TY - JOUR
T1 - Perifornical hypothalamic orexin and serotonin modulate the counterregulatory response to hypoglycemic and glucoprivic stimuli
AU - Otlivanchik, Oleg
AU - Le Foll, Christelle
AU - Levin, Barry E.
N1 - Publisher Copyright:
© 2015 by the American Diabetes Association.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Previous reports suggested an important role for serotonin (5-hydroxytryptamine [5-HT]) in enhancing the counterregulatory response (CRR) to hypoglycemia. To elucidate the sites of action mediating this effect, we initially found that insulin-induced hypoglycemia stimulates 5-HT release in widespread forebrain regions, including the perifornical hypothalamus (PFH; 30%), ventromedial hypothalamus (34%), paraventricular hypothalamus (34%), paraventricular thalamic nucleus (64%), and cerebral cortex (63%). Of these, we focused on the PFH because of its known modulation of diverse neurohumoral and behavioral responses. In awake, behaving rats, bilateral PFH glucoprivation with 5-thioglucose stimulated adrenal medullary epinephrine (Epi) release (3,153%) and feeding (400%), while clamping PFH glucose at postprandial brain levels blunted the Epi response to hypoglycemia by 30%. The PFH contained both glucose-excited (GE) and glucose-inhibited (GI) neurons; GE neurons were primarily excited, while GI neurons were equally excited or inhibited by 5-HT at hypoglycemic glucose levels in vitro. Also, 5-HT stimulated lactate production by cultured hypothalamic astrocytes. Depleting PFH 5-HT blunted the Epi (but not feeding) response to focal PFH (69%) and systemic glucoprivation (39%), while increasing PFH 5-HT levels amplified the Epi response to hypoglycemia by 32%. Finally, the orexin 1 receptor antagonist SB334867A attenuated both the Epi (65%) and feeding (47%) responses to focal PFH glucoprivation. Thus we have identified the PFH as a glucoregulatory region where both 5-HT and orexin modulate the CRR and feeding responses to glucoprivation.
AB - Previous reports suggested an important role for serotonin (5-hydroxytryptamine [5-HT]) in enhancing the counterregulatory response (CRR) to hypoglycemia. To elucidate the sites of action mediating this effect, we initially found that insulin-induced hypoglycemia stimulates 5-HT release in widespread forebrain regions, including the perifornical hypothalamus (PFH; 30%), ventromedial hypothalamus (34%), paraventricular hypothalamus (34%), paraventricular thalamic nucleus (64%), and cerebral cortex (63%). Of these, we focused on the PFH because of its known modulation of diverse neurohumoral and behavioral responses. In awake, behaving rats, bilateral PFH glucoprivation with 5-thioglucose stimulated adrenal medullary epinephrine (Epi) release (3,153%) and feeding (400%), while clamping PFH glucose at postprandial brain levels blunted the Epi response to hypoglycemia by 30%. The PFH contained both glucose-excited (GE) and glucose-inhibited (GI) neurons; GE neurons were primarily excited, while GI neurons were equally excited or inhibited by 5-HT at hypoglycemic glucose levels in vitro. Also, 5-HT stimulated lactate production by cultured hypothalamic astrocytes. Depleting PFH 5-HT blunted the Epi (but not feeding) response to focal PFH (69%) and systemic glucoprivation (39%), while increasing PFH 5-HT levels amplified the Epi response to hypoglycemia by 32%. Finally, the orexin 1 receptor antagonist SB334867A attenuated both the Epi (65%) and feeding (47%) responses to focal PFH glucoprivation. Thus we have identified the PFH as a glucoregulatory region where both 5-HT and orexin modulate the CRR and feeding responses to glucoprivation.
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U2 - 10.2337/db14-0671
DO - 10.2337/db14-0671
M3 - Article
C2 - 25114294
AN - SCOPUS:84920059453
SN - 0012-1797
VL - 64
SP - 226
EP - 235
JO - Diabetes
JF - Diabetes
IS - 1
ER -