Abstract
Pharmacologic activation of the hindbrain dorsal vagal complex energy sensor 5′-adenosine monophosphate-activated protein kinase (AMPK) causes site-specific adjustments in hypothalamic AMPK activity. DVC A2 noradrenergic neurons are a likely source of metabolo-sensory cues to downstream network components as they express substrate fuel-sensitive AMPK. This study investigated the hypothesis that DVC AMPK controls hypothalamic sensor, metabolic effector transmitter, and counter-regulatory hormone responses to insulin-induced hypoglycemia. Male rats were injected into the caudal fourth ventricle with the AMPK inhibitor compound C (Ccor vehicle before hypoglycemia. Arcuate (ARH), ventromedial (VMN), and dorsomedial (DMN) nuclei and lateral hypothalamic area (LHA) were micropunch-dissected for norepinephrine ELISA and Western blot analyses. Hypoglycemic stimulation of norepinephrine activity in each site was impeded by compound C. Hypoglycemia caused drug-revocable (ARH) or -refractory (VMN, DMN) reductions in AMPK, alongside hindbrain AMPK-dependent augmentation of phospho-AMPK expression in each location. Compound C prevented hypoglycemic augmentation of gluco-stimulatory ARH neuropeptide Y, VMN neuronal nitric oxide synthase, and LHA orexin-A expression, while hypoglycemic suppression of the catabolic neuron protein markers ARH pro-opiomelanocortin and VMN glutamate decarboxylase65/67 was respectively averted or unaffected by drug treatment. DMN RFamide-related peptide-1 and -3 profiles were correspondingly amplified or suppressed hindbrain AMPK-reliant mechanisms during hypoglycemia. Results show that DVC AMPK is required for hypoglycemic intensification of norepinephrine activity in characterized hypothalamic gluco-regulatory structures, and that this sensor regulates AMPK activation and metabolic effector transmission in those sites.
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