Nature: The neural circuit mechanism of estrogen driving an active lifestyle

Click on the blue letters to pay attention to the estrogen in our hypothalamus that regulates food intake, energy consumption, and can redistribute white adipose tissue
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Estrogen in skeletal muscle, liver, adipose tissue and immune cells is related to insulin sensitivity and lipid accumulation
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Estrogen deficiency promotes metabolic dysfunction, which can lead to low activity, obesity, metabolic syndrome, and type 2 diabetes
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The estrogen-sensitive neurons in the ventrolateral ventromedial nucleus of the hypothalamus (VMHvl) can promote the redistribution of energy by estrogen in female mice
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On October 13, 2021, the Holly A.
Ingraham research team at the University of California, San Francisco School of Medicine found that sedentary behavior (activity that takes the dominant posture as sitting or lying) after knocking out estrogen causes chronic activation of VMHvl brain regions Neurons expressing melanocortin 4 receptor or estrogen receptor-α can reverse the above-mentioned obstacles
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Changes in behavior after specifically knocking out estrogen receptor-α on hypothalamic neurons.
Researchers used the AAV-cre virus binding tool to specifically knock out estrogen receptor-α expressed by neurons in the VMHvl region of female mice.
(Referred to as VMHvl-ERα neuron) after weight gain, nocturnal activity decreases; but knocking out the estrogen receptor-α in the arcuate nucleus of the hypothalamus does not cause this change
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Injection of estradiol benzoate (estrogens) in ovariectomized female mice (OVX, which mainly secretes estrogen) can cause VMHvl-ERα neurons to respond to increased estrogen levels, which is specifically phosphorylated The expression of ribosomal protein S6 (pS6), while the expression of pS6 in female mice is almost unchanged after ERα is knocked out, which indicates that VMHvl-ERα neurons are more sensitive to estrogen, and this sensitivity may depend on ERα
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Why are VMHvl-ERα neurons so sensitive to estrogen? The differential gene expression of VMHvl-ERα neurons in ovariectomized mice after receiving blank solution and estradiol was compared by single-cell sequencing, and it was found that the expression of melanocortin 4 receptor (MCR4) was enriched
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During the pre-estrus period, the expression of Mc4r in female mice was significantly increased (high levels of estrogen during this period), and when the expression of estrogen was low, the expression of Mc4r was lower, which indicates that the expression of Mc4r is regulated by estrogen
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MCR4 plays a key role in appetite control and weight regulation, and the mutation causes obesity
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MCR4 is expressed in the ventromedial nucleus of the hypothalamus and is involved in regulating movement
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Its agonists can be used for the treatment of obesity and sexual dysfunction
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The researchers further discovered that Mc4r gene is the direct transcription target of ERa through the latest protein-DNA interaction technology CUT&RUN, and estrogen can regulate the expression of MCR4 through its receptor Erα
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Chronically activate the neurons expressing MCR4 in the brain area of ​​VMHvl through chemical genetics technology.
After chronically activating the neurons expressing MCR4 in the brain area of ​​VMHvl, female and male mice are more active.

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Overexpression of VMHvl brain area MCR4 can also promote the activities of female mice
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After inhibiting this type of neuron, when it should be active at night, the mice chose not to consume energy behavior-sitting for a long time, the activity behavior was significantly reduced
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Ovariectomized female mice are also reluctant to move, but after activating the neurons in the brain area of ​​VMHvl that express MCR4, they can promote their activity
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This indicates that activating the neurons expressing MCR4 in the brain region of VMHvl can compensate for the deficiency of estrogen
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MCR4-expressing neurons in VMHvl brain area projected to virus tracing experiments.
It was found that MCR4-expressing neurons in VMHvl brain area projected to the dorsal hippocampus CA1 area, hippocampus, and periaqueductal gray matter (PAG)
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In summary, this article reveals that there is a type of estrogen-sensitive neurons in the hypothalamus that project to the hippocampus and hindbrain.
This type of neuron allows female mice to rebalance the energy metabolism of estrogen and promote spontaneous activity
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[References] https://doi.
org/10.
1038/s41586-021-04010-3 The pictures in the article are from the references