Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.
Neuron. 2011 Nov 17;72(4):616-29. doi: 10.1016/j.neuron.2011.08.027.
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.
下丘脑食欲素/下丘脑分泌素（orx/hcrt）神经元调节能量平衡、觉醒和奖赏；其缺失会导致嗜睡症和体重增加。葡萄糖可以降低 orx/hcrt 细胞的活性，但其他膳食宏量营养素是否有类似的影响尚不清楚。我们发现，在脑片膜片钳实验中，以及在中枢或外周给予氨基酸后，用 c-Fos 表达分析检测体内的小鼠，orx/hcrt 细胞受到营养相关的氨基酸混合物的刺激。氨基酸的生理混合物通过涉及抑制 K(ATP) 通道和激活系统 A 氨基酸转运体的双重机制来兴奋 orx/hcrt 细胞。非必需氨基酸比必需氨基酸更能激活 orx/hcrt 细胞。此外，生理浓度的氨基酸存在可抑制 orx/hcrt 细胞对葡萄糖的反应。这些结果表明了一种新的下丘脑整合宏量营养素信号的机制，并暗示 orx/hcrt 细胞在细胞外液中感知宏量营养素平衡，而不是净能量值。
