Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose.
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.
Murphy
Beth Ann
BA
Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey, USA.
Fioramonti
Xavier
X
Jochnowitz
Nina
N
Fakira
Kurt
K
Gagen
Karen
K
Contie
Sylvain
S
Lorsignol
Anne
A
Penicaud
Luc
L
Martin
William J
WJ
Routh
Vanessa H
VH
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism*; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency*; D006706:Homeostasis; D066298:In Vitro Techniques; D020738:Leptin / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D009433:Neural Inhibition; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission
D020738:Leptin; D009478:Neuropeptide Y; D055372:AMP-Activated Protein Kinases; D005947:Glucose