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.

Adenosine monophosphate‐activated protein kinase (AMPK) is a cellular energy sensor activated during energy stress that plays a key role in maintaining energy homeostasis. This ubiquitous signaling pathway has been implicated in multiple functions including mitochondrial biogenesis, redox regulation, cell growth and proliferation, cell autophagy and inflammation. The protective role of AMPK in cardiovascular function and the involvement of dysfunctional AMPK in the pathogenesis of cardiovascular disease have been highlighted in recent years. In this review, we summarize and discuss the role of AMPK in the regulation of blood flow in response to metabolic demand and the basis of the AMPK physiological anticontractile, antioxidant, anti‐inflammatory, and antiatherogenic actions in the vascular system. Investigations by others and us have demonstrated the key role of vascular AMPK in the regulation of endothelial function, redox homeostasis, and inflammation, in addition to its protective role in the hypoxia and ischemia/reperfusion injury. The pathophysiological implications of AMPK involvement in vascular function with regard to the vascular complications of metabolic disease and the therapeutic potential of AMPK activators are also discussed.

Obesity is a metabolic disorder of increasing prevalence worldwide and a risk factor for the development of insulin resistance (IR), metabolic syndrome and type 2 diabetes. Obesity is related to endothelial dysfunction through indirect mechanisms such as IR and the associated risk factors, and through direct mechanisms including the production of proinflammatory adipokines and elevated levels of free fatty acids (FFAs) by adipose tissue. Both clinical and experimental studies using genetic and diet-induced animal models of obesity have consistently shown impaired metabolic, agonistor flow-induced vasodilatations correlated with the amount of visceral adipose tissue and improved by dietary interventions and exercise. Compromised bioavailability of NO due to oxidative stress emerges as a main cause of endothelial dysfunction in obesity. Inflamed adipose tissue due to hypoxia, and in particular perivascular adipose tissue (PVAT), secrete larger amounts of reactive oxygen species (ROS) and adipokines that deteriorate NO signaling pathways. Abnormal production and activity of the vasoconstrictor/proatherogenic peptide endothelin-1 (ET-1) is also a hallmark of the obesity- associated endothelial dysfunction. Obesity, and in particular visceral obesity, is one of the main causes of IR, and the pathogenic factors that induce endothelial dysfunction in the earlier stages of obesity will further deteriorate the insulin signaling pathways in endothelial cells thus leading to blunted vasodilatation and abnormal capillary recruitment and substrate delivery by insulin to the target tissues. The present review is an attempt to summarize the current knowledge and the latest novel findings on the pathogenic mechanisms underlying endothelial dysfunction in obesity, in particular the local contribution of oxidative stress and inflammatory response from PVAT, and its role in the obesity-associated cardiovascular and metabolic complications.

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 canonical view about the effect of thyroid hormones (THs) on thermogenesis assumes that the hypothalamus acts merely as a modulator of the sympathetic outflow on brown adipose tissue (BAT). Recent data have challenged that vision by demonstrating that THs act on the ventromedial nucleus of the hypothalamus (VMH) to inhibit AMP-activated protein kinase (AMPK), which regulates the thermogenic program in BAT, leading to increased thermogenesis and weight loss. Current data have shown that in addition to activation of brown fat, the browning of white adipose tissue (WAT) might also be an important thermogenic mechanism. However, the possible central effects of THs on the browning of white fat remain unclear. Here, we show that 3,3′,5,5′ tetraiodothyroxyne (T₄)-induced hyperthyroidism promotes a marked browning of WAT. Of note, central or VMH-specific administration of 3,3′,5-triiodothyronine (T₃) recapitulates that effect. The specific genetic activation of hypothalamic AMPK in the VMH reversed the central effect of T₃on browning. Finally, we also showed that the expression of browning genes in human WAT correlates with serum T₄. Overall, these data indicate that THs induce browning of WAT and that this mechanism is mediated via the central effects of THs on energy balance.