Perifornical hypothalamic orexin and serotonin modulate the counterregulatory response to hypoglycemic and glucoprivic stimuli.-猫眼课题宝

DOI：

10.2337/db14-0671

发表时间：

2015-01

期刊：

Diabetes

影响因子：

7.7

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Otlivanchik O;Le Foll C;Levin BE

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274798/?report=classic

以往的报道表明，5-羟色胺(5-羟色胺[5-HT])在增强对低血糖的反调节反应(CRR)中起着重要作用。为了阐明介导这一效应的作用部位，我们初步发现，胰岛素诱导的低血糖刺激广泛的前脑区域5-羟色胺的释放，包括穹隆周围下丘脑(30%)、下丘脑腹内侧(34%)、室旁下丘脑(34%)、丘脑室旁核(%)和大脑皮层(63%)。其中，我们关注的是PFH，因为它对不同的神经体液和行为反应具有已知的调节作用。在清醒的行为大鼠中，双侧PFH与5-硫代葡萄糖配对可刺激肾上腺髓质肾上腺素(Epi)的释放(3,153%)和摄食(400%)，而将PFH葡萄糖夹在餐后脑水平可使EPi对低血糖的反应减弱30%。PFH既有葡萄糖兴奋(GE)神经元，也有葡萄糖抑制(GI)神经元，在体外低血糖水平下，GE神经元主要兴奋，而GI神经元同样受到5-HT的兴奋或抑制。此外，5-羟色胺还能刺激培养的下丘脑星形胶质细胞产生乳酸。消耗PFH 5-HT可钝化EPI(但不喂食)对局灶性PFH(69%)和全身性糖代谢(39%)的反应，而增加PFH 5-HT水平则将EPI对低血糖的反应放大32%。最后，食欲素1受体拮抗剂SB334867A减弱了EPI(65%)和摄食(47%)对局灶性PFH糖基化的反应。因此，我们确定PFH是一个糖调控区，5-羟色胺和增食欲素都在其中调节CRR和对葡萄糖普利的摄食反应。

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.