Arcuate Na+,K+-ATPase senses systemic energy states and regulates feeding behavior through glucose-inhibited neurons

作者：Kurita Hideharu; Xu Kai Y; Maejima Yuko; Nakata Masanori; Dezaki Katsuya; Santoso Putra; Yang Yifei; Arai Takeshi; Gantulga Darambazar; Muroya Shinji; Lefor Alan K; Kakei Masafumi; Watanabe Eiju; Yada Toshihiko^*

来源：American Journal of Physiology - Endocrinology And Metabolism, 2015, 309(4): E320-E333.

DOI：10.1152/ajpendo.00446.2014

• arcuate nucleus
• Na+,K+-ATPase
• alpha 3-isoform
• neuropeptide Y
• agouti-related protein
• feeding behavior
• SSA412
• ouabain
• fasting
• ghrelin
• glucose
• ATP
• glucose-inhibited neuron

Feeding is regulated by perception in the hypothalamus, particularly the first-order arcuate nucleus (ARC) neurons, of the body's energy state. However, the cellular device for converting energy states to the activity of critical neurons in ARC is less defined. We here show that Na+, K+-ATPase (NKA) in ARC senses energy states to regulate feeding. Fasting-induced systemic ghrelin rise and glucose lowering reduced ATP-hydrolyzing activity of NKA and its substrate ATP level, respectively, preferentially in ARC. Lowering glucose concentration (LG), which mimics fasting, decreased intracellular NAD(P)H and increased Na+ concentration in single ARC neurons that subsequently exhibited [Ca2+](i) responses to LG, showing that they were glucose-inhibited (GI) neurons. Third ventricular injection of the NKA inhibitor ouabain induced c-Fos expression in agouti-related protein (AgRP) neurons in ARC and evoked neuropeptide Y (NPY)-dependent feeding. When injected focally into ARC, ouabain stimulated feeding and mRNA expressions for NPY and AgRP. Ouabain increased [Ca2+](i) in single NPY/AgRP neurons with greater amplitude than in proopiomelanocortin neurons in ARC. Conversely, the specific NKA activator SSA412 suppressed fasting-induced feeding and LG-induced [Ca2+](i) increases in ARC GI neurons. NPY/AgRP neurons highly expressed NKA alpha 3, whose knockdown impaired feeding behavior. These results demonstrate that fasting, via ghrelin rise and LG, suppresses NKA enzyme/pump activity in ARC and thereby promotes the activation of GI neurons and NPY/AgRP-dependent feeding. This study identifies ARC NKA as a hypothalamic sensor and converter of metabolic states to key neuronal activity and feeding behaviour, providing a new target to treat hyperphagic obesity and diabetes.

• 出版日期2015-8-15