Estrogen-regulated brain circuit helps females control obesity

The team reveals in the journal Science Advances an estrogen-activated neurocircuit that stimulates thermogenesis, or body heat production, and physical activity in animal models. The circuit begins in neurons located in a region of the hypothalamus called the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH). These neurons interact with estrogen via estrogen receptor-alpha (ER-alpha) and respond to the hormone by connecting to and communicating with serotonin-producing neurons located in another brain region called dorsal raphe nucleus (DRN).

The circuit not only responds to estrogen, but also to changes in ambient temperature and in the nutritional status of the animal. Interestingly, the circuit seems to be functional in males but, at this point, its physiological relevance is not clear.

"My lab has long been interested in understanding sex differences in metabolic control," said co-corresponding author Dr. Yong Xu, professor of pediatrics- nutrition and molecular and cellular biology at Baylor. "For instance, before menopause women are typically protected from metabolic problems that may lead to weight gain, when compared to age-matched men. However, after menopause, this benefit seems to disappear. Researchers around the world agree that estrogen is one important player in this benefit."

In previous work, the researchers showed that one of the estrogen receptors, ER-alpha, is expressed in several brain regions, including the v1VMH of the hypothalamus. When v1VMH neurons expressing ER-alpha respond to estrogen, the animals increase thermogenesis and physical activity. Both responses are beneficial as they increase energy expenditure, which can prevent obesity.

"What we didn't know at that time were the neurocircuits that mediate these responses," Xu said. "Using modern neuroscience technology, we identified a neurocircuit that connects ER-alpha-expressing neurons in the vlVMH region with neurons in the DRN region. We confirmed that estrogen-mediated activation of this circuit actually stimulates thermogenesis and physical activity."

The researchers also found that the circuit responds to changes in ambient temperature and in the nutritional status of the animal.

"For example, the circuit can be activated when it's cold, stimulating thermogenesis and physical activity, which would help the animal stay warm," Xu said. "The circuit can be inhibited when the animal is hungry, which would shut down thermogenesis and physical activity, saving energy to adapt to the lack of nutrients."

Xu and his colleagues studied this circuit in females, but also in males.

"We found that the circuit is conserved in males -- they have the same neurons that express ER-alpha and project into the same downstream brain regions. If the circuit is artificially activated in males, the same responses occur -- thermogenesis and physical activity are stimulated. However, we still don't know the role this circuit plays in males. Further studies will help answer this question."

Other contributors to this research are Hui Ye, Bing Feng, Chunmei Wang, Kenji Saito, Yongjie Yang, Lucas Ibrahimi, Sarah Schaul, Nirali Patel, Leslie Saenz, Pei Luo, Penghua Lai, Valeria Torres, Maya Kota, Devin Dixit, Xing Cai, Na Qu, Ilirjana Hyseni, Kaifan Yu, Yuwei Jiang, Qingchun Tong, Zheng Sun, Benjamin R. Arenkiel, Yanlin He and Pingwen Xu. The authors are affiliated with Baylor College of Medicine, the University of Illinois at Chicago, Louisiana State University System or the University of Texas Health Science Center at Houston.

This work was supported by the following grants from National Institutes of Health: P01 DK113954, R01DK117281, R01 DK115761, R01739 DK125480; R01 DK120858, R00 DK107008, R01 DK123098, K01740 DK119471; K01 DK111771; P20 GM135002; R01 DK114279, R21 NS108091, R01 DK109934; Q01ES027544 and R03AG070687. Further support was provided by USDA/CRIS (51000-064-01S), DOD (Innovative Grant W81XWH-19-PRMRP-DA.; DOD W81XWH 9-1-0429), DRTC (The Pilot and Feasibility Award DK020595), and the American Diabetes Association (1-17-PDF-138).