Seeking to better understand the key role the female hormone estrogen plays in maintaining energy balance and weight control, a group led by researchers at Baylor College of Medicine looked into estrogen interactions with specific brain regions that provide these anti-obesity benefits.
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.”
“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.”
Tamoxifen is a selective estrogen receptor modulator that has been used for effective treatment of hormone responsive breast cancers for more than 40 years (Jordan, 2003). As an adjuvant, tamoxifen therapy can decrease the incidence of breast cancer recurrence by up to 40% (Davies et al., 2011).
This exceptionally effective therapy remains standard of care for people with hormone-responsive cancers, and reduction of recurrence persists for at least 10 years of continuous tamoxifen treatment (Davies et al., 2013; Chlebowski et al., 2014; Gierach et al., 2017).
In contrast to these benefits, tamoxifen therapy has been associated with a variety of negative side effects, including increased risk for hot flashes (Love et al., 1991; Howell et al., 2005; Francis et al., 2015), endometrial cancer and venous thromboembolic events (Fisher et al., 1998; Cuzick et al., 2007), bone loss (Powles et al., 1996), and fatigue (Haghighat et al., 2003). These responses markedly impact quality of life. Accordingly, ~25% of eligible patients fail to start or complete this life-saving therapy due to side effects and safety concerns (Friese et al., 2013; Berkowitz et al., 2021).
The tissues and cells that mediate these negative side effects remain unclear. Unraveling the cells and mechanisms that mediate the positive effects of tamoxifen from those that mediate the negative side effects is necessary for understanding the multifaceted effects of tamoxifen therapy on physiology. Ultimately, this knowledge could lead to the design of new or adjuvant therapies that circumvent the side effects, improve patient quality of life, and perhaps enhance survival via increased patient compliance.
Within the brain, the hypothalamus and preoptic area (hypothalamus-POA) is highly enriched for estrogen receptor expression and represents an excellent anatomical candidate for mediating many of the side effects of tamoxifen therapy in humans. Estrogen receptor alpha (ERα) signaling regulates body temperature (Bowe et al., 2006; Musatov et al., 2007; Mittelman-Smith et al., 2012; Martínez de Morentin et al., 2014), physical activity (Musatov et al., 2007; Correa et al., 2015; van Veen et al., 2020), and bone density (Farman et al., 2016; Zhang et al., 2016; Herber et al., 2019) through distinct neuronal populations.
Indeed, the hypothalamus-POA is a demonstrated target of tamoxifen, leading to changes in food intake and body weight (Wade and Heller, 1993; López et al., 2006; Lampert et al., 2013) and changes in the hypothalamic-pituitary-ovarian (Wilson et al., 2003; Aquino et al., 2016) and hypothalamic-pituitary-adrenal (Wilson et al., 2003) axes.
Tamoxifen has also been shown to affect gene expression in the hypothalamus; its administration blocks the estrogen dependent induction of the progesterone receptor (Pgr) in the ventromedial hypothalamus (VMH) and increases the expression of estrogen receptor beta (Esr2) in the paraventricular nucleus of the hypothalamus (PVH) (Patisaul et al., 2003; Aquino et al., 2016; Sá et al., 2016).
We hypothesized that tamoxifen alters estrogen receptor signaling in the hypothalamus-POA to mediate key negative side effects of tamoxifen therapy. To test this hypothesis, we modeled tamoxifen treatment in mice with a 28-day treatment course based on human dosage (Slee et al., 1988) and asked if mice experience physiological effects similar to humans.
We measured movement, bone density, and the temperature of the body core, tail skin, and thermogenic brown adipose tissue (BAT). Profiling genome-wide expression changes of individual cells in the hypothalamus-POA using Drop-seq, a droplet-based single-cell RNA sequencing technology, revealed transcriptional changes induced by tamoxifen in multiple cell types.
Finally, we show that ERα expression in the hypothalamus-POA is necessary for the tamoxifen-induced chances in gene expression in the hypothalamus-POA and the effects on thermoregulation, bone density, and movement. Together, these findings suggest that tamoxifen treatment modulates ERα signaling in the central nervous system to alter fundamental aspects of physiology and health. Dissecting central versus peripheral effects and mechanisms of tamoxifen therapy is the first step toward identifying strategies to mitigate the adverse side effects of this life-saving treatment.
reference link :https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7924955/
More information: Hui Ye et al, An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity, Science Advances (2022). DOI: 10.1126/sciadv.abk0185. www.science.org/doi/10.1126/sciadv.abk0185