figure 1). Diffusion tensor imaging studies were acquired in a 7T equipment and mean diffusivity (MD) and fractional anisotropy (FA) were measured in hypothalamus, hippocampus, and cortex regions. In a parallel cohort, we acquired 1H High Resolution Magic Angle Spinning (HRMAS) spectra in a 11.7T system. Glucose group experienced a decreased in MD 30 minutes after glucose injection. However, this response seems to be partially inhibited in TGN group, especially in hypothalamus. Metabolic studies show a decreased glutamate concentration in cortex and hippocampus of TGN group, as compared to glucose and control groups, while GABA concentration is higher. Glucose administration induces a cerebral response detectable with DTI. Use of TGN inhibits AQP4 and partially avoids its function, noting that AQP4 is involved in cellular volume regulation. Metabolic results correspond with an alteration of the glutamate cycle due to AQP4 obstruction, that yield a net increase of this metabolite concentration. (247 of 250 words)

Supplemental material, JCB910535 Supplemental Material for Excitatory/inhibitory neuronal metabolic balance in mouse hippocampus upon infusion of [U-13C6]glucose by Antoine Cherix, Guillaume Donati, Blanca Lizarbe, Bernard Lanz, Carole Poitry-Yamate, Hongxia Lei and Rolf Gruetter in Journal of Cerebral Blood Flow & Metabolism

Trabajo presentado en el 37th Annual Meeting; European Society for Magnetic Resonance In Medicine and Biology (ESMRMB), celebrado en Rotterdam (Países Bajos) del 3 al 5 de octubre de 2019., [Purpose/Introduction]: Obesity development is linked to inflammation in the hypothalamus, the brain structure responsible for appetite regulation and energy homeostasis. Furthermore, appetite has in mammals a hedonic component, controlled by the reward centers, affected during inflammation1. In rodents, inflammation has been characterized, at a histological level, by the emergence of microgliosis and astrogliosis, events that can be detected before gain in body weight. Studies using Magnetic Resonance Imaging (MRI) have identified a rise in the transverse relaxation time (T2) –a surrogate marker of astrocytosis- in the hypothalamus of long-term highfat diet (HFD) mice and in obese patients. Nevertheless, no MRI hypothalamic inflammatory markers of the initial stages of obesity have yet been investigated, and the role of the reward centers remains to be determined. Therefore, the aim of this study was to assess the onset of obesity development in mice in vivo using MRI. We evaluated the longitudinal changes of T2, magnetization transfer ratios (MTR) and apparent diffusion coefficients (ADC) in mice during the initial stages of high-fat or standard diet consumption., [Subjects and Methods]: Two animal groups, fed with either standard food chow (n = 7) or with a 60% high-fat (butter-based) diet (n = 8) were investigated before diet diversification (T = 0) and on days 1, 7 and 14. Body weight and blood glucose levels were controlled at every time point. MRI were performed in a 7T magnet (Bruker Biospect). Briefly, the hypothalamus (Hyp), nucleus accumbens (ACB) and infralimbic area (ILA) were localized in a T2-image using an anatomical atlas, and T2 (50 images, TE: 12–600 ms,TR = 5000 ms), MTR (MT pulse on/off, TE/TR = 9.8/2500 ms) maps and DWI (9 b:200-2000 smm-2) were acquired (5 slices, 1.25 mm thickness, 0.16 9 0.16 mm2). Longitudinal changes of the fitted parameters were assessed statistically using SPSS and a generalized estimated equations model, [Results]: Body weight and blood glucose levels increased significantly on HFD mice from days 1 and 7, respectively, and control animals increased only body weight after 14 days (Figure 1).

Resumen del póster presentado presentado al CIBERDEM Annual Meeting, celebrado en Cerdanyola del Vallès, Barcelona (España) del 11 al 13 de mayo de 2016., Neurons located within different hypothalamic nuclei integrate glucose and hormone signaling to contribute to the regulation of metabolic homeostasis by balancing caloric input and energy expenditure. One of these nuclei, the arcuate nucleus (ARC) plays a central role in the regulation of food intake by processing signals related to hunger or satiety, but the mechanisms by which these signals are processed for the systemic control of energy metabolism in the hypothalamus are largely unknown. Previous studies demonstrated that the homeodomain transcription factor Alx3 is important for the maintenance of pancreatic islet-dependent glucose homeostasis. In the present study, we describe the expression of Alx3 in the ARC and provide evidence for a possible role in the central control of energy homeostasis. We found that food intake in Alx3-deficient mice was reduced relative to wild type animals, but we observed no differences in body weight, suggesting the existence of a metabolic imbalance. Indirect calorimetry demonstrated the presence of reduced oxygen consumption and energy expenditure without affecting locomotor activity. There was a small reduction in respiratory exchange ratio during the night-to-light transition. 18F-Fludeoxyglucose uptake measured by positron emission tomography as well as functional diffusion-weighted magnetic resonance Imaging (DWI) in response to fasting confirmed the existence of altered neural activity in the ARC of Alx3-deficient mice. Immunofluorescence, RT-qPCR and western blot experiments revealed the expression of Alx3 in POMC and NPY neurons in the ARC. Alx3-deficient mice also showed increased body fat mass relative to lean mass, increased expression of proadipogenic genes in adipose tissue, and increased adipocytes size relative to control mice. Our data support the notion that Alx3 expressed in the hypothalamic ARC contributes to the regulation of energy homeostasis and relative body composition.

