Ismael González-García
@helmholtz-muenchen.de
Helmholtz Zentrum Munchen
Scopus Publications
Scholar Citations
Scholar h-index
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Scopus Publications
María Luengo-Mateos, Antía González-Vila, Ana María Torres Caldas, Ali M. Alasaoufi, Marco González-Domínguez, Miguel López, Ismael González-García, and Olga Barca-Mayo
Elsevier BV
Nathalia R.V. Dragano, Edward Milbank, Roberta Haddad-Tóvolli, Pablo Garrido-Gil, Eva Nóvoa, Marcos F. Fondevilla, Valentina Capelli, Ariane Maria Zanesco, Carina Solon, Joseane Morari,et al.
Elsevier BV
Sebastián Zagmutt, Paula Mera, Ismael González-García, Kevin Ibeas, María del Mar Romero, Arnaud Obri, Beatriz Martin, Anna Esteve-Codina, M. Carmen Soler-Vázquez, Marianela Bastias-Pérez,et al.
Springer Science and Business Media LLC
Abstract Background Fatty acid metabolism in the hypothalamus has an important role in food intake, but its specific role in AgRP neurons is poorly understood. Here, we examined whether carnitinea palmitoyltransferase 1A (CPT1A), a key enzyme in mitochondrial fatty acid oxidation, affects energy balance. Methods To obtain Cpt1aKO mice and their control littermates, Cpt1a(flox/flox) mice were crossed with tamoxifen-inducible AgRPCreERT2 mice. Food intake and body weight were analyzed weekly in both males and females. At 12 weeks of age, metabolic flexibility was determined by ghrelin-induced food intake and fasting–refeeding satiety tests. Energy expenditure was analyzed by calorimetric system and thermogenic activity of brown adipose tissue. To study fluid balance the analysis of urine and water intake volumes; osmolality of urine and plasma; as well as serum levels of angiotensin and components of RAAS (renin–angiotensin–aldosterone system) were measured. At the central level, changes in AgRP neurons were determined by: (1) analyzing specific AgRP gene expression in RiboTag–Cpt1aKO mice obtained by crossing Cpt1aKO mice with RiboTag mice; (2) measuring presynaptic terminal formation in the AgRP neurons with the injection of the AAV1-EF1a-DIO-synaptophysin-GFP in the arcuate nucleus of the hypothalamus; (3) analyzing AgRP neuronal viability and spine formations by the injection AAV9-EF1a-DIO-mCherry in the arcuate nucleus of the hypothalamus; (4) analyzing in situ the specific AgRP mitochondria in the ZsGreen-Cpt1aKO obtained by breeding ZsGreen mice with Cpt1aKO mice. Two-way ANOVA analyses were performed to determine the contributions of the effect of lack of CPT1A in AgRP neurons in the sex. Results Changes in food intake were just seen in male Cpt1aKO mice while only female Cpt1aKO mice increased energy expenditure. The lack of Cpt1a in the AgRP neurons enhanced brown adipose tissue activity, mainly in females, and induced a substantial reduction in fat deposits and body weight. Strikingly, both male and female Cpt1aKO mice showed polydipsia and polyuria, with more reduced serum vasopressin levels in females and without osmolality alterations, indicating a direct involvement of Cpt1a in AgRP neurons in fluid balance. AgRP neurons from Cpt1aKO mice showed a sex-dependent gene expression pattern, reduced mitochondria and decreased presynaptic innervation to the paraventricular nucleus, without neuronal viability alterations. Conclusions Our results highlight that fatty acid metabolism and CPT1A in AgRP neurons show marked sex differences and play a relevant role in the neuronal processes necessary for the maintenance of whole-body fluid and energy balance.
T. Gruber, F. Lechner, C. Murat, Raian E. Contreras, E. Sanchez-Quant, V. Miok, Konstantinos Makris, O. Le Thuc, Ismael González-García, Elena García-Clavé,et al.
