Activation of Central Orexin/Hypocretin Neurons by Dietary Amino Acids

Mahesh M. Kharnani et al., Activation of Central Orexin/Hypocretin Neurons by Dietary Amino Acids, Neuron, Volume 72, Issue 4, 616-629, 17 November 2011

Highlights

• Brain orexin/hypocretin cells are stimulated by dietary amino acids (AAs)
• AA sensing involves K-ATP channels and system-A transporters
• Nonessential AAs stimulate orexin/hypocretin cells more than essential AAs
• AA presence prevents glucose from blocking orexin/hypocretin cells

Summary
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 KATP 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.