Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats.
OBJECTIVE
Appropriate counter-regulatory hormonal responses are essential for recovery from hypoglycaemia. Although the hypothalamus is known to be involved in these responses, the molecular mechanisms have not been fully elucidated. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, being activated during energy depletion. As AMPK is expressed in the hypothalamus, an important site of neuroendocrine regulation, the present study was undertaken to determine whether hypothalamic AMPK mediates counter-regulatory responses to hypoglycaemia.


METHODS
Hypoglycaemia was induced by i.p. injection of regular insulin (6 U/kg) in Sprague-Dawley rats. Hypothalamic AMPK phosphorylation and activities were determined 1 h after i.p. insulin injection. To investigate the role of hypothalamic AMPK activation in mediating counter-regulatory responses, an AMPK inhibitor, compound C, was pre-administered intracerebroventricularly (i.c.v.) or dominant-negative (DN)-AMPK was overexpressed in the hypothalamus before induction of hypoglycaemia.


RESULTS
Insulin-induced hypoglycaemia increased hypothalamic AMPK phosphorylation and alpha2-AMPK activities in rats. The change was significant in the arcuate nucleus/ventromedial hypothalamus (ARC/VMH) and paraventricular nuclei (PVN). Prior i.c.v. administration of compound C attenuated hypoglycaemia-induced increases in plasma concentrations of corticosterone, glucagon and catecholamines, resulting in severe and prolonged hypoglycaemia. ARC/VMH DN-AMPK overexpression impaired early counter-regulation, as evidenced by reduced glucagon and catecholamine responses. In contrast, PVN DN-AMPK overexpression attenuated late counter-regulation and corticosterone responses.


CONCLUSIONS
Systemic hypoglycaemia causes hypothalamic AMPK activation, which is important for counter-regulatory hormonal responses. Our data indicate that hypothalamic AMPK acts as a fuel gauge, sensing the whole-body energy state and regulating not only energy homeostasis but also neuroendocrine functions.
Han
S-M
SM
Department of Internal Medicine, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul 138-736, South Korea.
Namkoong
C
C
Jang
P G
PG
Park
I S
IS
Hong
S W
SW
Katakami
H
H
Chun
S
S
Kim
S W
SW
Park
J-Y
JY
Lee
K-U
KU
Kim
M-S
MS
D055372:AMP-Activated Protein Kinases; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007004:Hypoglycemic Agents; D007031:Hypothalamus / Q000201:enzymology* / Q000378:metabolism; D007276:Injections, Intraventricular; D007328:Insulin; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009490:Neurosecretory Systems / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases