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Estrogen receptor in two kinds of neurons fights obesity, infertility

Obesity manifests as a problem of hips, thighs and bellies but it begins in the brain, and the female hormone estrogen can play a key role through a specific receptor on two different populations in the hypothalamus, said a group of researchers led by Baylor College of Medicine and The University of Texas Southwestern Medical School in Dallas.

In fact, these two populations of neurons – steroidgenic factor-1 (SF-1) neurons and the pro-opiomelanocortin (POMC) neurons – play different but important roles in metabolism, fat distribution and appetite control, said the scientists in a report that appears in the current issue of the journal Cell Metabolism.

Selective benefits

"Before menopause, women are protected from obesity and associated disorders by estrogen," said Dr. Yong Xu, a first author of the study and assistant professor of pediatrics – nutrition in the USDA Agricultural Research Service Children’s Nutrition Research Center at BCM and Texas Children’s Hospital. After menopause, the risk of obesity in women rises, he said. The risks of estrogen replacement therapy, however, outweigh its effect on reducing obesity.

"That made us try to identify the specific site of the action of estrogen," Xu said. "That may help us development treatments with more selective benefits."

They focused their work on neurons in the hypothalamus of brain that carry an estrogen receptor alpha – a molecule that takes estrogen signals into the neurons. The hypothalamus links the nervous system to the endocrine system to regulate multiple physiological processes, including those controlling body weight

Determining effect of estrogen

To determine the effect of estrogen, they studied four different kinds of mice – one that had no estrogen receptor alpha in the brain at all, one that lacked estrogen receptors in the SF-1 neurons, another that lacked estrogen receptors in the POMC neurons and a fourth that lacked the estrogen receptor in both the SF-1 and POMC neurons. They found that the lack of estrogen receptor in the different kinds of neurons had very different effects.

The mice that lacked the estrogen receptor throughout the brain ate more and used less energy as their metabolism decreased. That meant that they stored more fat and they stored it in the visceral region. Abdominal fat is linked to increased heart and metabolic disease. Mice that lack the receptor in SF-1 neurons have a lower energy expenditure (indicating lower metabolism) and increased fat deposits in the abdominal or visceral area. Mice that lack estrogen receptor alpha in the POMC neurons overeat, but the lack does not seem to influence the distribution of their fat or their metabolism. When the mice lack estrogen receptor alpha in the two populations of neurons, the effect is additive – the mice eat more, have a decreased metabolism and store fat in the viscera.

"When we talk about estrogen and estrogen receptors, we are not just talking about women," said Xu. "If men have mutations in the estrogen receptor alpha, they will develop obesity. In agreement with these findings in humans, we showed that male mice lacking the receptor in the brain gained more weight."

However, male mice lacking the estrogen receptor alpha in SF1 and/or POMC neurons do not show similar obesity seen in female mice with the same mutations. These results indicate that different populations of neurons in male brains are involved in this effect.

Metabolic, reproductive cues

Their studies also show that this estrogen/estrogen receptor effect in these populations of neurons have an important effect on fertility.

"This is an emerging field. We know the regulations on metabolism and reproduction need to be tightly coordinated, but we do not know how and where these two systems communicate," he said. "When the estrogen receptor is deleted from POMC or SF1 neurons, mice also developed infertility or subfertility, in addition to obesity. These results suggest that these hypothalamic populations are among the key sites where metabolic and reproductive cues are integrated. Changes in food availability and energy storage of the body may be reflected, at least partially, by estrogen signals in these neurons, which ultimately tells the animals to or not to reproduce."

Others who took part in this research include Liangru Zhu, Xiaorui Zhang and Fang Zou of BCM; Thekkethil P. Nedungadi (another first author), Nasim Sobhani, Boman G.Irani, Kathryn E. Davis, Lana M. Gent, Lisa D. Hahner, Carol F. Elias, Joel K. Elmquist and Deborah J. Clegg, all of UT Southwestern, and Sohaib A. Khan of the University of Cincinnati College of Medicine.

Funding for this work came from the American Heart Association, the National Institutes of Health, USDA and the American Diabetes Association.