Abstract
The mediobasal hypothalamus (MBH) shapes the neural regulation of glucostasis by 5′-AMP-activated protein kinase (AMPK)-dependent mechanisms. Yet, the neurochemical identity and neuroanatomical distribution of MBH neurons that express glucoprivic-sensitive AMPK remain unclear. The neurotransmitters γ-aminobutyric acid (GABA) and nitric oxide (NO) act within the MBH to correspondingly inhibit or stimulate glucose counter-regulation. The current review highlights recent findings that GABA and NO, neurons located in the ventromedial hypothalamic nucleus (VMN), a distinct important element of the MBH, are direct targets of noradrenergic regulatory signaling, and thereby, likely operate under the control of hindbrain metabolic-sensory neurons. The ovarian hormone estradiol acts within the VMN to govern energy homeostasis. Discussed here is current evidence that estradiol regulates GABA and NO nerve cell receptivity to norepinephrine and moreover, controls the noradrenergic regulation of AMPK activity in each cell type. Future gains in insight on mechanisms underpinning estradiol’s impact on neurotransmitter communication between the hindbrain and hypothalamic AMPKergic neurons are expected to disclose viable new molecular targets for the therapeutic simulation of hormonal enhancement of neuro-metabolic stability during circumstances of diminished endogenous estrogen secretion or glucose dysregulation.
Highlights
Insulin-induced hypoglycemia (IIH) is a relentless, worrisome complication of the meticulous therapeutic management of type I and long-term type II diabetes mellitus patients, and is a major impediment to optimal glycemic control
Using combinatory immunocytochemistry/laser-catapult microdissection for the discriminative harvesting of ventromedial hypothalamic nucleus (VMN) nitric oxide (NO) and GABA neurons, our studies revealed that each population is likely a direct target for noradrenergic input as these nerve cells express alpha1- (α1-), alpha2- (α2-), and beta1- (β1-) adrenoreceptor (AR) proteins [24]
Our results indicate that VMN NO and GABA neurons exhibit common and dissimilar AR protein responses to hypoglycemia, as well as discrepant AR acclimation to recurring insulin-induced hypoglycemia (RIIH)
Summary
Insulin-induced hypoglycemia (IIH) is a relentless, worrisome complication of the meticulous therapeutic management of type I and long-term type II diabetes mellitus patients, and is a major impediment to optimal glycemic control. Using the same methodological approach for the selective procurement of VMN NO and GABA neurons and techniques for the administration of NE to the VMN [35], our laboratory examined the premise that one or both neuron populations express AMPK and that VMN ERs modulate the noradrenergic regulation of sensor protein expression and/or activation Whereas both ERα and -β were observed to stimulate total AMPK protein expression in nitrergic neurons under control conditions, this protein profile was diminished in response to NE, an action that required ERβ signaling. The study results show that the hypoglycemic activation of VMN NO and GABA AMPK involves the α1-AR signal up-regulation of pAMPK profiles in nitrergic neurons or the down-regulation of the total AMPK protein in GABAergic nerve cells. Our studies bolster the need to consider how adaptive adjustments in between-hypoglycemia patterns of A2 neurotransmission may have physiological relevance for glucostatic as well as non-glucostatic neural functions controlled by this hindbrain cell group
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