Circulating angiotensin II (Ang II) is vital for arterial pressure elevation following intermittent hypoxia in rats, although its importance in the induction of sympathetic changes is unclear. We tested the contribution of the renin-angiotensin system to the effects of acute intermittent hypoxia (AIH) in anaesthetized and ventilated rats. There was a 33.7 ± 2.9% increase in sympathetic nerve activity (SNA), while sympathetic chemoreflex sensitivity and central sympathetic-respiratory coupling increased by one-fold following AIH. The sympathetic effects of AIH were prevented by blocking angiotensin type 1 receptors with systemic losartan. Intermittent systemic injections of Ang II (Int.Ang II) elicited similar sympathetic responses to AIH. To identify the neural pathways responsible for the effects of AIH and Int.Ang II, we performed bilateral carotid body denervation, which reduced the increase in SNA by 56% and 45%, respectively. Conversely, pharmacological inhibition of the subfornical organ (SFO), an established target of circulating Ang II, reduced the increase in SNA following AIH and Int.Ang II by 65% and 59%, respectively, although it did not prevent the sensitization of the sympathetic peripheral chemoreflex, nor the increase in central sympathetic-respiratory coupling. Combined carotid body denervation and inhibition of the SFO eliminated the enhancement of SNA following AIH and Int.Ang II. Repeated systemic injections of phenylephrine caused an elevation in SNA similar to AIH, and this effect was prevented by a renin inhibitor, aliskiren. Our findings show that the sympathetic effects of AIH are the result of RAS-mediated activations of the carotid bodies and the SFO.

The importance of hypothalamic insulin signaling on feeding and glucose metabolism remains unclear. We report that insulin acts on AgRP neurons to acutely decrease meal size and thereby limit postprandial glucose and insulin excursions. The promotion of insulin signaling in AgRP neurons decreased meal size without altering total caloric intake, whereas the genetic ablation of the insulin receptor had the opposite effect. The promotion of insulin signaling also decreased the intake of sucrose-sweetened water or high-fat food over standard chow, without influencing food-seeking and hedonic behaviors. The ability of heightened insulin signaling to override the hedonistic consumption of highly palatable high-fat food attenuated the development of systemic insulin resistance, without affecting body weight. Our findings define an unprecedented mechanism by which insulin acutely influences glucose metabolism. Approaches that enhance insulin signaling in AgRP neurons may provide a means for altering feeding behavior in a nutrient-dense environment to combat the metabolic syndrome.

Intermittent hypoxia causes a persistent increase in sympathetic nerve activity (SNA), which progresses to hypertension in conditions such as obstructive sleep apnea. Orexins (A and B) are hypothalamic neurotransmitters with arousal-promoting and sympathoexcitatory effects. We investigated whether the sustained elevation of SNA, termed sympathetic long-term facilitation, after acute intermittent hypoxia (AIH) is caused by endogenous orexin acting on spinal sympathetic preganglionic neurons. The role of orexin in the increased SNA response to AIH was investigated in urethane-anesthetized, vagotomized, and artificially ventilated Sprague-Dawley rats (n 5 58). A spinally infused subthreshold dose of orexin-A (intermittent; 10 pmol  10) produced long-term enhancement in SNA (41.4% 6 6.9%) from baseline. This phenomenon was not produced by the same dose of orexin-A administered as a bolus intrathecal infusion (100 pmol; 7.3% 6 2.3%). The dual orexin receptor blocker, Almorexant, attenuated the effect of sympathetic long-term facilitation generated by intermittent orexin-A (20.7% 6 4.5% for Almorexant at 30 mg•kg 21 and 18.5% 6 1.2% for 75 mg•kg 21), but not in AIH. The peripheral chemoreflex sympathoexcitatory response to hypoxia was greatly enhanced by intermittent orexin-A and AIH. In both cases, the sympathetic chemoreflex sensitization was reduced by Almorexant. Taken together, spinally acting orexin-A is mechanistically sufficient to evoke sympathetic long-term facilitation. However, AIH-induced sympathetic long-term facilitation appears to rely on mechanisms that are independent of orexin neurotransmission. Our findings further reveal that the activation of spinal orexin receptors is critical to enhance peripheral chemoreceptor responses to hypoxia after AIH.