Molecular disruption of hypothalamic nutrient sensing induces obesity.

Abstract

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.

• Authors: Wu He, Tony K T Lam, Silvana Obici, Luciano Rossetti
• Journal: Nature neuroscience (Nat Neurosci) Vol. 9 Issue 2 Pg. 227-33 (Feb 2006) ISSN: 1097-6256 [Print] United States
• PMID: 16415870 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carboxy-Lyases
• malonyl-CoA decarboxylase

Topics

• Animals
• Blotting, Western
• Carboxy-Lyases (metabolism)
• Eating (physiology)
• Energy Intake (physiology)
• Fluorescent Antibody Technique
• Glucose Clamp Technique
• Hypothalamus (metabolism)
• Lipid Metabolism
• Male
• Obesity (metabolism)
• Rats
• Rats, Sprague-Dawley