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

Abstract

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.

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Fat deposits in such ectopic tissues are unhealthy and can initiate tissue inflammation, endoplasmic reticulum (ER) stress, and endothelial dysfunction, accelerating the development of obesityassociated pathologies, such as insulin resistance and type 2 diabetes (T2D) (Hotamisligil et al, 1993(Hotamisligil et al, , 1996Ozcan et al, 2004). In line with this proposed model of lipotoxicity, ectopic accumulation of reactive lipid species such as diacylglycerol, free fatty acids, free cholesterol, and ceramides have all been demonstrated to impair systems metabolism through local tissue inflammation and induction of ER stress (Unger, 2002;Virtue and Vidal-Puig, 2008;Symons and Abel, 2013;Contreras et al, 2014).…”

Obesity-induced hepatic steatosis is mediated by endoplasmic reticulum stress in the subfornical organ of the brain

“…To more specifically interrogate the SFO, we utilized an approach to genetically reduce ER stress selectively in the SFO. An effective means to prevent and rescue ER stress is via overexpression of the ER chaperone GRP78, which prevents downstream UPR activation (24,35,36). In this context, we recently developed an adenoviral vector that allows for overexpression of the full-length murine sequence of GRP78 (AdGRP78) (24).…”

Lipoprotein lipase in hypothalamus is a key regulator of body weight gain and glucose homeostasis in mice

“…While knockdown of LPL altered MBH ceramide content, overexpression had no consequences on intracellular ceramide content, suggesting that alternative intracellular signals are mobilised in conditions of abundant NEFA entry. Indeed, LPL can provide NEFA to brain cells, which are transformed to reach different fates, such as β-oxidation, ceramide or endocannabinoid synthesis, therefore exerting metabolic effects through the modulation of autonomic nervous system, as has been already been shown for ceramides [36] and endocannabinoids [37]. A non-exclusive hypothesis would be the presence, in the MBH, of neuronal populations with different ranges of sensitivity for NEFA.…”