Hypothalamic protein kinase C regulates glucose production.
OBJECTIVE
A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K(+) (K(ATP)) channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K(ATP) channels remain unknown.


METHODS
To examine whether hypothalamic protein kinase C (PKC) mediates the ability of central nervous system lipids to activate K(ATP) channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of K(ATP) channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo.


RESULTS
We first reported that direct activation of hypothalamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) suppressed glucose production. Coadministration of hypothalamic PKC-delta inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-delta and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the K(ATP) channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production.


CONCLUSIONS
These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.
Departments of Molecular Pharmacology, Medicine, and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
Rachel
R
Ross
Penny Y T
PY
Wang
Madhu
M
Chari
Carol K L
CK
Lam
Liora
L
Caspi
Hiraku
H
Ono
Evan D
ED
Muse
Xiaosong
X
Li
Roger
R
Gutierrez-Juarez
Peter E
PE
Light
Gary J
GJ
Schwartz
Luciano
L
Rossetti
Tony K T
TK
Lam
D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology; D004075:Diglycerides / Q000008:administration & dosage / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis*; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D054086:KATP Channels / Q000037:antagonists & inhibitors; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
C520323:1-oleoyl-2-acetoyl-sn-glycerol; D000098:Acetophenones; D001578:Benzopyrans; D004075:Diglycerides; D007004:Hypoglycemic Agents; D054086:KATP Channels; C085746:rottlerin; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D005947:Glucose; D005905:Glyburide