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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.

Original publication

DOI

10.1016/j.neuron.2011.08.027

Type

Journal article

Journal

Neuron

Publication Date

17/11/2011

Volume

72

Pages

616 - 629

Keywords

Amino Acid Transport Systems, Amino Acids, Animals, Dietary Proteins, Hypothalamus, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Neuropeptides, Orexins, Patch-Clamp Techniques