Estrogen receptor–α in medial amygdala neurons regulates body weight
Pingwen XuXuehong CaoYanlin HeLiangru ZhuYongjie YangKenji SaitoChunmei WangXiaofeng YanAntentor HintonFang ZouHongfang DingYan XiaChunling YanGang ShuSan‐Pin WuBin YangYuxin FengDeborah J. CleggRichard DeMarchiSA KhanSophia Y. TsaiFrancesco J. DeMayoQi WuQingchun TongYong Xu
90
Citation
50
Reference
10
Related Paper
Citation Trend
Abstract:
Estrogen receptor–α (ERα) activity in the brain prevents obesity in both males and females. However, the ERα-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single-minded–1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels of ERα. Specific deletion of the gene encoding ERα (Esr1) from SIM1 neurons, which are mostly within the MeA, caused hypoactivity and obesity in both male and female mice fed with regular chow, increased susceptibility to diet-induced obesity (DIO) in males but not in females, and blunted the body weight–lowering effects of a glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate. Furthermore, selective adeno-associated virus-mediated deletion of Esr1 in the MeA of adult male mice produced a rapid body weight gain that was associated with remarkable reductions in physical activity but did not alter food intake. Conversely, overexpression of ERα in the MeA markedly reduced the severity of DIO in male mice. Finally, an ERα agonist depolarized MeA SIM1 neurons and increased their firing rate, and designer receptors exclusively activated by designer drug–mediated (DREADD-mediated) activation of these neurons increased physical activity in mice. Collectively, our results support a model where ERα signals activate MeA neurons to stimulate physical activity, which in turn prevents body weight gain.Keywords:
Hypoactivity
Estrogen receptor alpha
Estrogen receptor beta
Estrogen receptor alpha
Estrogen-related receptor alpha
Estrogen-related receptor gamma
Cite
Citations (0)
Estrogen receptor alpha
Estrogen receptor beta
Cite
Citations (0)
The role of the estrogen receptor in the regulation of reproductive functions as well as its localization in reproductive tissues is well established. The estrogen receptor subtypes namely estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2) are the mediators of the physiological responses that are brought about by estrogens. Various mouse models such as the ESR1, ESR2 and ESR1/2 knock-outs have been developed to determine the function of these receptors. Although the reproductive abnormalities of these mouse models have been well characterized, there is limited literature about transgenic mice that were specifically generated to serve as models of endocrine disruption in the ovary. Recently, we generated a transgenic mouse model in which ESR1 is overexpressed in several tissues (ESR1 OE), including the ovaries. The goal is to use these mice as models for endocrine disruption in the ovary. Previous studies using quantitative real-time PCR determined that the mRNA levels of ESR1 were significantly higher in the ESR1 OE mice compared to controls. The unique feature of this model is that it was designed using the doxycycline responsive system, thus giving us the ability to regulate the overexpression of ESR1 by administering doxycycline via food to the mice. In our previous experiment, doxycycline (200 mg/kg) was administered to the mice via food for 5 days. The results showed that there were no differences in the mRNA levels between ESR1 OE and controls, hence confirming that doxycycline treatment did indeed shut-off overexpression of ESR1. Although our ultimate goal is to determine whether overexpression of ESR1 during development results in aberrant responses to endogenous hormones or exogenous chemicals later as adults, it is necessary to first characterize this mouse model to build a foundation to design future experiments. Since ESR1 can regulate transcription of several genes, we hypothesized that ESR1 OE in the ovary alters expression of ESR2, aryl hydrocarbon receptor (AhR), androgen receptor (AR), progesterone receptor (PR), luteinizing hormone receptor (LHR) as well as follicle-stimulating hormone receptor (FSHR). The ovaries of the ESR1 OE and controls were isolated and subjected to quantitative real-time PCR using primers for the receptors. The results indicate that the mRNA levels of ESR2 were significantly lower in the ESR1 OE ovaries compared to the controls (control = 1.14 ± 0.02 genomic equivalents (ge); ESR1 OE = 0.47 ± 0.01 ge; n = 3; p ≤ 0.05). The mRNA levels of AhR as well as AR were significantly higher in ESR1 OE compared to controls (AhR mRNA levels in control = 0.23 ± 0.02 ge; ESR1 OE = 0.49 ± 0.09 ge; n = 4; p ≤ 0.05; AR mRNA levels in control = 0.78 ± 0.08 ge; ESR1 OE = 1.13 ± 0.23 ge; n = 4; p ≤ 0.05). However, the mRNA levels of PR, LHR and FSHR in ESR1 OE were not significantly different from controls (PR mRNA levels in control = 0.92 ± 0.54 ge; ESR1 OE = 0.92 ± 0.82 ge; n = 4; p = 0.1; LHR mRNA levels in control = 0.42 ± 0.36 ge; ESR1 OE = 0.42 ± 0.15 ge; n = 4; p = 0.65; FSHR mRNA levels in control = 1.18 ± 0.18 ge; ESR1 OE = 1.37 ± 0.26 ge; n = 4; p = 0.27). These data suggest possible cross-talk between ESR1 and AhR as well as AR in gene regulation. Support: NIH R21ES13061
Estrogen receptor alpha
Estrogen receptor beta
Alpha (finance)
Cite
Citations (0)
Estrogen receptor alpha
Estrogen receptor beta
Alpha (finance)
Cite
Citations (6)
Although callous-unemotional (CU) traits have been associated with amygdala hypoactivity, it is unclear whether such traits are associated with amygdala structure. This study examines the relationship between amygdala structure and CU traits and considers sex differences in hemisphere-related asymmetries in this relationship. In this brain imaging study of children ( n = 272), a significant sex × hemisphere × CU traits interaction was observed. Females with high CU traits and males with low CU exhibited a rightward exaggerated amygdala volume asymmetry, whereas females with low CU traits and males with high CU traits did not. Findings may reflect sex-related influences related to CU traits and amygdala volume and are broadly consistent with a neurodevelopment perspective on psychopathic-like traits in children.
Hypoactivity
Cite
Citations (7)
Abstract Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-β (ERβ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERβ-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERβ-inactivated than in WT mice, demonstrating that ERβ reduces estrogen receptor-α (ERα)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERα-inactivated mice was intermediate between that seen in WT and ERαβ double-inactivated mice. Thus, ERβ inhibits ERα-mediated gene transcription in the presence of ERα, whereas, in the absence of ERα, it can partially replace ERα. In conclusion, our in vivo data indicate that an important physiological role of ERβ is to modulate ERα-mediated gene transcription supporting a “Ying Yang” relationship between ERα and ERβ in mice.
Estrogen receptor alpha
Estrogen receptor beta
Hormone response element
Cite
Citations (476)
Estrogen receptors(ERs),belonging to the nuclear receptor superfamily,mainly include ER-α66,ER-α36,ER-α46 and ER-β.Each of them performs specific functions by binding to its ligand such as estrogen.Recently,ER-α36,a novel variant of human estrogen receptor-alpha(ER-α) was identified and cloned.ER-α36 primarily localizes to the plasma membrane and cytoplasma and inhibits the transactivation of both ER-α66 and ER-β.Being predominantly a membrane-based ER,it mediates non-genomic estrogen signaling and involves in resistance to endocrine therapy such as tamoxifen in breast cancer.
Estrogen receptor alpha
Estrogen receptor beta
Estrogen-related receptor gamma
PELP-1
Cite
Citations (0)
Estrogen receptor alpha
Estrogen receptor beta
Estrogen-related receptor gamma
Cite
Citations (38)
Estrogen receptor alpha
Estrogen receptor beta
Cite
Citations (5)