Publications by authors named "Núria Casals"

55 Publications

Carnitine palmitoyltransferase 1C negatively regulates the endocannabinoid hydrolase ABHD6 in mice, depending on nutritional status.

Br J Pharmacol 2021 Apr 12;178(7):1507-1523. Epub 2021 Feb 12.

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain.

Background And Purpose: The enzyme α/β-hydrolase domain containing 6 (ABHD6), a new member of the endocannabinoid system, is a promising therapeutic target against neuronal-related diseases. However, how ABHD6 activity is regulated is not known. ABHD6 coexists in protein complexes with the brain-specific carnitine palmitoyltransferase 1C (CPT1C). CPT1C is involved in neuro-metabolic functions, depending on brain malonyl-CoA levels. Our aim was to study CPT1C-ABHD6 interaction and determine whether CPT1C is a key regulator of ABHD6 activity depending on nutritional status.

Experimental Approach: Co-immunoprecipitation and FRET assays were used to explore ABHD6 interaction with CPT1C or modified malonyl-CoA-insensitive or C-terminal truncated CPT1C forms. Cannabinoid CB receptor-mediated signalling was investigated by determining cAMP levels. A novel highly sensitive fluorescent method was optimized to measure ABHD6 activity in non-neuronal and neuronal cells and in brain tissues from wild-type (WT) and CPT1C-KO mice.

Key Results: CPT1C interacted with ABHD6 and negatively regulated its hydrolase activity, thereby regulating 2-AG downstream signalling. Accordingly, brain tissues of CPT1C-KO mice showed increased ABHD6 activity. CPT1C malonyl-CoA sensing was key to the regulatory role on ABHD6 activity and CB receptor signalling. Fasting, which attenuates brain malonyl-CoA, significantly increased ABHD6 activity in hypothalamus from WT, but not CPT1C-KO, mice.

Conclusions And Implications: Our finding that negative regulation of ABHD6 activity, particularly in the hypothalamus, is sensitive to nutritional status throws new light on the characterization and the importance of the proteins involved as potential targets against diseases affecting the CNS.
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http://dx.doi.org/10.1111/bph.15377DOI Listing
April 2021

The return of malonyl-CoA to the brain: Cognition and other stories.

Prog Lipid Res 2021 Jan 10;81:101071. Epub 2020 Nov 10.

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, E-08195 Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain. Electronic address:

Nutrients, hormones and the energy sensor AMP-activated protein kinase (AMPK) tightly regulate the intracellular levels of the metabolic intermediary malonyl-CoA, which is a precursor of fatty acid synthesis and a negative regulator of fatty acid oxidation. In the brain, the involvement of malonyl-CoA in the control of food intake and energy homeostasis has been known for decades. However, recent data uncover a new role in cognition and brain development. The sensing of malonyl-CoA by carnitine palmitoyltransferase 1 (CPT1) proteins regulates a variety of functions, such as the fate of neuronal stem cell precursors, the motility of lysosomes in developing axons, the trafficking of glutamate receptors to the neuron surface (necessary for proper synaptic function) and the metabolic coupling between astrocytes and neurons. We discuss the relevance of those recent findings evidencing how nutrients and metabolic disorders impact cognition. We also enumerate all nutritional and hormonal conditions that are known to regulate malonyl-CoA levels in the brain, reflect on protein malonylation as a new post-translational modification, and give a reasoned vision of the opportunities and challenges that future research in the field could address.
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http://dx.doi.org/10.1016/j.plipres.2020.101071DOI Listing
January 2021

Central Ceramide Signaling Mediates Obesity-Induced Precocious Puberty.

Cell Metab 2020 Dec 19;32(6):951-966.e8. Epub 2020 Oct 19.

Instituto Maimónides de Investigation Biomédica de Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Córdoba and Hospital Universitario Reina Sofia, 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 14004 Córdoba, Spain; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, Turku, Finland. Electronic address:

Childhood obesity, especially in girls, is frequently bound to earlier puberty, which is linked to higher disease burden later in life. The mechanisms underlying this association remain elusive. Here we show that brain ceramides participate in the control of female puberty and contribute to its alteration in early-onset obesity in rats. Postnatal overweight caused earlier puberty and increased hypothalamic ceramide content, while pharmacological activation of ceramide synthesis mimicked the pubertal advancement caused by obesity, specifically in females. Conversely, central blockade of de novo ceramide synthesis delayed puberty and prevented the effects of the puberty-activating signal, kisspeptin. This phenomenon seemingly involves a circuit encompassing the paraventricular nucleus (PVN) and ovarian sympathetic innervation. Early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. In turn, obesity-induced pubertal precocity was reversed by virogenetic suppression of SPTLC1 in the PVN. Our data unveil a pathway, linking kisspeptin, PVN ceramides, and sympathetic ovarian innervation, as key for obesity-induced pubertal precocity.
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http://dx.doi.org/10.1016/j.cmet.2020.10.001DOI Listing
December 2020

Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.

