To better understand the key role the female hormone estrogen plays in maintaining energy balance and weight control, a team led by researchers at the Baylor College of Medicine has been looking into estrogen interactions with specific brain regions that provide these anti-obesity benefits. The group reports (“An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity”) in Science Advances that an estrogen-activated neurocircuit stimulates thermogenesis, or body heat production, and physical activity in mouse 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.

“Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) 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 ERαvlVMH neurons,” write the investigators.

“We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). “Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HTDRN neurons mediate the stimulatory effects of ERαvlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERαvlVMH neurons is required for the maintenance of energy balance.

“Together, these findings support a model that ERαvlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HTDRN neurons.”

“My lab has long been interested in understanding sex differences in metabolic control,” said co-corresponding author Yong Xu, MD, PhD, 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.”

Research in previous studies

In previous work, the scientists 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, and 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,” he continued. “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.”