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Title: Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance
Author: Contreras, Cristina
González García, Isabel
Martínez-Sánchez, Noelia
Seoane-Collazo, Patricia
Jacas, Jordi
Morgan, Donald A.
Serra i Cucurull, Dolors
Gallego, Rosalía
Gonzalez, Francisco
Casals, Núria
Nogueiras, Rubén
Rahmouni, Kamal
Diéguez, Carlos
López, Miguel
Keywords: Metabolisme
Resistència a la insulina
Fisiologia patològica
Rates (Animals de laboratori)
Insulin resistance
Pathological physiology
Weight loss
Rats as laboratory animals
Issue Date: 2-Oct-2014
Publisher: Elsevier
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 (glucoseregulated 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.
Note: Reproducció del document publicat a:
It is part of: Cell Reports, 2014, vol. 9, num. 1, p. 366-377
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ISSN: 2211-1247
Appears in Collections:Articles publicats en revistes (Bioquímica i Fisiologia)

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