J Cell Biol 2020 10;219(10)

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain.

Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1. In normal conditions, CPT1C down-regulates SAC1 catalytic activity, allowing efficient GluA1 trafficking to the plasma membrane. However, under low malonyl-CoA levels, such as during glucose depletion, CPT1C-dependent inhibition of SAC1 is released, facilitating SAC1's translocation to ER-TGN contact sites to decrease TGN PI(4)P pools and trigger GluA1 retention at the TGN. Results reveal that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and provide the first report of a SAC1 inhibitor. Moreover, they shed light on how nutrients can affect synaptic function and cognition.
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http://dx.doi.org/10.1083/jcb.201912045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659714PMC
October 2020

Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD.

FASEB J 2020 09 15;34(9):11816-11837. Epub 2020 Jul 15.

Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.
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http://dx.doi.org/10.1096/fj.202000678RDOI Listing
September 2020

An overview of nanomedicines for neuron targeting.

Nanomedicine (Lond) 2020 07 3;15(16):1617-1636. Epub 2020 Jul 3.

Department of Basic Sciences, Faculty of Medicine & Health Sciences, Universitat Internacional de Catalunya, 08195, Sant Cugat del Vallès, Spain.

Medical treatments of neuron-related disorders are limited due to the difficulty of targeting brain cells. Major drawbacks are the presence of the blood-brain barrier and the lack of specificity of the drugs for the diseased cells. Nanomedicine-based approaches provide promising opportunities for overcoming these limitations. Although many previous reviews are focused on brain targeting with nanomedicines in general, none of those are concerned explicitly on the neurons, while targeting neuronal cells in central nervous diseases is now one of the biggest challenges in nanomedicine and neuroscience. We review the most relevant advances in nanomedicine design and strategies for neuronal drug delivery that might successfully bridge the gap between laboratory and bedside treatment in neurology.
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http://dx.doi.org/10.2217/nnm-2020-0088DOI Listing
July 2020

Drug uptake-based chemoresistance in breast cancer treatment.

Biochem Pharmacol 2020 07 7;177:113959. Epub 2020 Apr 7.

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, E-08195 Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain. Electronic address:

Breast cancer is the most prevalent type of tumor and the second leading cause of death due to cancer among women. Although screening methods, diagnosis and therapeutic options have improved in the last decade, chemoresistance remains an important challenge. There is evidence relating breast cancer resistance with signaling pathways involving hormone and growth receptors, survival, apoptosis and the activation of efflux pumps. However, the resistance mechanisms linked to drug uptake are poorly understood, despite it often being observed that the drug content is lower in resistant cancer cells and that the entry of the drug into these cells is a limiting process for the subsequent therapeutic effect.In this review, we provide an overview of drug uptake-based resistance mechanisms developed by cancer cells in the four main types of chemotherapy used in breast cancer: anthracyclines, taxanes, oxazaphosphorines and platinum-based drugs. The contribution of tumor microenvironment to reduced drug-uptake and multidrug resistance is also analyzed. As a developing field, nanomedicine-based approaches provide promising opportunities to improve drug specific targeting, cell interaction and uptake into cancer cells. The endocytic-mediated pathways attributed to the different types of nanoformulations as well as the contribution of nanotherapeutics to overcoming chemoresistance affecting drug uptake in breast cancer will be described. New approaches focusing on drug uptake mechanisms could improve breast cancer chemotherapy, obtaining better dose-response outcomes and reducing toxic side effects.
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http://dx.doi.org/10.1016/j.bcp.2020.113959DOI Listing
July 2020

Proteasomal-Mediated Degradation of AKAP150 Accompanies AMPAR Endocytosis during cLTD.

eNeuro 2020 Mar/Apr;7(2). Epub 2020 Apr 16.

Institut de Neurociències and Dpt. Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès 08193, Spain

The number and function of synaptic AMPA receptors (AMPARs) tightly regulates excitatory synaptic transmission. Current evidence suggests that AMPARs are inserted into the postsynaptic membrane during long-term potentiation (LTP) and are removed from the membrane during long-term depression (LTD). Dephosphorylation of GluA1 at Ser-845 and enhanced endocytosis are critical events in the modulation of LTD. Moreover, changes in scaffold proteins from the postsynaptic density (PSD) could be also related to AMPAR regulation in LTD. In the present study we analyzed the effect of chemical LTD (cLTD) on A-kinase anchoring protein (AKAP)150 and AMPARs levels in mouse-cultured neurons. We show that cLTD induces AKAP150 protein degradation via proteasome, coinciding with GluA1 dephosphorylation at Ser-845 and endocytosis of GluA1-containing AMPARs. Pharmacological inhibition of proteasome activity, but not phosphatase calcineurin (CaN), reverted cLTD-induced AKAP150 protein degradation. Importantly, AKAP150 silencing induced dephosphorylation of GluA1 Ser-845 and GluA1-AMPARs endocytosis while AKAP150 overexpression blocked cLTD-mediated GluA1-AMPARs endocytosis. Our results provide direct evidence that cLTD-induced AKAP150 degradation by the proteasome contributes to synaptic AMPARs endocytosis.
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http://dx.doi.org/10.1523/ENEURO.0218-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163082PMC
April 2020

Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.

Elife 2019 12 23;8. Epub 2019 Dec 23.

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain.

Anterograde transport of late endosomes or lysosomes (LE/Lys) is crucial for proper axon growth. However, the role of energetic nutrients has been poorly explored. Malonyl-CoA is a precursor of fatty acids, and its intracellular levels highly fluctuate depending on glucose availability or the energy sensor AMP-activated protein kinase (AMPK). We demonstrate in HeLa cells that carnitine palmitoyltransferase 1C (CPT1C) senses malonyl-CoA and enhances LE/Lys anterograde transport by interacting with the endoplasmic reticulum protein protrudin and facilitating the transfer of Kinesin-1 from protrudin to LE/Lys. In cultured mouse cortical neurons, glucose deprivation, pharmacological activation of AMPK or inhibition of malonyl-CoA synthesis decreases LE/Lys abundance at the axon terminal, and shortens axon length in a CPT1C-dependent manner. These results identify CPT1C as a new regulator of anterograde LE/Lys transport in response to malonyl-CoA changes, and give insight into how axon growth is controlled by nutrients.
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http://dx.doi.org/10.7554/eLife.51063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927751PMC
December 2019

Hypothalamic endocannabinoids inversely correlate with the development of diet-induced obesity in male and female mice.

J Lipid Res 2019 07 28;60(7):1260-1269. Epub 2019 May 28.

Basic Sciences Department, Faculty of Medicine and Health Sciences Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain

The endocannabinoid (eCB) system regulates energy homeostasis and is linked to obesity development. However, the exact dynamic and regulation of eCBs in the hypothalamus during obesity progression remain incompletely described and understood. Our study examined the time course of responses in two hypothalamic eCBs, 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamine (AEA), in male and female mice during diet-induced obesity and explored the association of eCB levels with changes in brown adipose tissue (BAT) thermogenesis and body weight. We fed mice a high-fat diet (HFD), which induced a transient increase (substantial at 7 days) in hypothalamic eCBs, followed by a progressive decrease to basal levels with a long-term HFD. This transient rise at early stages of obesity is considered a physiologic compensatory response to BAT thermogenesis, which is activated by diet surplus. The eCB dynamic was sexually dimorphic: hypothalamic eCBs levels were higher in female mice, who became obese at later time points than males. The hypothalamic eCBs time course positively correlated with thermogenesis activation, but negatively matched body weight, leptinemia, and circulating eCB levels. Increased expression of eCB-synthetizing enzymes accompanied the transient hypothalamic eCB elevation. Icv injection of eCB did not promote BAT thermogenesis; however, administration of thermogenic molecules, such as central leptin or a peripheral β3-adrenoreceptor agonist, induced a significant increase in hypothalamic eCBs, suggesting a directional link from BAT thermogenesis to hypothalamic eCBs. This study contributes to the understanding of hypothalamic regulation of obesity.
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http://dx.doi.org/10.1194/jlr.M092742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602126PMC
July 2019

Blood-brain barrier dysfunction underlying Alzheimer's disease is induced by an SSAO/VAP-1-dependent cerebrovascular activation with enhanced Aβ deposition.

Biochim Biophys Acta Mol Basis Dis 2019 09 30;1865(9):2189-2202. Epub 2019 Apr 30.

Biochemistry and Molecular Biology Department, Institute of Neurosciences (INc), Universitat Autònoma de Barcelona (UAB), Bellaterra, Barcelona, Spain. Electronic address:

Dysfunctions of the vascular system directly contribute to the onset and progression of Alzheimer's disease (AD). The blood-brain barrier (BBB) shows signs of malfunction at early stages of the disease. When Abeta peptide (Aβ) is deposited on brain vessels, it induces vascular degeneration by producing reactive oxygen species and promoting inflammation. These molecular processes are also related to an excessive SSAO/VAP-1 (semicarbazide-sensitive amine oxidase) enzymatic activity, observed in plasma and in cerebrovascular tissue of AD patients. We studied the contribution of vascular SSAO/VAP-1 to the BBB dysfunction in AD using in vitro BBB models. Our results show that SSAO/VAP-1 expression is associated to endothelial activation by altering the release of pro-inflammatory and pro-angiogenic angioneurins, most highly IL-6, IL-8 and VEGF. It is also related to a BBB structure alteration, with a decrease in tight-junction proteins such as zona occludens or claudin-5. Moreover, the BBB function reveals increased permeability and leukocyte adhesion in cells expressing SSAO/VAP-1, as well as an enhancement of the vascular Aβ deposition induced by mechanisms both dependent and independent of the enzymatic activity of SSAO/VAP-1. These results reveal an interesting role of vascular SSAO/VAP-1 in BBB dysfunction related to AD progression, opening a new window in the search of alternative therapeutic targets for fighting AD.
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http://dx.doi.org/10.1016/j.bbadis.2019.04.016DOI Listing
September 2019

CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity.

