Hap1 protein could lead to future drug targets for eating disorders

Apr 16 2006

Researchers have discovered how the protein Hap1, which is abundant in the brain's hypothalamus, serves as the link between circulating insulin in the blood and the neural circuitry that controls feeding behavior in mice.

Illumination of the neural pathway used by hormones to regulate appetite and eating behavior could eventually provide new drug targets for treating eating disorders and obesity.

The research, reported on-line in the journal Nature Medicine.

The hypothalamus serves as the central switching control for neural signals that regulate food intake and energy balance. Hormones such as insulin and leptin, which circulate in the blood plasma, are known to play an important role in regulating the brain's feeding signals, but scientists have not fully understand how these hormones interact with the brain circuitry. Neurotransmitters in the hypothalamus, including GABA (gamma aminobutyric acid), are known to be an important part of the pathway that regulates feeding behavior.

Scientists at Emory University School of Medicine had previously identified the Hap1 protein as crucial for the normal function of the hypothalamus. In experiments with knockout mice in which the Hap1 gene was eliminated, the mice failed to eat after birth. In addition, deleting Hap1 caused degeneration of some neurons in the hypothalamus.

In order to find out more about the function of Hap1 and the neural pathways it employs, a team of scientists from Emory, The Rockefeller University, the Burnham Institute for Medical Research, and the University of California, San Diego, conducted a series of experiments in mice. They found that fasting increased the level of Hap1 in the hypothalamus of the mice and that administering insulin decreased the Hap1 level. Suppressing Hap1 expression through RNA interference reduced mouse food intake and body weight. They also found that reducing Hap1 decreased the level and activity of GABA receptors in the hypothalamus.

"We concluded that increased levels of Hap1 correlated with increased feeding behavior in the mice, and our research helps explain how Hap1 is linked to feeding-related molecules such as insulin, and to hypothalamic neuronal function," said Xiao-Jiang Li, PhD, professor of human genetics at Emory University School of Medicine and senior author of the study. "GABA is known to have a stimulating effect on feeding behavior. Because insulin decreases Hap1 levels, and reducing Hap1 decreases the GABA receptor activity, we believe Hap1 is the link between circulating insulin and the regulation of GABA receptors in the hypothalamus in controlling eating behavior."

"Scientists know that diabetes and obesity are related to abnormalities of hypothalamic function," Li said. "This is a complicated pathway, and Hap1 can help us explain it and hopefully manipulate it to treat disorders associated with abnormal energy balance in the brain."

Stuart A. Lipton, MD, PhD, director and professor of the Center for Neuroscience and Aging at the Burnham Institute for Medical Research in La Jolla, further stated, Rthe new work opens up additional targets for obesity research. For example, a drug that decreases Hap1 in the hypothalamus would decrease the electrical drive that underlies eating behavior, resulting in weight loss and potentially longer lifespan.