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

Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal model s. In humans, narcolepsy is rarely due to hypocretin mutations, but this sy stem is deficient in the cerebrospinal fluid (CSF) and brain of a small num ber of patients. A recent study also indicates increased body mass index (B MI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQ B1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was m easurable (169 to 376pg/ml) in all controls. Levels were unaffected by free zing/thawing or prolonged storage and did not display any concentration gra dient. Hypocretin-1 was dramatically decreased (< 100pg/ml) in 32 of 38 pat ients (all HILA-positive). Four patients had normal levels (2 HLA-negative) . Two HLA-positive patients had high levels (609 and 637pg/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 nar colepsy, providing possible diagnostic applications. Increased BMI and lept in indicate altered energy homeostasis. Sleep and energy metabolism are lik ely to be functionally connected through the hypocretin system.