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 knockout 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.

Physiological Role of Orexinergic System for Health

“…To support the role of orexins in obesity resistance, several animal studies have demonstrated that OrxA injections into several cerebral areas, such as the rostral LH, paraventricular nucleus, TMN, LC, DRN, nucleus accumbens, and substantia nigra, improve SPA and NEAT [ 132 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 ], while repeated injections of OrxA into LH are associated with reduced fat mass [ 153 ]. Orexins also exert a sympathoexcitatory effect, as demonstrated by increased blood pressure and heart rate, increased sympathetic outflow to brown adipose tissue (BAT), and increased plasma epinephrine and noradrenaline release [ 141 , 154 , 155 , 156 ]. The sympathetic outflow to BAT may be a cause of the increase in NEAT due to orexin [ 157 ].…”

Orexin, serotonin, and energy balance

“…In addition, orexin is largely sympathoexcitatory (Teske & Mavanji, 2012 ). Studies in rodents demonstrate that orexin enhanced sympathetic outflow as indicated by elevated blood pressure and heart rate (Teske & Mavanji, 2012 ), increased renal sympathetic nerve activity including to the brown adipose tissue (BAT) (Straat et al, 2020 ), and elevated plasma epinephrine, noradrenaline release, and firing rate of sympathetic nerves (Teske & Mavanji, 2012 ). This indicates that orexin‐induced NEAT has “extra” caloric expenditure which may be via sympathetic output to BAT (Morrison et al, 2014 ).…”

Current Understanding of Narcolepsy 1 and its Comorbidities: What Clinicians Need to Know

“…Patients with narcolepsy often gain weight, and the body mass index (BMI) of adults in this group is approximately 15% higher than the average BMI [ 4 ]. This has been attributed to orexin-mediated food-seeking behavior [ 70 ], a lower metabolic rate in orexin-deficient individuals [ 71 ], and the effect of the orexin system on brown adipose tissue functionality, which could be partly responsible for the impaired energy homeostasis, potentially resulting in increased adiposity and weight gain in patients with NT1 [ 71 ]. Compared with individuals without narcolepsy, patients with narcolepsy have a higher prevalence of diabetes (by 9.3%) and obesity (by 8.8%) [ 22 ].…”