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo(11)C-acetate and PET-CT scanning to show that colonic acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through (13)C high-resolution magic-angle-spinning that (13)C acetate from fermentation of (13)C-labelled carbohydrate in the colon increases hypothalamic (13)C acetate above baseline levels. Hypothalamic (13)C acetate regionally increases the (13)C labelling of the glutamate-glutamine and GABA neuroglial cycles, with hypothalamic (13)C lactate reaching higher levels than the 'remaining brain'. These observations suggest that acetate has a direct role in central appetite regulation.

El hipotálamo juega en los mamíferos superiores un papel central en la integración de funciones vitales como la regulación del metabolismo energético global, la saciedad y el hambre, el control de la presión sanguínea y la temperatura corporal, la sed, hidratación y metabolismo salino del organismo, y las funciones testiculares y ováricas, entre otras. Muchas de estas funciones neuroendocrinas se realizan mediante el control del funcionamiento de la hipófisis, utilizando un complejo sistema de retroalimentación que modula la secreción de una gran variedad de hormonas hipofisarias con efectos sistémicos de vital importancia, incluyendo las hormonas tiroideas o la hormona del crecimiento, entre otras. El hipotálamo consta de aproximadamente una docena de subestructuras, conocidas como núcleos hipotalámicos, que se encargan de controlar los diversos procesos. Hasta muy recientemente no ha sido posible evaluar la función hipotalámica directamente in vivo, un aspecto que se resolvía mediante procedimientos indirectos como la determinación de cambios en el peso corporal, eliminación de líquidos, alteraciones en la termorregulación o desequilibrios en el perfil de hormonas en sangre. En esta revisión describiremos toda una nueva serie de métodos de imagen no invasiva para la evaluación directa de la función hipotalámica y su impacto potencial en nuestro conocimiento actual de la regulación de las interacciones neuroendocrinas, con especial referencia a la regulación hipotalámica del apetito in vivo., Este trabajo ha sido financiado en parte por las ayudas: SAF-2008-01327, SAF2011-23622 del Ministerio de Economía y Competitividad y S2010/BMD-2349 de la Comunidad de Madrid concedidas a Sebastián Cerdán y la beca predoctoral BES 2009-027615 del Ministerio de Economía y Competitividad concedida a Blanca Lizarbe.

Trabajo presentado al 30th Annual Scientific Meeting of European Society for Magnetic Resonance In Medicine and Biology, celebrado en Toulouse (Francia) del 3 al 5 de Octubre de 2013.

Trabajo presentado al 21th Annual Meeting & Exhibition of International Society for Magnetic Resonance in Medicine, celebrado en Salt Lake City (US) del 20 al 26 de Abril de 2013., Obesity is a pandemic syndrome often associated to the most prevalent and morbid pathologies in developed countries. Body adiposity is thought to be regulated systemically through an endocrine ‘adiposity’-negative feedback loop, mainly supported by leptin interacting with hypothalamic nuclei. The leptin-null ob/ob mouse model exhibits decreased energy expenditure, hyperphagia and obesity. In this communication, we wish to characterize the activation by fasting in individual hypothalamic nuclei from ob/ob mice, using DWI at high b values, DWI at low b values and T2* imaging, comparing the results obtained with the three techniques.

Trabajo presentado al 21th Annual Meeting & Exhibition of International Society for Magnetic Resonance in Medicine, celebrado en Salt Lake City (US) del 20 al 26 de Abril de 2013.