Ismael González-García and Cristina García-Cáceres
Springer Science and Business Media LLC
Ismael González-García and Miguel López
Elsevier BV
Ismael González-García, Elena García-Clavé, Alberto Cebrian-Serrano, Ophélia Le Thuc, Raian E. Contreras, Yanjun Xu, Tim Gruber, Sonja C. Schriever, Beata Legutko, Jutta Lintelmann,et al.
Elsevier BV
Luiza Maria Lutomska, Viktorian Miok, Natalie Krahmer, Ismael González García, Tim Gruber, Ophélia Le Thuc, Cahuê DB Murat, Beata Legutko, Michael Sterr, Gesine Saher,et al.
Wiley
Hypothalamic astrocytes are particularly affected by energy-dense food consumption. How the anatomical location of these glial cells and their spatial molecular distribution in the arcuate nucleus of the hypothalamus (ARC) determine the cellular response to a high caloric diet remains unclear. In this study, we investigated their distinctive molecular responses following exposure to a high-fat high-sugar (HFHS) diet, specifically in the ARC. Using RNA sequencing and proteomics, we showed that astrocytes have a distinct transcriptomic and proteomic profile dependent on their anatomical location, with a major proteomic reprogramming in hypothalamic astrocytes. By ARC single-cell sequencing, we observed that a HFHS diet dictates time- and cell- specific transcriptomic responses, revealing that astrocytes have the most distinct regulatory pattern compared to other cell types. Lastly, we topographically and molecularly characterized astrocytes expressing glial fibrillary acidic protein and/or aldehyde dehydrogenase 1 family member L1 in the ARC, of which the abundance was significantly increased, as well as the alteration in their spatial and molecular profiles, with a HFHS diet. Together, our results provide a detailed multi-omics view on the spatial and temporal changes of astrocytes particularly in the ARC during different time points of adaptation to a high calorie diet.
Ismael González-García, Adela Urisarri, Rubén Nogueiras, Carlos Diéguez, María L. Couce, and Miguel López
Springer Science and Business Media LLC
The maintenance and regulation of body temperature in neonates is critical for survival. However, the mechanisms by which human neonates achieve body temperature control are unclear. Current evidence has demonstrated that infrared thermography is a suitable non-invasive technique that can be safely applied to human babies to investigate brown adipose tissue thermogenesis.
Ismael González-García, Óscar Freire-Agulleiro, Naoki Nakaya, Francisco J. Ortega, Pablo Garrido-Gil, Laura Liñares-Pose, Johan Fernø, José Luis Labandeira-Garcia, Carlos Diéguez, Afia Sultana,et al.
Elsevier BV
Adela Urisarri, Ismael González-García, Ánxela Estévez-Salguero, María P. Pata, Edward Milbank, Noemi López, Natalia Mandiá, Carmen Grijota-Martinez, Carlos A. Salgado, Rubén Nogueiras,et al.
Springer Science and Business Media LLC
AbstractThe classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns.
Marta Tarquis-Medina, Katharina Scheibner, Ismael González-García, Aimée Bastidas-Ponce, Michael Sterr, Jessica Jaki, Silvia Schirge, Cristina García-Cáceres, Heiko Lickert, and Mostafa Bakhti
MDPI AG
Synaptotagmin-13 (Syt13) is an atypical member of the vesicle trafficking synaptotagmin protein family. The expression pattern and the biological function of this Ca2+-independent protein are not well resolved. Here, we have generated a novel Syt13-Venus fusion (Syt13-VF) fluorescence reporter allele to track and isolate tissues and cells expressing Syt13 protein. The reporter allele is regulated by endogenous cis-regulatory elements of Syt13 and the fusion protein follows an identical expression pattern of the endogenous Syt13 protein. The homozygous reporter mice are viable and fertile. We identify the expression of the Syt13-VF reporter in different regions of the brain with high expression in tyrosine hydroxylase (TH)-expressing and oxytocin-producing neuroendocrine cells. Moreover, Syt13-VF is highly restricted to all enteroendocrine cells in the adult intestine that can be traced in live imaging. Finally, Syt13-VF protein is expressed in the pancreatic endocrine lineage, allowing their specific isolation by flow sorting. These findings demonstrate high expression levels of Syt13 in the endocrine lineages in three major organs harboring these secretory cells. Collectively, the Syt13-VF reporter mouse line provides a unique and reliable tool to dissect the spatio-temporal expression pattern of Syt13 and enables isolation of Syt13-expressing cells that will aid in deciphering the molecular functions of this protein in the neuroendocrine system.
Edward Milbank, Nathalia R. V. Dragano, Ismael González-García, Marcos Rios Garcia, Verónica Rivas-Limeres, Liliana Perdomo, Grégory Hilairet, Francisco Ruiz-Pino, Patricia Mallegol, Donald A. Morgan,et al.
Springer Science and Business Media LLC
Current pharmacological therapies for treating obesity are of limited efficacy. Genetic ablation or loss of function of AMP-activated protein kinase alpha 1 (AMPKα1) in steroidogenic factor 1 (SF1) neurons of the ventromedial nucleus of the hypothalamus (VMH) induces feeding-independent resistance to obesity due to sympathetic activation of brown adipose tissue (BAT) thermogenesis. Here, we show that body weight of obese mice can be reduced by intravenous injection of small extracellular vesicles (sEVs) delivering a plasmid encoding an AMPKα1 dominant negative mutant (AMPKα1-DN) targeted to VMH-SF1 neurons. The beneficial effect of SF1-AMPKα1-DN-loaded sEVs is feeding-independent and involves sympathetic nerve activation and increased UCP1-dependent thermogenesis in BAT. Our results underscore the potential of sEVs to specifically target AMPK in hypothalamic neurons and introduce a broader strategy to manipulate body weight and reduce obesity.
Kelly Meneyrol, Ánxela Estévez-Salguero, Ismael González-García, Jeanne Guitton, Mohammed Taouis, Yacir Benomar, Christophe Magnan, Miguel López, and Hervé Le Stunff
Elsevier BV
Oestrogens regulate body weight through their action on hypothalamus to modulate food intake and energy expenditure. Hypothalamic de novo ceramide synthesis play a central role on obesity induced by oestrogen deficiency. Depletion in oestrogens is also known to be associated with glucose intolerance, which favours type 2 diabetes (T2D). However, the implication of hypothalamic ceramide in the regulation of glucose homeostasis by oestrogen is unknown. Here, we studied glucose homeostasis and insulin secretion in ovariectomized (OVX) female rats. OVX induces body weight gain associated with a hypothalamic inflammation and impaired glucose homeostasis. Genetic blockade of ceramide synthesis in the ventromedial nucleus of the hypothalamus (VMH) reverses hypothalamic inflammation and partly restored glucose tolerance induced by OVX. Furthermore, glucose-stimulated insulin secretion (GSIS) is increased in OVX rats due to a raise of insulin secretion second phase, a characteristic of early stage of T2D. In contrast, GSIS from isolated islets of OVX rats is totally blunted. Inhibition of ceramide synthesis in the VMH restores GSIS from isolated OVX islets and represses the second phase of insulin secretion. Stimulation of oestrogen receptor α (ERα) by oestradiol down-regulates ceramide synthesis in hypothalamic neuronal GT1-7 cells but no in microglial SIM-A9 cells. In contrast, genetic inactivation of ERα in VMH upregulates ceramide synthesis. These results indicate that hypothalamic neuronal de novo ceramide synthesis triggers the OVX-dependent impairment of glucose homeostasis which is partly mediated by a dysregulation of GSIS.
