Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance
Author
Contreras, Cristina
González-García, Ismael
Martínez-Sánchez, Noelia
Seoane-Collazo, Patricia
Jacas i Mateu, Jordi
Morgan, Donald A.
Serra, Dolors
Gallego, Rosalía
Gonzalez, Francisco
Casals i Farré, Núria
Nogueiras, Rubén
Rahmouni, Kamal
Diéguez, Carlos
López, Miguel
Publication date
2014-10ISSN
2211-1247
Abstract
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.
Document Type
Article
Document version
Accepted version
Language
English
Subject (CDU)
61 - Medical sciences
Keywords
Hipotàlem
Obesitat
Lípids
Hipotálamo
Obesidad
Lípidos
Hypothalamus
Obesity
Lipids
Pages
13
Publisher
Elsevier
Collection
9;1
Is part of
Cell Reports
Citation
Contreras, Cristina; González-García, Ismael; Martínez-Sánchez, Noelia [et al.]. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Press, 2014, vol. 9, núm. 1, p. 366-377. Disponible en: <https://www.sciencedirect.com/science/article/pii/S2211124714007335?via%3Dihub>. Fecha de acceso: 22 dic. 2019. DOI: 10.1016/j.celrep.2014.08.057
Grant agreement number
info:eu-repo/grantAgreement/EC/FP7/281854
info:eu-repo/grantAgreement/EC/FP7/245009
info:eu-repo/grantAgreement/ES/3PN/BFU-2010-14968
info:eu-repo/grantAgreement/ES/3PN/SAF2011-30520-C02-01
info:eu-repo/grantAgreement/ES/1PE/BFU2012-35255
info:eu-repo/grantAgreement/ES/3PN/SAF2011-30520-C02-02
info:eu-repo/grantAgreement/ES/3PN/BFU2011-29102
This item appears in the following Collection(s)
- Ciències de la Salut [725]
Rights
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-nd/3.0/