Molecular disruption of hypothalamic nutrient sensing induces obesity.
The sensing of circulating nutrients within the mediobasal hypothalamus may be critical for energy homeostasis. To induce a sustained impairment in hypothalamic nutrient sensing, adeno-associated viruses (AAV) expressing malonyl-coenzyme A decarboxylase (MCD; an enzyme involved in the degradation of malonyl coenzyme A) were injected bilaterally into the mediobasal hypothalamus of rats. MCD overexpression led to decreased abundance of long-chain fatty acyl-coenzyme A in the mediobasal hypothalamus and blunted the hypothalamic responses to increased lipid availability. The enhanced expression of MCD within this hypothalamic region induced a rapid increase in food intake and progressive weight gain. Obesity was sustained for at least 4 months and occurred despite increased plasma concentrations of leptin and insulin. These findings indicate that nutritional modulation of the hypothalamic abundance of malonyl-coenzyme A is required to restrain food intake and that a primary impairment in this central nutrient-sensing pathway is sufficient to disrupt energy homeostasis and induce obesity.
He
Wu
W
Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Lam
Tony K T
TK
Obici
Silvana
S
Rossetti
Luciano
L
D000818:Animals; D015153:Blotting, Western; D002262:Carboxy-Lyases / Q000378:metabolism*; D004435:Eating / Q000502:physiology*; D002149:Energy Intake / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D015309:Glucose Clamp Technique; D007031:Hypothalamus / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase