Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance
Summary: 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 overexpress...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714007335 |
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| author | Cristina Contreras Ismael González-García Noelia Martínez-Sánchez Patricia Seoane-Collazo Jordi Jacas Donald A. Morgan Dolors Serra Rosalía Gallego Francisco Gonzalez Núria Casals Rubén Nogueiras Kamal Rahmouni Carlos Diéguez Miguel López |
| author_facet | Cristina Contreras Ismael González-García Noelia Martínez-Sánchez Patricia Seoane-Collazo Jordi Jacas Donald A. Morgan Dolors Serra Rosalía Gallego Francisco Gonzalez Núria Casals Rubén Nogueiras Kamal Rahmouni Carlos Diéguez Miguel López |
| author_sort | Cristina Contreras |
| collection | DOAJ |
| description | Summary: 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. : The brain senses lipids, such as fatty acids, and modifies energy metabolism accordingly. However, it is unclear whether other lipid species may be involved. Contreras et al. now demonstrate that ceramides regulate energy balance through the induction of hypothalamic lipotoxicity and modulation of endoplasmic reticulum functionality. This leads to changes in sympathetic tone and brown adipose tissue (BAT)-induced thermogenesis, impacting body weight. |
| first_indexed | 2024-12-23T20:03:47Z |
| format | Article |
| id | doaj.art-f06bb0b9e1cb40c5b47c9f6730ef7d7c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-23T20:03:47Z |
| publishDate | 2014-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-f06bb0b9e1cb40c5b47c9f6730ef7d7c2022-12-21T17:33:00ZengElsevierCell Reports2211-12472014-10-0191366377Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy BalanceCristina Contreras0Ismael González-García1Noelia Martínez-Sánchez2Patricia Seoane-Collazo3Jordi Jacas4Donald A. Morgan5Dolors Serra6Rosalía Gallego7Francisco Gonzalez8Núria Casals9Rubén Nogueiras10Kamal Rahmouni11Carlos Diéguez12Miguel López13Department 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, SpainDepartment 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, SpainDepartment 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, SpainDepartment 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, SpainCIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain; Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallés, 08195 Barcelona, SpainDepartment of Pharmacology, University of Iowa, Iowa City, IA 52242, USACIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain; Department of Biochemistry and Molecular Biology, School of Pharmacy, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, SpainDepartment of Morphological Sciences, School of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainDepartment of Surgery, CIMUS, University of Santiago de Compostela-Instituto de Invesstiagacion Sanitaria, 15782 Santiago de Compostela, Spain; Service of Ophthalmology, Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, SpainCIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain; Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallés, 08195 Barcelona, SpainDepartment 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, SpainDepartment of Pharmacology, University of Iowa, Iowa City, IA 52242, USA; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USADepartment 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, SpainDepartment 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; Corresponding authorSummary: 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. : The brain senses lipids, such as fatty acids, and modifies energy metabolism accordingly. However, it is unclear whether other lipid species may be involved. Contreras et al. now demonstrate that ceramides regulate energy balance through the induction of hypothalamic lipotoxicity and modulation of endoplasmic reticulum functionality. This leads to changes in sympathetic tone and brown adipose tissue (BAT)-induced thermogenesis, impacting body weight.http://www.sciencedirect.com/science/article/pii/S2211124714007335 |
| spellingShingle | Cristina Contreras Ismael González-García Noelia Martínez-Sánchez Patricia Seoane-Collazo Jordi Jacas Donald A. Morgan Dolors Serra Rosalía Gallego Francisco Gonzalez Núria Casals Rubén Nogueiras Kamal Rahmouni Carlos Diéguez Miguel López Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance Cell Reports |
| title | Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance |
| title_full | Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance |
| title_fullStr | Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance |
| title_full_unstemmed | Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance |
| title_short | Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance |
| title_sort | central ceramide induced hypothalamic lipotoxicity and er stress regulate energy balance |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714007335 |
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