Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy

Abstract

Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.

Hypocretin‐1 (orexin‐A) concentrations in cerebrospinal fluid are low in patients with Guillain–Barré syndrome

“…Cerebrospinal fluid levels of hypocretin-1 were measured using RIA kits (Phoenix Pharmaceuticals, Mountain View, CA, USA) as reported elsewhere. 1 As the method for measuring hypocretin-2 is not yet established, it was not studied. Statistical analysis was made using one-way ANOVA and Fisher's least significant difference test (PLSD), and Fisher's exact probability test.…”

“…1 These peptides have aroused interest in light of two recent reports linking dysfunction of the hypocretin peptide-receptor system to animal models of narcolepsy. In 2000, Nishino et al reported that hypocretin-1 in the cerebrospinal fluid (CSF) was significantly lower in patients with narcolepsy compared with healthy controls.…”

“…In 2000, Nishino et al reported that hypocretin-1 in the cerebrospinal fluid (CSF) was significantly lower in patients with narcolepsy compared with healthy controls. 1 Human narcolepsy has been shown to be closely associated with a specific human histocompatibility leukocyte antigen (HLA). 2 Because most diseases associated with a specific HLA are autoimmune in nature, the finding suggests that autoimmunity is involved in the pathophysiology of narcolepsy.…”

Pituitary Macrotumor Causing Narcolepsy‐Cataplexy in a Dachshund

“…Hypocretin peptides were originally described as modulators of food intake, with central administration of hypocretin enhancing food intake in rodents 25. Despite this observation, body mass indices have been found to be increased rather than decreased in narcoleptic humans, with the most marked increases in body mass indices seen in those with undetectable CSF hypocretin levels 25, 26. Also, hypocretin deficiency might not be as important as deficiencies of other neuropeptides that are colocalized in neurons that produce hypocretin.…”

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

“…Orexin deficiency has been shown to be involved in the pathogenesis of narcolepsy in human and animal models, such as mice with knockout mutations in the gene for prepro-orexin (prepro-orexin knockout mice, referred to throughout the remainder of this article as orexin knockout mice) and orexin neuron-deficient mice [10,11]. In humans, narcolepsy is accompanied by energy imbalance, such as decreased energy intake and increased BMI, resulting in an increase in the incidence of type 2 diabetes [12][13][14][15]. Mice deficient in orexin neurons also exhibit late-onset obesity, despite eating less [16], and on a high-fat diet, become heavier than wildtype mice [17].…”