Mol Metab 2019 01 2;19:75-85. Epub 2018 Nov 2.

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, 08195, Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain. Electronic address:

Objective: Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity.

Methods: CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed.

Results: Under 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development, whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, and disrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onset leptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was a downstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight loss in KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quite opposite, the expression of CPT1C in the VMH restored the phenotype.

Conclusion: CPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH. This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity.
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http://dx.doi.org/10.1016/j.molmet.2018.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323189PMC
January 2019

Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.

Front Mol Neurosci 2018 8;11:275. Epub 2018 Aug 8.

Laboratori de Neurofisiologia, Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain.

In neurons, AMPA receptor (AMPAR) function depends essentially on their constituent components:the ion channel forming subunits and ion channel associated proteins. On the other hand, AMPAR trafficking is tightly regulated by a vast number of intracellular neuronal proteins that bind to AMPAR subunits. It has been recently shown that the interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase 1C (CPT1C), a novel protein partner of AMPARs, is important in modulating surface expression of these ionotropic glutamate receptors. Indeed, synaptic transmission in CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that protein. However, the molecular mechanisms of such modulation remain unknown although a putative role of CPT1C in depalmitoylating GluA1 has been hypothesized. Here, we explore that possibility and show that CPT1C effect on AMPARs is likely due to changes in the palmitoylation state of GluA1. Based on analysis, Ser 252, His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C palmitoyl thioesterase (PTE) activity. When these residues are mutated or when PTE activity is inhibited, the CPT1C effect on AMPAR trafficking is abolished, validating the CPT1C catalytic triad as being responsible for PTE activity on AMPAR. Moreover, the histidine residue (His 470) of CPT1C is crucial for the increase in GluA1 surface expression in neurons and the H470A mutation impairs the depalmitoylating catalytic activity of CPT1C. Finally, we show that CPT1C effect seems to be specific for this CPT1 isoform and it takes place solely at endoplasmic reticulum (ER). This work adds another facet to the impressive degree of molecular mechanisms regulating AMPAR physiology.
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http://dx.doi.org/10.3389/fnmol.2018.00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092487PMC
August 2018

CPT1C promotes human mesenchymal stem cells survival under glucose deprivation through the modulation of autophagy.

Sci Rep 2018 05 3;8(1):6997. Epub 2018 May 3.

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), 08195, Sant Cugat del Vallès, Spain.

Human mesenchymal stem cells (hMSCs) are widely used in regenerative medicine. In some applications, they must survive under low nutrient conditions engendered by avascularity. Strategies to improve hMSCs survival may be of high relevance in tissue engineering. Carnitine palmitoyltransferase 1 C (CPT1C) is a pseudoenzyme exclusively expressed in neurons and cancer cells. In the present study, we show that CPT1C is also expressed in hMSCs and protects them against glucose starvation, glycolysis inhibition, and oxygen/glucose deprivation. CPT1C overexpression in hMSCs did not increase fatty acid oxidation capacity, indicating that the role of CPT1C in these cells is different from that described in tumor cells. The increased survival of CPT1C-overexpressing hMSCs observed during glucose deficiency was found to be the result of autophagy enhancement, leading to a greater number of lipid droplets and increased intracellular ATP levels. In fact, inhibition of autophagy or lipolysis was observed to completely block the protective effects of CPT1C. Our results indicate that CPT1C-mediated autophagy enhancement in glucose deprivation conditions allows a greater availability of lipids to be used as fuel substrate for ATP generation, revealing a new role of CPT1C in stem cell adaptation to low nutrient environments.
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http://dx.doi.org/10.1038/s41598-018-25485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934389PMC
May 2018

Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex.

Mol Neurobiol 2018 Sep 2;55(9):7216-7228. Epub 2018 Feb 2.

Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l'Alimentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-30, E-08028, Barcelona, Spain.

Lipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A activity and GABAT activity are reduced after ghrelin treatment. Furthermore, in primary cortical neurons, ghrelin reduces GABA release through a CPT1A reduction. By using CPT1A floxed mice, we have observed that genetic ablation of CPT1A recapitulates the effect of ghrelin on GABA release in cortical neurons, inducing reductions in mitochondrial oxygen consumption, cell content of citrate and α-ketoglutarate, and GABA shunt enzyme activity. Taken together, these observations indicate that ghrelin-induced changes in CPT1A activity modulate mitochondrial function, yielding changes in GABA metabolism. This evidence suggests that the action of ghrelin on GABA release is region specific within the brain, providing a basis for differential effects of ghrelin in the central nervous system.
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http://dx.doi.org/10.1007/s12035-018-0921-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096967PMC
September 2018

Uridine-5'-Triphosphate Partially Blocks Differentiation Signals and Favors a more Repair State in Cultured rat Schwann Cells.

Neuroscience 2018 02 11;372:255-265. Epub 2018 Jan 11.

