Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1

Abstract

Narcolepsy type 1 is a neurological sleep-wake disorder caused by the destruction of orexin (hypocretin)-producing neurons. These neurons are particularly located in the lateral hypothalamus and have widespread projections throughout the brain, where they are involved, e.g., in the regulation of the sleep-wake cycle and appetite. Interestingly, a higher prevalence of obesity has been reported in patients with narcolepsy type 1 compared to healthy controls, despite a normal to decreased food intake and comparable physical activity. This suggests the involvement of tissues implicated in total energy expenditure, including skeletal muscle, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Recent evidence from pre-clinical studies with orexin knock-out mice demonstrates a crucial role for the orexin system in the functionality of brown adipose tissue (BAT), probably through multiple pathways. Since BAT is a highly metabolically active organ that combusts fatty acids and glucose toward heat, thereby contributing to energy metabolism, this raises the question of whether BAT plays a role in the development of obesity and related metabolic diseases in narcolepsy type 1. BAT is densely innervated by the sympathetic nervous system that activates BAT, for instance, following cold exposure. The sympathetic outflow toward BAT is mainly mediated by the dorsomedial, ventromedial, arcuate, and paraventricular nuclei in the hypothalamus. This review focuses on the current knowledge on the role of the orexin system in the control of energy balance, with specific focus on BAT metabolism and adiposity in both preclinical and clinical studies.

Keywords: brown adipose tissue; energy metabolism; hypothalamus; narcolepsy type 1; obesity; orexin; sympathetic nervous system.

Figure 1

Hypothalamic pathways involved in sympathetic activation of BAT by cold and orexin. Cold exposure activates BAT by stimulation of the preoptic area of the hypothalamus (POA). This leads to suppression of the inhibiting GABAergic tone toward the dorsomedial nucleus of the hypothalamus (DMH), resulting in stimulation of rostral raphe pallidus (rRPa) neurons that are located in the medulla oblongata. From the rRPa, the activity of sympathetic neurons that run toward brown adipocytes is subsequently activated to release noradrenalin (NE), which binds to adrenergic receptors on brown adipocytes to induce thermogenesis. Several other brain pathways converge onto BAT. For instance, the ventromedial nucleus of the hypothalamus (VMH) possesses several receptors for peripheral signals such as GLP-1, leptin, thyroid hormone, estradiol, and bone morphogenetic protein 8B (BMP8B), which lead to activation of BAT via inhibition of AMP-activated protein kinase (AMPK) and stimulation of the rRPa. In addition, the arcuate nucleus of the hypothalamus (ARC) is involved in the thermoregulatory responses by BAT via the anorexigenic POMC neurons and orexigenic agouti-related peptide (AgRP) and neuropeptide-Y (NPY) neurons. Activation of pro-opiomelanocortin (POMC) neurons leads to stimulation of melanocortin receptors (MCRs) in the paraventricular nucleus of the hypothalamus (PVN), which in turn inhibits the GABAergic tone toward the rRPa. On the contrary, stimulation of AgRP neurons in the ARC results in inhibition of the MCR. NPY neurons in the ARC stimulate the neuropeptide-Y receptor (NPYR) on the PVN, thereby suppressing BAT thermogenesis through the GABAergic tone from the PVN toward the rRPa. Within the ARC, leptin stimulates POMC neurons and inhibits AgRP neurons, thereby stimulating BAT thermogenesis. Orexin is connected to BAT via several pathways. First, orexin-producing neurons, predominantly present in the lateral hypothalamic area (LHA), are able to inhibit the GABAergic tone of neurons in the LHA toward neurons in the DMH, thereby stimulating rRPa neurons. Furthermore, there is a link between the VMH and LHA via AMPK inhibition. Inhibition of AMPK in the VMH leads to stimulation of orexin-producing neurons and, subsequently, stimulation of rRPa neurons, resulting in sympathetic activation of BAT. Orexin-producing neurons also project to the ARC, where they inhibit POMC neurons and stimulate NPY neurons. Several food-related cues are able to influence orexin signaling. Glucose levels are negatively correlated with orexin signaling. Leptin is able to attenuate orexin-neuron activity, while ghrelin enhances orexin-neuron activity. BMP8B-R, bone morphogenetic protein 8B receptor; ER, estradiol receptor; GABA-R, GABA receptor; GHS-R, growth hormone secretagogue receptor (e.g., ghrelin receptor); GLP-1R, glucagon-like-peptide-1 receptor; GLUT, glucose transporter; LEP-R, leptin receptor; TR, thyroid receptor.