Fat at Menopause Linked to Brain Estrogen Receptors

BOSTON, Aug. 20 -- A cluster of estrogen receptors deep in the brain may hold clues to why women gain weight gain weight at menopause.

University of Cincinnati researchers think they've linked the estrogen receptors to how hormonal changes increase visceral fat at menopause, at least in female rats.

In the animals, the investigators reported at the American Chemical Society meeting here, destroying estrogen receptor-alpha cells in the ventrolateral portion of the ventromedial hypothalamus causes body changes reminiscent of human menopause.

The finding could lead to selective forms of hormone replacement therapy that target only the cells involved in such changes, said Deborah Clegg, Ph.D., of the University of Cincinnati Academic Health Center.

But if therapy could target just the estrogen receptor-alpha cells in the brain, and not those in the breast or elsewhere in the body, Dr. Clegg said, it might outweigh risks uncovered in the Women's Health Initiative study.

"This is a very novel finding and it's very important," Dr. Clegg said in an interview after her presentation, "and we hope one day to be able to take it into the clinic."

In a series of experiments, Dr. Clegg and colleagues injected normal healthy female rats with an adeno-associated virus that destroyed estrogen-receptor alpha cells, using a technique called RNA interference.

The injections were targeted to the ventrolateral portion of the ventromedial hypothalamus -- a region the size of a pencil eraser in the animals -- and had no systemic effects, Dr. Clegg said.

As a result, the animals continued to have normal estrogen responses throughout the rest of their bodies, she said.

However, she said, the treated animals reduced their energy expenditure by 10% on average, measured by indirect calorimetry, which evaluates calories burned over time by the animals.

Although the animals didn't eat any more, the drop in energy use resulted in about a 10% increase in body weight.

The increased weight was mainly owing to fat deposited in the abdominal area, as measured by magnetic resonance imaging and nuclear magnetic resonance scanning, Dr. Clegg said.

"They look like post-menopausal women, except that they have normal levels of estrogen," Dr. Clegg said.

All the differences were significant at P<0.05, Dr. Clegg said, compared with control rats given either saline injections or an inactivated form of the virus.

The same effect had been seen earlier, when researchers used electricity to burn out the same brain region, but it had not previously been linked to a specific population of cells, Dr. Clegg said.

"The accumulation of abdominal fat puts both men and women at a heightened risk of cardiovascular disease, diabetes, and insulin resistance," Dr. Clegg said.

As long as women carry fat in their hips and thighs, they're protected, she said, "but when they go through menopause and the body fat shifts to the abdomen, they have to start battling all of these medical complications."