Department of Basic Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain. Electronic address:

Schwann cells (SCs) play a key role in peripheral nerve regeneration. After damage, they respond acquiring a repair phenotype that allows them to proliferate, migrate and redirect axonal growth. Previous studies have shown that Uridine-5'-Triphosphate (UTP) and its purinergic receptors participate in several pathophysiological responses in the nervous system. Our group has previously described how UTP induces the migration of a Schwannoma cell line and promotes wound healing. These data suggest that UTP participates in the signaling involved in the regeneration process. In the present study we evaluated UTP effects in isolated rat SCs and cocultures of SCs and dorsal root ganglia neurons. UTP reduced cAMP-dependent Krox-20 induction in SCs. UTP also reduced the N-cadherin re-expression that occurs when SCs and axons make contact. In myelinating cocultures, a non-significant tendency to a lower expression of P0 and MAG proteins in presence of UTP was observed. We also demonstrated that UTP induced SC migration without affecting cell proliferation. Interestingly, UTP was found to block neuregulin-induced phosphorylation of the ErbB3 receptor, a pathway involved in the regeneration process. These results indicate that UTP could acts as a brake to the differentiation signals, promoting a more migratory state in the repair-SCs.
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http://dx.doi.org/10.1016/j.neuroscience.2018.01.010DOI Listing
February 2018

Increased inflammation, oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice.

Sci Rep 2017 11 22;7(1):16082. Epub 2017 Nov 22.

Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028, Barcelona, Spain.

Obesity is associated with severe metabolic diseases such as type 2 diabetes, insulin resistance, cardiovascular disease and some forms of cancer. The pathophysiology of obesity-induced metabolic diseases has been strongly related to white adipose tissue (WAT) dysfunction through several mechanisms such as fibrosis, apoptosis, inflammation, ER and oxidative stress. However, little is known of whether these processes are also present in brown adipose tissue (BAT) during obesity, and the potential consequences on mitochondrial activity. Here we characterized the BAT of obese and hyperglycemic mice treated with a high-fat diet (HFD) for 20 weeks. The hypertrophic BAT from obese mice showed no signs of fibrosis nor apoptosis, but higher levels of inflammation, ER stress, ROS generation and antioxidant enzyme activity than the lean counterparts. The response was attenuated compared with obesity-induced WAT derangements, which suggests that BAT is more resistant to the obesity-induced insult. In fact, mitochondrial respiration in BAT from obese mice was enhanced, with a 2-fold increase in basal oxygen consumption, through the upregulation of complex III of the electron transport chain and UCP1. Altogether, our results show that obesity is accompanied by an increase in BAT mitochondrial activity, inflammation and oxidative damage.
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http://dx.doi.org/10.1038/s41598-017-16463-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700117PMC
November 2017

Astrocytes and oligodendrocytes in grey and white matter regions of the brain metabolize fatty acids.

Sci Rep 2017 09 7;7(1):10779. Epub 2017 Sep 7.

Life and Medical Sciences Institute (LIMES), University of Bonn, Carl-Troll-Straße 31, D-53115, Bonn, Germany.

The grey and white matter regions of the mammalian brain consist of both neurons and neuroglial cells. Among the neuroglia, the two macroglia oligodendrocytes and astrocytes are the most abundant cell types. While the major function of oligodendrocytes is the formation of the lipid-rich myelin structure, the heterogeneous group of astrocytes fulfils a multitude of important roles in cerebral development and homeostasis. Brain lipid homeostasis involves the synthesis of a specific cerebral lipidome by local lipid metabolism. In this study we have investigated the fatty acid uptake and lipid biosynthesis in grey and white matter regions of the murine brain. Key findings were: (i) white matter oligodendrocytes and astrocytes take up saturated and unsaturated fatty acids, (ii) different grey matter regions show varying lipid labelling intensities, (iii) the medial habenula, an epithalamic grey matter structure, and the oligodendrocytes and astrocytes therein are targeted by fatty acids, and (iv) in the medial habenula, the neutral lipid containing lipid droplets are found in cells facing the ventricle but undetectable in the habenular parenchyma. Our data indicate a role for oligodendrocytes and astrocytes in local lipid metabolism of white and grey matter regions in the brain.
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http://dx.doi.org/10.1038/s41598-017-11103-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589817PMC
September 2017

Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance.

Cell Metab 2017 Jul;26(1):212-229.e12

Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain. Electronic address:

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.
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http://dx.doi.org/10.1016/j.cmet.2017.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501726PMC
July 2017

Hypothalamic Regulation of Liver and Muscle Nutrient Partitioning by Brain-Specific Carnitine Palmitoyltransferase 1C in Male Mice.

Endocrinology 2017 07;158(7):2226-2238

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Barcelona, Spain.

