Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production.
The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo beta-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.
Obici
Silvana
S
Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Feng
Zhaohui
Z
Arduini
Arduino
A
Conti
Roberto
R
Rossetti
Luciano
L
D054369:Agouti-Related Protein; D000818:Animals; D001483:Base Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004435:Eating; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000201:enzymology*; D007328:Insulin / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism; D016337:RNA, Catalytic / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D054369:Agouti-Related Protein; D005227:Fatty Acids; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D011506:Proteins; D016337:RNA, Catalytic; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose