www.sc iammind.com SCIENTIFIC AMERICAN MIND 11

The Medication Munchies Mystery

Antipsychotic drugs have alleviated the debilitating symp-toms of thousands of patients with schizophrenia and bipo-lar disorder, but often at a high price. These drugs can also trigger excessive weight gain, leading to life-threatening complications such as diabetes or heart disease. Now sci-entists at Johns Hopkins University have uncovered the mechanism by which these drugs stimulate the appetite—a fi nding that could lead to new agents without the side effect of constant hunger.

Neuroscientists Solomon H. Snyder and Sangwon Kim found that when they administered clozapine, a powerful antipsychotic, to mice, the animals experienced a spike of the appetite-stimulating enzyme AMPK. Then they discovered that blocking a receptor for histamine caused a boost in AMPK similar to the effects of clozapine. Histamine, well known for causing allergy symptoms, has been long suspected to play a role in weight control, but the mechanism has been unknown. The researchers confi rmed their fi nding by administering clozapine to mice genetically engineered to lack the histamine receptor, and these rodents showed no increase in AMPK.

“This is the fi rst time histamine and AMPK have been linked,” Kim says. By blocking histamine receptors, clozapine and other antipsychotics prevent cells from receiving the body’s signal to turn off AMPK production. As a result, AMPK builds up in the hypothalamus and continues to

stimulate appetite, even when enough food has been consumed. He suggests that pharmaceutical companies may be able to screen out antipsychotic drugs with antihistamine properties and thereby avoid the side effects of weight gain. The researchers say their work may also lead to safer weight-loss drugs. —Karen Schrock

The results have

implications far beyond

sleep disorders.

Tinkering with Our Clock

Inserting a gene that controls human sleep habits into mice can transform the rodents into “early birds.” This result provides insight into the molecular mechanisms that drive biological clocks.

Most organisms have an internal clock that synchronizes their activities to the 24-hour day—the so-called circadian rhythm. PER2 is one of the genes that controls this rhythm in humans. But in 0.3 percent of the population, the gene goes awry, causing familial advanced sleep phase syndrome (FASPS), which drives people early to bed and very early to rise. Despite causing such a striking effect, the change in the protein encoded by the mutant PER2 gene is quite subtle: a single protein building block, or amino acid, is changed from a serine to a glycine.

To better understand how PER2 works, Louis J. Ptᡠcek and Ying-Hui Fu of the University of

California, San Francisco, genetically engineered mice with the human gene. Sure enough, when the animals received the FASPS PER2 mutation, their natural rhythm shortened from an average

of 23.7 hours to less than 22. When the researchers made another simple amino acid switch in the protein, turning the same serine into an aspartate, the period lengthened to 24.8 hours. Resetting of the mice’s clock seemed linked to the activity of the gene. The fi rst mutation lowered gene expression, and the second boosted it.

According to Fu, the results have implications far beyond sleep disorders. Night-shift nurses are more prone to breast cancer, she notes, and chemotherapy is more effective at certain

times. Strokes, aneurysms, asthma and depression tend to occur at particular times of day. “Sleep is at the center of all body functions, so understanding circadian rhythm will help us understand related problems,” Fu says.

—Karen A. Frenkel

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