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2014-10-02

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cc-by (c) Contreras, Cristina et al., 2014
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/165037

Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance

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https://doi.org/10.1016/j.celrep.2014.08.057

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.

Subject

Metabolisme, Resistència a la insulina, Fisiologia patològica, Obesitat, Aprimament, Rates (Animals de laboratori)

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Metabolism, Insulin resistance, Pathological physiology, Obesity, Weight loss, Rats as laboratory animals

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Articles publicats en revistes (Bioquímica i Fisiologia)

Citation

CONTRERAS, Cristina, et al. Central Ceramide-Induced Hypothalamic Lipotoxicity and ER Stress Regulate Energy Balance. Cell Reports. 2014. Vol. 9, num. 1, pags. 366-377. ISSN 2211-1247. [consulted: 10 of August of 2026]. Available at: https://hdl.handle.net/2445/165037

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