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.

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.

AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disorders.

The chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to endoplasmic reticulum (ER) stress. This study investigated the role of hypothalamic GRP78 on energy balance, with particular interest in thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and rats administered thapsigargin, and by combining metabolic, histologic, physiologic, pharmacologic, thermographic, and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78. Our data showed that rats fed a high-fat diet or that were centrally administered thapsigargin displayed hypothalamic ER stress, whereas genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were independent of feeding and leptin but were related to increased thermogenic activation of brown adipose tissue and induction of browning in WAT and could be reversed by antagonism of β3 adrenergic receptors. This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.

Nicotine, the main addictive component of tobacco, promotes body weight reduction in humans and rodents. Recent evidence has suggested that nicotine acts in the central nervous system to modulate energy balance. Specifically, nicotine modulates hypothalamic AMP-activated protein kinase to decrease feeding and to increase brown adipose tissue thermogenesis through the sympathetic nervous system, leading to weight loss. Of note, most of this evidence has been obtained in animal models fed with normal diet or low-fat diet (LFD). However, its effectiveness in obese models remains elusive. Because obesity causes resistance towards many factors involved in energy homeostasis, the aim of this study has been to compare the effect of nicotine in a diet-induced obese (DIO) model, namely rats fed a high-fat diet, with rats fed a LFD. Our data show that chronic peripheral nicotine treatment reduced body weight by decreasing food intake and increasing brown adipose tissue thermogenesis in both LFD and DIO rats. This overall negative energy balance was associated to decreased activation of hypothalamic AMP-activated protein kinase in both models. Furthermore, nicotine improved serum lipid profile, decreased insulin serum levels, as well as reduced steatosis, inflammation, and endoplasmic reticulum stress in the liver of DIO rats but not in LFD rats. Overall, this evidence suggests that nicotine diminishes body weight and improves metabolic disorders linked to DIO and might offer a clear-cut strategy to develop new therapeutic approaches against obesity and its metabolic complications.