Tesis Doctoral presentada por Blanca Lizarbe Serra, licenciada en Física, para optar al grado de Doctor por la Universidad Autónoma de Madrid, y realizada en el Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-IIBM).-- Esta obra está bajo una licencia Creative Commons Reconocimiento-No Comercial-Sin Obra Derivada 4.0 Internacional., [EN]: Obesity is a pandemic syndrome that underlies the most morbid and prevalent diseases in developed countries. It results from an imbalance in appetite regulation and energy expenditure, two processes that are fundamentally controlled by the hypothalamus. Magnetic Resonance Imaging methods are excellently endowed to assess brain anatomy and function, under physiological and pathological conditions, providing an always increasing array of approaches. In this dissertation, I will introduce a collection of new strategies to evaluate non-invasively appetite regulation in the brain of mice and humans, based in the use of diffusion weighted magnetic resonance imaging methods. Chapter 1 introduces general concepts on the magnetic resonance imaging phenomenon and its applications, reviewing the key physiological mechanisms supporting hypothalamic appetite regulation. A short compilation of the most common neuroimaging techniques used to evaluate appetiterelated processes is also included. Chapter 2 describes the development and implementation of a new functional diffusion weighted imaging method applied to the detection of hypothalamic activity by fasting in mice and humans. Chapter 3 covers four different experimental manipulations designed to probe the role of specific hypothalamic nuclei in the regulation of appetite control and energy balance, under conditions where these are intentionally altered. Finally, Chapter 4 compares the use of the methodology analysed with different models of diffusion- with the results obtained with a more conventional functional imaging technique, both applied to the paradigm of glucose administration to fasting mice. In conclusion, this dissertation demonstrates that diffusion weighted magnetic resonance imaging methods provide a novel and useful approach to investigate appetite regulation non-invasively., [ES]: La obesidad es un síndrome pandémico que subyace a las enfermedades más prevalentes y mórbidas en los países desarrollados. Es resultado de un desequilibrio en la regulación del apetito y del gasto energético; dos mecanismos que están fundamentalmente controlados por el hipotálamo. Las técnicas de imagen por resonancia magnética constituyen una herramienta excelente de evaluación anatómica y funcional del cerebro, en condiciones fisiológicas y patológicas, proporcionando un constante creciente tipo de aplicaciones. La tesis que aquí presento se ha centrado en el desarrollo de nuevas estrategias para evaluar de forma no invasiva los procesos de regulación cerebral del apetito en ratones y seres humanos, utilizando técnicas de resonancia magnética pesada en difusión. El Capítulo 1 proporciona una introducción a los principios básicos de la imagen por resonancia magnética, así como alguna de sus aplicaciones, recopilando las principales nociones fisiológicas de los mecanismos hipotalámicos de la regulación del apetito. También incluye s una breve compilación de las técnicas de neuroimagen más utilizadas en la evaluación de procesos relacionados con el apetito. En el Capítulo 2 describo el desarrollo y la implementación de una nueva técnica de imagen funcional basada en difusión para la detección de la actividad hipotalámica por apetito, en ratones y en seres humanos. El Capítulo 3 está dedicado a la aplicación de esta técnica a cuatro situaciones experimentales distintas, diseñadas para evaluar la respuesta específica de los núcleos hipotalámicos en procesos en los que la regulación del apetito y el balance energético están alterados. Finalmente, en el Capítulo 4 muestro la comparación del uso de la metodología analizada con distintos modelos de difusión- con los resultados obtenidos mediante la aplicación de una técnica funcional más convencional, ambas aplicadas al estudio de los efectos hipotalámicos de la administración de glucosa a ratones ayunados. En conclusión, mi Tesis doctoral demuestra que la técnica de imagen de resonancia magnética pesada en difusión proporciona un instrumento nuevo y robusto para el estudio de la regulación del apetito de forma no invasiva.

El hipotálamo juega en los mamíferos superiores un papel central en la integración de funciones vitales como la regulación del metabolismo energético global, la saciedad y el hambre, el control de la presión sanguínea y la temperatura corporal, la sed, hidratación y metabolismo salino del organismo, y las funciones testiculares y ováricas, entre otras. Muchas de estas funciones neuroendocrinas se realizan mediante el control del funcionamiento de la hipófisis, utilizando un complejo sistema de retroalimentación que modula la secreción de una gran variedad de hormonas hipofisarias con efectos sistémicos de vital importancia, incluyendo las hormonas tiroideas o la hormona del crecimiento, entre otras. El hipotálamo consta de aproximadamente una docena de subestructuras, conocidas como núcleos hipotalámicos, que se encargan de controlar los diversos procesos. Hasta muy recientemente no ha sido posible evaluar la función hipotalámica directamente in vivo, un aspecto que se resolvía mediante procedimientos indirectos como la determinación de cambios en el peso corporal, eliminación de líquidos, alteraciones en la termorregulación o desequilibrios en el perfil de hormonas en sangre. En esta revisión describiremos toda una nueva serie de métodos de imagen no invasiva para la evaluación directa de la función hipotalámica y su impacto potencial en nuestro conocimiento actual de la regulación de las interacciones neuroendocrinas, con especial referencia a la regulación hipotalámica del apetito in vivo. Este trabajo ha sido financiado en parte por las ayudas: SAF-2008-01327, SAF2011-23622 del Ministerio de Economía y Competitividad y S2010/BMD-2349 de la Comunidad de Madrid concedidas a Sebastián Cerdán y la beca predoctoral BES 2009-027615 del Ministerio de Economía y Competitividad concedida a Blanca Lizarbe.

Trabajo presentado al 29th Annual Scientific Meeting of European Society for Magnetic Resonance In Medicine and Biology, celebrado en Lisboa (Portugal) del 4 al 6 de Octubre de 2012.

Trabajo presentado al 29th Annual Scientific Meeting of European Society for Magnetic Resonance In Medicine and Biology, celebrado en Lisboa (Portugal) del 4 la 6 de Octubre de 2012.