An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity

Authors: YE, HUI - University Of Illinois; FENG, BING - Pennington Biomedical Research Center; WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); SAITO, KENJI - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); OBRAHIMI, LUCAS - University Of Illinois; SCHAUL, SARAH - University Of Illinois; PATEL, NIRALI - University Of Illinois; SAENZ, LESLIE - University Of Illinois; LUO, PEI - University Of Illinois; LAI, PENGHUA - University Of Illinois; TORRES, VALERIA - University Of Illinois; KOTA, MAYA - University Of Illinois; DIXIT, DEVIN - University Of Illinois; CAI, XING - Children'S Nutrition Research Center (CNRC); QU, NA - Children'S Nutrition Research Center (CNRC); HYSENI, ILIRJANA - Children'S Nutrition Research Center (CNRC); YU, KAIFAN - Children'S Nutrition Research Center (CNRC); JIANG, YUWEI - University Of Illinois; TONG, QINGCHUN - University Of Texas Health Science Center; SUN, ZHENG - Baylor College Of Medicine; ARENKIEL, BENJAMIN - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Pennington Biomedical Research Center; XU, PINGWEN - University Of Illinois; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/23/2021
Publication Date: 1/19/2022
Citation: Ye, H., Feng, B., Wang, C., Saito, K., Yang, Y., Obrahimi, L., Schaul, S., Patel, N., Saenz, L., Luo, P., Lai, P., Torres, V., Kota, M., Dixit, D., Cai, X., Qu, N., Hyseni, I., Yu, K., Jiang, Y., Tong, Q., Sun, Z., Arenkiel, B.R., He, Y., Xu, P., Xu, Y. 2022. An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity. Science Advances. 8(3). Article eabk0185. https://doi.org/10.1126/sciadv.abk0185.
DOI: https://doi.org/10.1126/sciadv.abk0185

Interpretive Summary: Estrogen can activate neurons that express Estrogen receptor–alpha (ER–alpha) to regulate energy balance, including feeding, physical activity and thermogenesis. Brown adipose tissue (BAT) produces heat, and this BAT thermogenesis is important for energy balance. We identified a subpopulation of ER–alpha neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) that project to and activate 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Further, we showed that activation of this ER–alpha**vlVMH to 5-HTDRN circuit can increase BAT thermogenesis and physical activity, which is an important mechanism for the regulation of energy balance.

Technical Abstract: Estrogen receptor–alpha (ER-alpha) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ER-alpha**vlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ER-alpha**vlVMH neurons. We found that selective activation of ER-alpha**vlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ER-alpha**vlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ER-alpha**vlVMH to DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HT**DRN neurons mediate the stimulatory effects of ER-alpha**vlVMH neurons on BAT thermogenesis and physical activity and that ER-alpha expressed by DRN-projecting ER-alpha**vlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ER-alpha**vlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HT**DRN neurons.