Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats.
Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) and to normalize food intake and glucose homeostasis in overfed rats. To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH). Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats. Thus central inhibition of lipid oxidation is sufficient to restore hypothalamic lipid sensing as well as glucose and energy homeostasis in this model and may be an effective approach to the treatment of diet-induced obesity and insulin resistance.
Pocai
Alessandro
A
Department of Medicine and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, New York, New York, USA.
Lam
Tony K T
TK
Obici
Silvana
S
Gutierrez-Juarez
Roger
R
Muse
Evan D
ED
Arduini
Arduino
A
Rossetti
Luciano
L
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D005947:Glucose / Q000096:biosynthesis*; D006706:Homeostasis; D006963:Hyperphagia / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose