title: Activation of central orexin/hypocretin neurons by dietary amino acids.
abstract: Hypothalamic orexin/hypocretin (orx/hcrt) neurons regulate energy balance, wakefulness, and reward; their loss produces narcolepsy and weight gain. Glucose can lower the activity of orx/hcrt cells, but whether other dietary macronutrients have similar effects is unclear. We show that orx/hcrt cells are stimulated by nutritionally relevant mixtures of amino acids (AAs), both in brain slice patch-clamp experiments, and in c-Fos expression assays following central or peripheral administration of AAs to mice in vivo. Physiological mixtures of AAs electrically excited orx/hcrt cells through a dual mechanism involving inhibition of K(ATP) channels and activation of system-A amino acid transporters. Nonessential AAs were more potent in activating orx/hcrt cells than essential AAs. Moreover, the presence of physiological concentrations of AAs suppressed the glucose responses of orx/hcrt cells. These results suggest a new mechanism of hypothalamic integration of macronutrient signals and imply that orx/hcrt cells sense macronutrient balance, rather than net energy value, in extracellular fluid.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
authors.forename: Mahesh M
authors.initials: MM
authors.lastname: Karnani
authors.forename: John
authors.initials: J
authors.lastname: Apergis-Schoute
authors.forename: Antoine
authors.initials: A
authors.lastname: Adamantidis
authors.forename: Lise T
authors.initials: LT
authors.lastname: Jensen
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.forename: Denis
authors.initials: D
authors.lastname: Burdakov
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism / Q000502:physiology; D000818:Animals; D004044:Dietary Proteins / Q000378:metabolism / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000096:biosynthesis*; D000068797:Orexins; D018408:Patch-Clamp Techniques
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; D004044:Dietary Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins