Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors.
Neurons in the supraoptic nuclei (SON) produce oxytocin and vasopressin and express insulin receptors (InsR) and glucokinase. Since oxytocin is an anorexigenic agent and glucokinase and InsR are hallmarks of cells that function as glucose and/or metabolic sensors, we evaluated the effect of glucose, insulin, and their downstream effector ATP-sensitive potassium (KATP) channels on calcium signaling in SON neurons and on oxytocin and vasopressin release from explants of the rat hypothalamo-neurohypophyseal system. We also evaluated the effect of blocking glucokinase and phosphatidylinositol 3 kinase (PI3K; mediates insulin-induced mobilization of glucose transporter, GLUT4) on responses to glucose and insulin. Glucose and insulin increased intracellular calcium ([Ca(2+)]i). The responses were glucokinase and PI3K dependent, respectively. Insulin and glucose alone increased vasopressin release (P < 0.002). Oxytocin release was increased by glucose in the presence of insulin. The oxytocin (OT) and vasopressin (VP) responses to insulin+glucose were blocked by the glucokinase inhibitor alloxan (4 mM; P ≤ 0.002) and the PI3K inhibitor wortmannin (50 nM; OT: P = 0.03; VP: P ≤ 0.002). Inactivating K ATP channels with 200 nM glibenclamide increased oxytocin and vasopressin release (OT: P < 0.003; VP: P < 0.05). These results suggest that insulin activation of PI3K increases glucokinase-mediated ATP production inducing closure of K ATP channels, opening of voltage-sensitive calcium channels, and stimulation of oxytocin and vasopressin release. The findings are consistent with SON oxytocin and vasopressin neurons functioning as glucose and "metabolic" sensors to participate in appetite regulation.
Department of Physiology, University of Colorado School of Medicine, Aurora, Colorado;
Zhilin
Z
Song
Barry E
BE
Levin
Wanida
W
Stevens
Celia D
CD
Sladek
D000818:Animals; D001069:Appetite Regulation; D020013:Calcium Signaling / Q000187:drug effects; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010121:Oxytocin / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D013495:Supraoptic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D046509:Tissue Culture Techniques; D014667:Vasopressins / Q000378:metabolism*
D007328:Insulin; D054086:KATP Channels; D000081082:Phosphoinositide-3 Kinase Inhibitors; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014667:Vasopressins; D010121:Oxytocin; D058539:Phosphatidylinositol 3-Kinase; D005941:Glucokinase; D011972:Receptor, Insulin; D005947:Glucose
calcium imaging; glucokinase; glucose-sensing; hormone release; insulin; phosphatidylinositol 3 kinase