Ismael González-García and Cristina García-Cáceres
MDPI AG
Astrocytes are a type of glial cell anatomically and functionally integrated into the neuronal regulatory circuits for the neuroendocrine control of metabolism. Being functional integral compounds of synapses, astrocytes are actively involved in the physiological regulatory aspects of metabolic control, but also in the pathological processes that link neuronal dysfunction and obesity. Between brain areas, the hypothalamus harbors specialized functional circuits that seem selectively vulnerable to metabolic damage, undergoing early cellular rearrangements which are thought to be at the core of the pathogenesis of diet-induced obesity. Such changes in the hypothalamic brain region consist of a rise in proinflammatory cytokines, the presence of a reactive phenotype in astrocytes and microglia, alterations in the cytoarchitecture and synaptology of hypothalamic circuits, and angiogenesis, a phenomenon that cannot be found elsewhere in the brain. Increasing evidence points to the direct involvement of hypothalamic astrocytes in such early metabolic disturbances, thus moving the study of these glial cells to the forefront of obesity research. Here we provide a comprehensive review of the most relevant findings of molecular and pathophysiological mechanisms by which hypothalamic astrocytes might be involved in the pathogenesis of obesity.
Ismael González‐García, Tim Gruber, and Cristina García‐Cáceres
Wiley
Astrocytes are specialised glial cells that integrate distinct inputs arising from neurones, other glial cells and the microcirculation to regulate diverse aspects of brain function. A growing body of emerging evidence supports that astrocytes, similar to neurones, also play active roles in the neuroendocrine control of metabolism by responding to afferent nutritional and hormonal cues and translating these metabolic cues into neuronal inputs. Specifically, insulin action in astrocytes has received special emphasis given its newly discovered regulatory role in brain glucose uptake, which until recently was assumed to be an insulin independent process. We now know that insulin signalling in astrocytes regulates metabolic processes and behavioural responses through coupling brain glucose uptake with nutrient availability to maintain energy balance and systemic glucose homeostasis. Moreover, genetic ablation of the insulin receptor in astrocytes is associated with anxiety- and depressive-like behaviours, confirming that these glial cells are involved in the regulation of cognition and mood via insulin action. Here, we provide a comprehensive review of the most relevant findings that have been made over the course of the last few years linking insulin signalling in astrocytes with the pathogenesis of brain metabolic and neurodegenerative diseases; a still unexplored field, but with a high translational potential for developing therapies.
Ismael González-García, Ophélia Le Thuc, Martin Jastroch, and Cristina García-Cáceres
Elsevier BV
The human brain is an energetically expensive organ, which uses approximately 20 percent of the resting body’s energy production despite occupying only 2% of the body’s mass. The energy is required to constantly encode and exchange information that is passing through neural impulses. The energy for these processes is supported by the powerhouses of the cell, the mitochondria. Mitochondria are highly dynamic bioenergetic organelles that can adjust size, shape, and location via fission and fusion events, collectively referred to as ‘mitochondrial dynamics’, to adjust cellular energy homeostasis by modulating energy efficiency and distribution, thereby responding to dynamic changes in energy demands. In neurons, when cellular energy requirements are high, mitochondrial fusion appears to support higher ATP production, in contrast to mitochondrial fission, which is usually associated with reduced mitochondrial activity and low energy states [1]. Most importantly, however, is the precise regulation by several mitochondrial fusion proteins, such as mitofusin 1 and 2 (Mfn1 and -2) and mitochondrial dynamin-like GTPase (Opa1), and mitochondrial fission proteins, such as dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) [2]. The tight control of mitochondrial dynamics in the brain is not only crucial for maintaining cellular integrity, but enables neurons to control glucose homeostasis and whole-body energy balance [1]. The groups of Claret and Horvath previously discovered how alterations of mitochondrial dynamics in Pro-opiomelanocortin (POMC) and Agouti related protein (AgRP) neurons impact on systemic energy balance [3,4]. Later studies have shown how mitochondrial dynamics can influence glucose-induced neuronal activation in specific hypothalamic nuclei, such as the arcuate nucleus (ARC) and the ventromedial nucleus (VMH), as well as in extrahypothalamic areas, such as the dorsal vagal complex (DVC) for control of glucose metabolism [5e8]. In this issue of Molecular Metabolism, Patel et al. advance our understanding of the brain-metabolism axis by showing that not only do mitochondrial dynamics in neurons control energy balance, but mitochondrial dynamics in astrocytes expressing the glial fibrillary acidic protein (GFAP) within brainstem areas play an equally powerful role [9]. A non-cell-specific viral approach in the DVC of rats reveals that increasing the activity of the mitochondrial fission protein Drp1 impairs insulin signaling, leading to increased food intake, subsequent body weight gain, and adiposity. Conversely, inhibiting Drp1 activity in highfat diet (HFD)-fed rats via viral induction of a dominant negative (DN) form was able to rescue the aforementioned phenotype, while the constitutively active form of Drp1 and HFD both increased levels of inducible nitric oxide synthase (iNOS) in the DVC. The results in vitro and in vivo suggest that iNOS levels correlate with Drp1 activity. Inhibiting either Drp1 or iNOS in the DVC restores the ability of insulin to reduce food intake in DIO animals and slows down body weight gain. Inhibiting Drp1 activity specifically in DVC GFAP-expressing astrocytes was sufficient to ameliorate metabolic health during short-term HFD feeding, thus confirming the previously observed phenotype of decreased feeding and ameliorated obesity.
