Caudal fourth ventricular administration of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside regulates glucose and counterregulatory hormone profiles, dorsal vagal complex metabolosensory neuron function, and hypothalamic Fos expression.

This study investigated the hypothesis that estrogen controls hindbrain AMP-activated protein kinase (AMPK) activity and regulation of blood glucose, counterregulatory hormone secretion, and hypothalamic nerve cell transcriptional status. Dorsal vagal complex A2 noradrenergic neurons were laser microdissected from estradiol benzoate (E)- or oil (O)-implanted ovariectomized female rats after caudal fourth ventricular (CV4) delivery of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR), for Western blot analysis. E advanced AICAR-induced increases in A2 phospho-AMPK (pAMPK) expression and in blood glucose levels and was required for augmentation of Fos, estrogen receptor-α (ERα), monocarboxylate transporter-2, and glucose transporter-3 protein in A2 neurons and enhancement of corticosterone secretion by this treatment paradigm. CV4 AICAR also resulted in site-specific modifications in Fos immunolabeling of hypothalamic metabolic structures, including the paraventricular, ventromedial, and arcuate nuclei. The current studies demonstrate that estrogen regulates AMPK activation in caudal hindbrain A2 noradrenergic neurons during pharmacological replication of energy shortage in this area of the brain, and that this sensor is involved in neural regulation of glucostasis, in part, through control of corticosterone secretion. The data provide unique evidence that A2 neurons express both ERα and -ß proteins and that AMPK upregulates cellular sensitivity to ERα-mediated signaling during simulated energy insufficiency. The results also imply that estrogen promotes glucose and lactate uptake by these cells under those conditions. Evidence for correlation between hindbrain AMPK and hypothalamic nerve cell genomic activation provides novel proof for functional connectivity between this hindbrain sensor and higher order metabolic brain loci while demonstrating a modulatory role for estrogen in this interaction.

Expanding role of ATP as a versatile messenger at carotid and aortic body chemoreceptors.

In mammals, peripheral arterial chemoreceptors monitor blood chemicals (e.g. O(2), CO(2), H(+), glucose) and maintain homeostasis via initiation of respiratory and cardiovascular reflexes. Whereas chemoreceptors in the carotid bodies (CBs), located bilaterally at the carotid bifurcation, control primarily respiratory functions, those in the more diffusely distributed aortic bodies (ABs) are thought to regulate mainly cardiovascular functions. Functionally, CBs sense partial pressure of O(2) ( ), whereas ABs are considered sensors of O(2) content. How these organs, with essentially a similar complement of chemoreceptor cells, differentially process these two different types of signals remains enigmatic. Here, we review evidence that implicates ATP as a central mediator during information processing in the CB. Recent data allow an integrative view concerning its interactions at purinergic P2X and P2Y receptors within the chemosensory complex that contains elements of a 'quadripartite synapse'. We also discuss recent studies on the cellular physiology of ABs located near the aortic arch, as well as immunohistochemical evidence suggesting the presence of pathways for P2X receptor signalling. Finally, we present a hypothetical 'quadripartite model' to explain how ATP, released from red blood cells during hypoxia, could contribute to the ability of ABs to sense O(2) content.

Immunohistochemical evidence for species-specific coexistence of catecholamines, serotonin, acetylcholine and nitric oxide in glomus cells of rat and guinea pig aortic bodies.

The aortic bodies are small paraganglia distributed along the vagus nerve and its branches in the vicinity of the aortic arch which, like the carotid bodies, act as arterial chemoreceptors. In the rat carotid body, corelease of ATP and acetylcholine (ACh) from glomus cells is considered to be the main mechanism mediating fast hypoxic chemotransmission while dopamine, serotonin, and nitric oxide (NO) exert modulating effects. The present study was aimed at determination of the endogenous sources of serotonin, ACh and NO within rat and guinea pig aortic bodies by immunohistochemical double- and triple-labeling approaches, utilizing antibodies to serotonin, the NO and ACh synthesizing enzymes neuronal NO synthase (nNOS) and choline acetyltransferase (ChAT), respectively, as well as to the vesicular acetylcholine transporter (VAChT). Additional marker antibodies were directed against the rate-limiting enzyme of catecholamine synthesis, i.e. tyrosine hydroxylase (TH), and the vesicular protein, synaptophysin (SYN). In both species, all aortic body glomus cells were immunoreactive to serotonin and cholinergic markers. In the rat, all glomus cells were additionally catecholaminergic, as indicated by TH-immunoreactivity, whereas this applied only to a subgroup of guinea pig glomus cells. On the other hand, all guinea pig glomus cells were nNOS-immunoreactive, whereas only nerve fibers but not glomus cells exhibited nNOS-immunoreactivity in the rat. These data support the concept that the chemoexcitatory transmitters ACh and serotonin are involved in hypoxic excitation of aortic chemoreceptor terminals in both species. The production of the inhibitory modulators, dopamine and NO, however, appears to be species-specifically regulated.