Frontier: Pathway to Obesity Found
News from the frontier

by Maria Schamis Turner

November, 2008

Consuming too many calories activates an immune response pathway in the hypothalamus that causes a dysfunction in the brain’s ability to regulate food intake and energy balance.

The IKKß/NF-κB (IKK-beta/NF-kappa-B) pathway is involved in the body’s immune response and is known to drive metabolic inflammation in different tissues in the body in response to injury or infections. Donsheng Cai and fellow researchers from the University of Wisconsin, Madison, and the University of California, San Diego, found that the transcription factor IKKß/NF-κB is present in the hypothalamus but is not normally activated in this region. They then studied the effects of chronic “overnutrition”—the regular consumption of too many calories— in mice, and found that over consumption activated the IKKß/NF-κB pathway in the hypothalamus.

Previous research has shown that overnutrition can cause hypothalamic resistance to insulin and leptin, two important metabolic hormones. Deleting insulin and leptin signaling in animals has been shown to lead to morbid obesity and other diseases. (See “‘Feeding’ Hormones Affect More Than Hunger,” September-October BrainWork.)

Further studies of the mice showed that the activation of the IKKß/NF-κB pathway in the hypothalamus caused both insulin and leptin resistance, leading Cai and his colleagues to postulate that the IKKß/NF-κB pathway may be the link between overnutrition and the dysfunction of these systems.

“One of the motivations for our research is to try and derive new, effective therapeutic strategies for obesity,” says Cai. “[Food control and exercise] cannot efficiently correct abnormal regulation in the brain. We’d like to corrector target the key mechanism, and I think the pathway we studied provides an important potential.”

The research was published in the Oct. 3 Cell.