Carnitine palmitoyltransferase (CPT) 1C, a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions. Based on global knockout (KO) models, CPT1C has demonstrated relevance in hippocampus-dependent spatial learning and in hypothalamic regulation of energy balance. Specifically, it has been shown that CPT1C is protective against high-fat diet-induced obesity (DIO), and that CPT1C KO mice show reduced peripheral fatty acid oxidation (FAO) during both fasting and DIO. However, the mechanisms mediating CPT1C-dependent regulation of energy homeostasis remain unclear. Here, we focus on the mechanistic understanding of hypothalamic CPT1C on the regulation of fuel selection in liver and muscle of male mice during energy deprivation situations, such as fasting. In CPT1C-deficient mice, modulation of the main hypothalamic energy sensors (5' adenosine monophosphate-activated protein kinase, Sirtuin 1, and mammalian target of rapamycin) was impaired and plasma catecholamine levels were decreased. Consequently, CPT1C-deficient mice presented defective fasting-induced FAO in liver, leading to higher triacylglycerol accumulation and lower glycogen levels. Moreover, muscle pyruvate dehydrogenase activity was increased, which was indicative of glycolysis enhancement. The respiratory quotient did not decrease in CPT1C KO mice after 48 hours of fasting, confirming a defective switch on fuel substrate selection under hypoglycemia. Phenotype reversion studies identified the mediobasal hypothalamus (MBH) as the main area mediating CPT1C effects on fuel selection. Overall, our data demonstrate that CPT1C in the MBH is necessary for proper hypothalamic sensing of a negative energy balance and fuel partitioning in liver and muscle.
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http://dx.doi.org/10.1210/en.2017-00151DOI Listing
July 2017

Mediterranean tomato-based sofrito protects against vascular alterations in obese Zucker rats by preserving NO bioavailability.

Mol Nutr Food Res 2017 09 5;61(9). Epub 2017 Apr 5.

Nutrition, Food Science Department and Gastronomy, XaRTA, INSA-UB Pharmacy, University of Barcelona, Barcelona, Spain.

Scope: Sofrito, a key component of the Mediterranean diet, provides nutritional interest due to its high content in bioactive compounds from tomato and olive oil, and especially to the lipid matrix in which these compounds are found. In this study, the potential beneficial effects of dietary intake of sofrito on obesity-related vascular alterations were explored in obese Zucker rats.

Methods And Results: Obese and lean rats were fed a control diet supplemented or not with 2% w/w sofrito for 8 weeks. Vascular function was evaluated in aorta in organ baths. Dihydroethidium staining and immunofluorescence was used to determine aortic superoxide and peroxynitrite production, respectively. Despite food and caloric intake was higher in sofrito-fed obese rats, no differences were appreciated on body weight compared to control rats. Sofrito attenuated phenylephrine-induced vasoconstriction. This effect was associated with preservation of nitric oxide on vasoconstriction and normalization of serum nitric oxide metabolites, vascular inducible nitric oxide synthase and vascular superoxide and peroxynitrite levels.

Conclusion: This is the first evidence of tomato-based sofrito protection against vascular alterations that could precede major cardiometabolic complications in obesity. These results contribute to explain the therapeutic properties of the Mediterranean diet in obesity-related disorders. Therefore, sofrito is an attractive dietary approach against vascular alterations in obesity.
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http://dx.doi.org/10.1002/mnfr.201601010DOI Listing
September 2017

Ceramides and mitochondrial fatty acid oxidation in obesity.

FASEB J 2017 04 21;31(4):1263-1272. Epub 2016 Dec 21.

Department of Biochemistry and Physiology, School of Pharmacy, Institut de Biomedicina, Universitat de Barcelona, Barcelona, Spain;

Obesity is an epidemic, complex disease that is characterized by increased glucose, lipids, and low-grade inflammation in the circulation, among other factors. It creates the perfect scenario for the production of ceramide, the building block of the sphingolipid family of lipids, which is involved in metabolic disorders such as obesity, diabetes, and cardiovascular disease. In addition, obesity causes a decrease in fatty acid oxidation (FAO), which contributes to lipid accumulation within the cells, conferring more susceptibility to cell dysfunction. C16:0 ceramide, a specific ceramide species, has been identified recently as the principal mediator of obesity-derived insulin resistance, impaired fatty acid oxidation, and hepatic steatosis. In this review, we have sought to cover the importance of the ceramide species and their metabolism, the main ceramide signaling pathways in obesity, and the link between C16:0 ceramide, FAO, and obesity.-Fucho, R., Casals, N., Serra, D., Herrero, L. Ceramides and mitochondrial fatty acid oxidation in obesity.
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http://dx.doi.org/10.1096/fj.201601156RDOI Listing
April 2017

Reduction of Hypothalamic Endoplasmic Reticulum Stress Activates Browning of White Fat and Ameliorates Obesity.

Diabetes 2017 Jan 15;66(1):87-99. Epub 2016 Sep 15.

Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

The chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to endoplasmic reticulum (ER) stress. This study investigated the role of hypothalamic GRP78 on energy balance, with particular interest in thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and rats administered thapsigargin, and by combining metabolic, histologic, physiologic, pharmacologic, thermographic, and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78. Our data showed that rats fed a high-fat diet or that were centrally administered thapsigargin displayed hypothalamic ER stress, whereas genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were independent of feeding and leptin but were related to increased thermogenic activation of brown adipose tissue and induction of browning in WAT and could be reversed by antagonism of β3 adrenergic receptors. This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.
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http://dx.doi.org/10.2337/db15-1547DOI Listing
January 2017

Carnitine palmitoyltransferase 1C: From cognition to cancer.

Prog Lipid Res 2016 Jan 18;61:134-48. Epub 2015 Dec 18.

CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; Department of Biochemistry and Molecular Biology, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain.

Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression. Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with l-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism. CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose- and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.
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http://dx.doi.org/10.1016/j.plipres.2015.11.004DOI Listing
January 2016

Novel Regulation of the Synthesis of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Subunit GluA1 by Carnitine Palmitoyltransferase 1C (CPT1C) in the Hippocampus.

J Biol Chem 2015 Oct 3;290(42):25548-60. Epub 2015 Sep 3.

From the Basic Sciences Department, Facultat de Medicina i Ciències de la Salut, Universitat Internacional de Catalunya, Sant Cugat del Vallès 08195, Spain, the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), 15706 Santiago de Compostela, Spain

The regulation of AMPA-type receptor (AMPAR) abundance in the postsynaptic membrane is an important mechanism involved in learning and memory formation. Recent data suggest that one of the constituents of the AMPAR complex is carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform located in the endoplasmic reticulum of neurons. Previous results had demonstrated that CPT1C deficiency disrupted spine maturation in hippocampal neurons and impaired spatial learning, but the role of CPT1C in AMPAR physiology had remained mostly unknown. In the present study, we show that CPT1C binds GluA1 and GluA2 and that the three proteins have the same expression profile during neuronal maturation. Moreover, in hippocampal neurons of CPT1C KO mice, AMPAR-mediated miniature excitatory postsynaptic currents and synaptic levels of AMPAR subunits GluA1 and GluA2 are significantly reduced. We show that AMPAR expression is dependent on CPT1C levels because total protein levels of GluA1 and GluA2 are decreased in CPT1C KO neurons and are increased in CPT1C-overexpressing neurons, whereas other synaptic proteins remain unaltered. Notably, mRNA levels of AMPARs remained unchanged in those cultures, indicating that CPT1C is post-transcriptionally involved. We demonstrate that CPT1C is directly involved in the de novo synthesis of GluA1 and not in protein degradation. Moreover, in CPT1C KO cultured neurons, GluA1 synthesis after chemical long term depression was clearly diminished, and brain-derived neurotrophic factor treatment was unable to phosphorylate the mammalian target of rapamycin (mTOR) and stimulate GluA1 protein synthesis. These data newly identify CPT1C as a regulator of AMPAR translation efficiency and therefore also synaptic function in the hippocampus.
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http://dx.doi.org/10.1074/jbc.M115.681064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646200PMC
October 2015

Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

JAMA Neurol 2015 May;72(5):561-70

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

Importance: The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients.

Objective: To identify the genetic cause for a novel form of pure autosomal dominant HSP.

Design, Setting, And Participants: We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened.

Main Outcome And Measure: Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene.

Results: We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c-/- mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation.

Conclusions And Relevance: This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.
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http://dx.doi.org/10.1001/jamaneurol.2014.4769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612424PMC
May 2015

Enhanced fatty acid oxidation in adipocytes and macrophages reduces lipid-induced triglyceride accumulation and inflammation.

Am J Physiol Endocrinol Metab 2015 May 24;308(9):E756-69. Epub 2015 Feb 24.

Department of Biochemistry and Molecular Biology, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Madrid, Spain;

Lipid overload in obesity and type 2 diabetes is associated with adipocyte dysfunction, inflammation, macrophage infiltration, and decreased fatty acid oxidation (FAO). Here, we report that the expression of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme in mitochondrial FAO, is higher in human adipose tissue macrophages than in adipocytes and that it is differentially expressed in visceral vs. subcutaneous adipose tissue in both an obese and a type 2 diabetes cohort. These observations led us to further investigate the potential role of CPT1A in adipocytes and macrophages. We expressed CPT1AM, a permanently active mutant form of CPT1A, in 3T3-L1 CARΔ1 adipocytes and RAW 264.7 macrophages through adenoviral infection. Enhanced FAO in palmitate-incubated adipocytes and macrophages reduced triglyceride content and inflammation, improved insulin sensitivity in adipocytes, and reduced endoplasmic reticulum stress and ROS damage in macrophages. We conclude that increasing FAO in adipocytes and macrophages improves palmitate-induced derangements. This indicates that enhancing FAO in metabolically relevant cells such as adipocytes and macrophages may be a promising strategy for the treatment of chronic inflammatory pathologies such as obesity and type 2 diabetes.
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http://dx.doi.org/10.1152/ajpendo.00362.2014DOI Listing
May 2015

Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance.

Cell Rep 2014 Oct 2;9(1):366-377. Epub 2014 Oct 2.

Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. Electronic address:

Hypothalamic endoplasmic reticulum (ER) stress is a key mechanism leading to obesity. Here, we demonstrate that ceramides induce lipotoxicity and hypothalamic ER stress, leading to sympathetic inhibition, reduced brown adipose tissue (BAT) thermogenesis, and weight gain. Genetic overexpression of the chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) in the ventromedial nucleus of the hypothalamus (VMH) abolishes ceramide action by reducing hypothalamic ER stress and increasing BAT thermogenesis, which leads to weight loss and improved glucose homeostasis. The pathophysiological relevance of this mechanism is demonstrated in obese Zucker rats, which show increased hypothalamic ceramide levels and ER stress. Overexpression of GRP78 in the VMH of these animals reduced body weight by increasing BAT thermogenesis as well as decreasing leptin and insulin resistance and hepatic steatosis. Overall, these data identify a triangulated signaling network involving central ceramides, hypothalamic lipotoxicity/ER stress, and BAT thermogenesis as a pathophysiological mechanism of obesity.
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http://dx.doi.org/10.1016/j.celrep.2014.08.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157160PMC
October 2014

Uridine 5'-triphosphate promotes in vitro Schwannoma cell migration through matrix metalloproteinase-2 activation.

PLoS One 2014 6;9(6):e98998. Epub 2014 Jun 6.

Department of Basic Sciences, Facultat de Medicina, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.

In response to peripheral nerve injury, Schwann cells adopt a migratory phenotype and modify the extracellular matrix to make it permissive for cell migration and axonal re-growth. Uridine 5'-triphosphate (UTP) and other nucleotides are released during nerve injury and activate purinergic receptors expressed on the Schwann cell surface, but little is known about the involvement of purine signalling in wound healing. We studied the effect of UTP on Schwannoma cell migration and wound closure and the intracellular signaling pathways involved. We found that UTP treatment induced Schwannoma cell migration through activation of P2Y2 receptors and through the increase of extracellular matrix metalloproteinase-2 (MMP-2) activation and expression. Knockdown P2Y2 receptor or MMP-2 expression greatly reduced wound closure and MMP-2 activation induced by UTP. MMP-2 activation evoked by injury or UTP was also mediated by phosphorylation of all 3 major mitogen-activated protein kinases (MAPKs): JNK, ERK1/2, and p38. Inhibition of these MAPK pathways decreased both MMP-2 activation and cell migration. Interestingly, MAPK phosphorylation evoked by UTP exhibited a biphasic pattern, with an early transient phosphorylation 5 min after treatment, and a late and sustained phosphorylation that appeared at 6 h and lasted up to 24 h. Inhibition of MMP-2 activity selectively blocked the late, but not the transient, phase of MAPK activation. These results suggest that MMP-2 activation and late MAPK phosphorylation are part of a positive feedback mechanism to maintain the migratory phenotype for wound healing. In conclusion, our findings show that treatment with UTP stimulates in vitro Schwannoma cell migration and wound repair through a MMP-2-dependent mechanism via P2Y2 receptors and MAPK pathway activation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098998PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048211PMC
January 2015

Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin.

Diabetes 2014 Oct 21;63(10):3242-52. Epub 2014 May 21.

Department of Metabolism and Aging, Scripps Research Institute, Jupiter, FL Department of Pharmacological & Physiological Science, Saint Louis University School of Medicine, St. Louis, MO

Rigorous control of substrate oxidation by humoral factors is essential for maintaining metabolic homeostasis. During feeding and fasting cycles, carbohydrates and fatty acids are the two primary substrates in oxidative metabolism. Here, we report a novel role for the peptide hormone adropin in regulating substrate oxidation preferences. Plasma levels of adropin increase with feeding and decrease upon fasting. A comparison of whole-body substrate preference and skeletal muscle substrate oxidation in adropin knockout and transgenic mice suggests adropin promotes carbohydrate oxidation over fat oxidation. In muscle, adropin activates pyruvate dehydrogenase (PDH), which is rate limiting for glucose oxidation and suppresses carnitine palmitoyltransferase-1B (CPT-1B), a key enzyme in fatty acid oxidation. Adropin downregulates PDH kinase-4 (PDK4) that inhibits PDH, thereby increasing PDH activity. The molecular mechanisms of adropin's effects involve acetylation (suggesting inhibition) of the transcriptional coactivator PGC-1α, downregulating expression of Cpt1b and Pdk4. Increased PGC-1α acetylation by adropin may be mediated by inhibiting Sirtuin-1 (SIRT1), a PGC-1α deacetylase. Altered SIRT1 and PGC-1α activity appear to mediate aspects of adropin's metabolic actions in muscle. Similar outcomes were observed in fasted mice treated with synthetic adropin. Together, these results suggest a role for adropin in regulating muscle substrate preference under various nutritional states.
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http://dx.doi.org/10.2337/db14-0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171656PMC
October 2014