Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose

Abstract

Fasting increases neuropeptide Y (NPY) expression, peptide levels, and the excitability of NPY-expressing neurons in the hypothalamic arcuate (ARC) nucleus. A subpopulation of ARC-NPY neurons ( approximately 40%) are glucose-inhibited (GI)-type glucose-sensing neurons. Hence, they depolarize in response to decreased glucose. Because fasting enhances NPY neurotransmission, we propose that during fasting, GI neurons depolarize in response to smaller decreases in glucose. This increased excitation in response to glucose decreases would increase NPY-GI neuronal excitability and enhance NPY neurotransmission. Using an in vitro hypothalamic explant system, we show that fasting enhances NPY release in response to decreased glucose concentration. By measuring relative changes in membrane potential using a membrane potential-sensitive dye, we demonstrate that during fasting, a smaller decrease in glucose depolarizes NPY-GI neurons. Furthermore, incubation in low (0.7 mM) glucose enhanced while leptin (10 nM) blocked depolarization of GI neurons in response to decreased glucose. Fasting, leptin, and glucose-induced changes in NPY-GI neuron glucose sensing were mediated by 5'-AMP-activated protein kinase (AMPK). We conclude that during energy sufficiency, leptin reduces the ability of NPY-GI neurons to sense decreased glucose. However, after a fast, decreased leptin and glucose activate AMPK in NPY-GI neurons. As a result, NPY-GI neurons become depolarized in response to smaller glucose fluctuations. Increased excitation of NPY-GI neurons enhances NPY release. NPY, in turn, shifts energy homeostasis toward increased food intake and decreased energy expenditure to restore energy balance.

Glucokinase activity in the arcuate nucleus regulates glucose intake

“…A possible cellular mechanism underlying the changes in food and glucose intake is increased activity of arcuate NPY neurons, since there were changes in release of NPY in response to glucose from ex vivo hypothalamic slices from iARC-GK rats. As has been reported previously (55), increasing glucose concentrations in the artificial CSF (aCSF) resulted in reduced NPY release from control hypothalami. In contrast, there was no decrease in NPY release from iARC-GK hypothalami with increasing glucose concentrations.…”

Orexin-A Activates Hypothalamic AMP-Activated Protein Kinase Signaling through a Ca2+-Dependent Mechanism Involving Voltage-Gated L-Type Calcium Channel

“…How L-type calcium channel potentiation affects the firing properties of NPY neurons is a very interesting question. NPY neurons are sensitive to energy status, and previous studies have revealed that AMPK activity controls excitation of NPY/agouti-related protein neurons (Murphy et al, 2009;Kohno et al, 2011). We hypothesize that L-type channel potentiation increased the frequency of action potentials via activation of AMPK.…”

“…For example, adiponectin increases food intake by activating AMPK in the arcuate hypothalamus (Kubota et al, 2007;Wen et al, 2010), and ghrelin promotes feeding through a mechanism involving the short-term activation of hypothalamic AMPK (Lopez et al, 2008). Accumulated evidence indicates that AMPK in NPY neurons senses hunger signals and shifts energy homeostasis toward increased food intake (Murphy et al, 2009;Kohno et al, 2011). For instance, decreased leptin and glucose after fasting activated AMPK in glucose-inhibited NPY neurons and increased neuron excitation, which led to NPY release and food intake (Murphy et al, 2009).…”

“…Accumulated evidence indicates that AMPK in NPY neurons senses hunger signals and shifts energy homeostasis toward increased food intake (Murphy et al, 2009;Kohno et al, 2011). For instance, decreased leptin and glucose after fasting activated AMPK in glucose-inhibited NPY neurons and increased neuron excitation, which led to NPY release and food intake (Murphy et al, 2009). A novel finding has revealed that a hunger signal results in a persistent upregulation of excitatory synaptic input to NPY neurons, then increases their firing rate via an AMPK-dependent positive feedback loop (Yang et al, 2011).…”

Lowering glucose level elevates [Ca2+]i in hypothalamic arcuate nucleus NPY neurons through P/Q-type Ca2+ channel activation and GSK3β inhibition

“…The knockout of mice AMPKα2 induces the responses to changes in extracellular glucose levels in NPY neurons [13] . The change in action potential can be stimulated by AMPK activator AICAR and blocked by AMPK inhibitor compound C [14][15][16] . Decreased glucose activates AMPK and elevates [Ca 2+ ] i in NPY neurons [15] .…”