Ismael González-García, Edward Milbank, Anxo Martinez-Ordoñez, Carlos Diéguez, Miguel López, and Cristina Contreras
Springer Science and Business Media LLC
Marina Badenes, Abdulbasit Amin, Ismael González-García, Inês Félix, Emma Burbridge, Miguel Cavadas, Francisco José Ortega, Érika de Carvalho, Pedro Faísca, Stefania Carobbio,et al.
Elsevier BV
Ismael González-García, Edward Milbank, Carlos Diéguez, Miguel López, and Cristina Contreras
MDPI AG
Brown adipose tissue (BAT) thermogenesis is a conserved mechanism to maintain body temperature in mammals. However, since BAT contribution to energy expenditure can represent a relevant modulator of metabolic homeostasis, many studies have focused on the nervous system and endocrine factors that control the activity of this tissue. There is long-established evidence that the counter-regulatory hormone glucagon negatively influences energy balance, enhances satiety, and increases energy expenditure. Despite compelling evidence showing that glucagon has direct action on BAT thermogenesis, recent findings are questioning this conventional attribute of glucagon action. Glucagon like peptide-1 (GLP-1) is an incretin secreted by the intestinal tract which strongly decreases feeding, and, furthermore, improves metabolic parameters associated with obesity and diabetes. Therefore, GLP-1 receptors (GLP-1-R) have emerged as a promising target in the treatment of metabolic disorders. In this short review, we will summarize the latest evidence in this regard, as well as the current therapeutic glucagon- and GLP-1-based approaches to treating obesity.
Birte Blankenhaus, Faouzi Braza, Rui Martins, Patricia Bastos-Amador, Ismael González-García, Ana Rita Carlos, Inês Mahu, Pedro Faisca, Jose Moura Nunes, Pedro Ventura,et al.
Elsevier BV
Ismael González-García, Cristina Contreras, Ánxela Estévez-Salguero, Francisco Ruíz-Pino, Benoit Colsh, Iván Pensado, Laura Liñares-Pose, Eva Rial-Pensado, Pablo B. Martínez de Morentin, Johan Fernø,et al.
Elsevier BV
Ismael González-García, Pablo B Martínez de Morentin, Ánxela Estévez-Salguero, Cristina Contreras, Amparo Romero-Picó, Johan Fernø, Rubén Nogueiras, Carlos Diéguez, Manuel Tena-Sempere, Sulay Tovar,et al.
Bioscientifica
Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.
Laura Liñares-Pose, Eva Rial-Pensado, Ánxela Estévez-Salguero, Edward Milbank, Ismael González-García, Claudia Rodríguez, Patricia Seoane-Collazo, Noelia Martinez-Sánchez, Rubén Nogueiras, Dolores Prieto,et al.
MDPI AG
Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD-induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity.
Silje Skrede, Ismael González-García, Luís Martins, Rolf Kristian Berge, Ruben Nogueiras, Manuel Tena-Sempere, Gunnar Mellgren, Vidar Martin Steen, Miguel López, and Johan Fernø
Oxford University Press (OUP)