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

• DOI: 10.1016/j.celrep.2014.08.057
• Publication Date: 2014-10-04T01:46:33Z
• Authors: Cristina Contreras; Ismael González-G...; Noelia Martínez-S...; Patricia Seoane-C...; Jordi Jacas; Donald A. Morgan; Dolors Serra; Rosalía Gallego; Francisco Gonzalez; Núria Casals; Rubén Nogueiras; Kamal Rahmouni; Carlos Diéguez; Miguel López
• Keywords: Male; Weight loss; 61; QH301-705.5; Fisiologia patològica; Rats as laboratory animals; Obesidad; Hypothalamus; Resistencia a la Insulina; Ceramides; Article; Rats, Sprague-Dawley; Aprimament; 03 medical and health sciences; Adipose Tissue, Brown; Weight Loss; Animals; Tejido Adiposo Pardo; Obesity; Biology (General); Pathological physiology; Rates (Animals de laboratori); Termogénesis; 2. Zero hunger; 0303 health sciences; Hipotàlem; Insulin resistance; Thermogenesis; Endoplasmic Reticulum Stress; Lipids; Metabolisme; Rats; Rats, Zucker; 3. Good health; Ceramidas; Metabolism; Lípids; Lípidos; Obesitat; Resistència a la insulina; Insulin Resistance; Hipotálamo

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.