Molecular disruption of hypothalamic nutrient sensing induces obesity

In their latest finding on the brain's role in controlling appetite and weight, researchers at the Albert Einstein College of Medicine have shown that reducing levels of fatty acids in the hypothalamus causes rats to overeat and become obese. Their results suggest that restoring fatty-acid levels in the brain may be a promising way to treat obesity.

The study, published in the January 15th on-line edition of Nature Neuroscience, was led by Dr. Luciano Rossetti, director of the Diabetes Research Center at Einstein.

The brain's hypothalamus keeps track of the body's nutritional status by monitoring the blood levels of several different hormones and nutrients. Taking this information into account, the hypothalamus regulates our energy intake and metabolism.

In a study published last year in Science, Dr. Rossetti and his colleagues showed how the hypothalamus monitors and regulates glucose levels in the body. The present study shows that this brain region also monitors fatty acid levels and responds by controlling appetite.

The study focused on malonyl CoA, a molecule suspected of being one of the critical nutrients influencing hypothalamic regulation of eating behavior. Previous studies had shown that hypothalamic levels of malonyl CoA increase markedly after meals and are suppressed by fasting.

The Einstein researchers wanted to know whether sustained suppression of this nutrient within the hypothalamus could result in obesity. To find out, they piggybacked an enzyme known to degrade malonyl CoA onto an adeno-associated virus and injected the virus into the hypothalamus of rats. The injections caused a chronic decrease in malonyl CoA levels, which dramatically increased the rats' food intake and led to obesity that was maintained for at least four months.

"We showed in this study that disrupting malonyl-CoA levels in this region of the brain impairs the nutrient-sensing mechanism by which the hypothalamus modulates food intake to maintain normal weight," says Dr. Rossetti, who is also the Judy R. and Alfred A. Rosenberg Professor of Diabetes Research at Einstein. "Figuring out a way to re-adjust malonyl-CoA levels in the human hypothalamus could lead to innovative therapies not only to treat obesity but to help prevent diabetes and other consequences of being overweight."