Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

Cao, Xuehong; Xu, Pingwen; Oyola, Mario G.; Xia, Yan; Yan, Xiao; Saito, Kenji; Zou, Feng-Cai; Wang, Chunmei; Yang, Yongjie; Hinton, Antentor; Yan, Cui‐Wei; Ding, Hongfang; Zhu, Liangru; Yu, Likai; Yang, Bin; Feng, Yi; Clegg, Deborah J.; Khan, Sohaib A.; DiMarchi, Richard D.; Mani, Shaila K.; Tong, Qingchun; Xu, Yong

doi:10.1172/jci74726

Cited by 109 publications

(115 citation statements)

References 52 publications

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“…Thus, PPT effects are likely mediated directly via ERα expressed by MeA SIM1 neurons. These findings are consistent with earlier observations that estrogens directly activate other neural populations (12,35,36). Furthermore, we tested the physiological functions of MeA SIM1 neural activation via the DRE-ADD approach.…”

Section: Mea Erα Prevents Dio In Malessupporting

confidence: 93%

“…One major finding of our study is that both male and female SIM1-ERα-KO to increased food intake in female mice (7). Furthermore, ERα expressed in the NTS (10), POAH (11), and DRN (11,12) is also implicated in the regulation of feeding in females. Collectively, these findings support a scenario where ERα populations in female brains are functionally segregated.…”

Section: Discussionmentioning

confidence: 70%

“…After several washes, sections were incubated overnight at room temperature with the primary antibodies, which were rabbit Living Colors DsRed polyclonal antibody (1:1,000; Clontech) or rabBehavioral tests for anxiety. An independent cohort of SIM1-ERα-KO and control littermates (both males and females, 8 weeks of age) were subjected to the open field tests, the light-dark tests, and the elevated plus maze tests, as we did before (12). Note that all the behavioral tests were performed at around 9 am-10 am during the light cycles.…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, deletion of Esr1 in female VMH neurons leads to decreased energy expenditure associated with reductions in the resting metabolic rate and thermogenesis, but this deletion does not affect food intake (7)(8)(9). In addition, ERα expressed in the nucleus of solitary tract (NTS) of the brainstem (10), in the preoptic anterior hypothalamus (POAH) (11), and in the dorsal raphe nucleus (DRN) (11,12) is implicated in the regulation of feeding in females.…”

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor–α in medial amygdala neurons regulates body weight

Xu¹,

Cao²,

He³

et al. 2015

J. Clin. Invest.

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Section: Mea Erα Prevents Dio In Malessupporting

confidence: 93%

Section: Discussionmentioning

confidence: 70%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor–α in medial amygdala neurons regulates body weight

Xu¹,

Cao²,

He³

et al. 2015

J. Clin. Invest.

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“…A model in which specific regions of the brain mediate the anabolic effects of ERα are further supported by the demonstration that deletion of Esr1 from pro-opiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) produces weight gain in female mice due to chronic hyperphagia (7). Regulation of food intake has been attributed to ERα expression in the preoptic anterior hypothalamus (POAH) (8), the dorsal raphe nucleus (DRN) (9), and the nucleus of the solitary tract (NTS) (10) of the hindbrain. While ERα expression in specific neurons and brain regions account for changes in heat production and food intake, the ERα-expressing neurons that alter physical activity have yet to be elucidated.…”

Section: Estrogen Receptor α and Body Weight Homeostasismentioning

confidence: 99%

Hypoactivity following perturbed estrogen signaling in the medial amygdala

Li¹,

Krashes²

2015

J. Clin. Invest.

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C o m m e n t a r y2 5 Estrogen receptor α and body weight homeostasisDecades of research have revealed that estrogen and its downstream target, estrogen receptor α (ERα, encoded by ESR1), are important mediators of body weight homeostasis (1-3). Multiple studies have demonstrated that activation of ERα by estrogen regulates food consumption, energy expenditure, and fat distribution (4-6). Importantly, these substantial alterations in energy balance are governed by neural mechanisms, as loss of ERα expression in the CNS impairs multiple facets of homeostatic equilibrium (7). Compared with control animals, mice with a CNS-specific ERα deficiency display increased body weight, adiposity, and visceral fat distribution as the result of hyperphagia, as well as decreased heat production and physical activity. Previous studies have aimed to anatomically pinpoint and dissect specific functions of ERα in distinct regions of the brain. Deletion of Esr1 in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) increases weight gain in female mice due to decreased energy expenditure through a reduction of resting metabolic rate and thermogenesis but no differences in physical activity or energy intake (7). A model in which specific regions of the brain mediate the anabolic effects of ERα are further supported by the demonstration that deletion of Esr1 from pro-opiomelanocortin (POMC) neurons of the arcuate nucleus of the hypothalamus (ARC) produces weight gain in female mice due to chronic hyperphagia (7). Regulation of food intake has been attributed to ERα expression in the preoptic anterior hypothalamus (POAH) (8), the dorsal raphe nucleus (DRN) (9), and the nucleus of the solitary tract (NTS) (10) of the hindbrain. While ERα expression in specific neurons and brain regions account for changes in heat production and food intake, the ERα-expressing neurons that alter physical activity have yet to be elucidated. In this issue, Xu et al. demonstrate that targeted deletion of Ers1 from single-minded-1 (SIM1) neurons, which are abundantly expressed in the medial amygdala (MeA), causes hypoactivity and obesity in both male and female mice (11). Metabolic consequences of ERα deficiency in SIM1 neuronsXu et al. explored potential areas of the brain that coexpress ERα and the transcription factor SIM1 by systematically quantifying overlap, and they deduced that the most abundant SIM1-expressing ERα neurons are located in the MeA (~80%) in both males and females (11). Interestingly, the number of SIM1-expressing ERα neurons in the MeA was higher in males (~7,000) compared with females (~4,000), a discrepancy that may account for disparate phenotypes between sexes. Although ERα-expressing SIM1 neurons were found in the paraventricular hypothalamic nucleus (PVN) and POAH, colocalization of SIM1 and ERα was minimal in these regions, compared with the MeA.Having located the anatomical sites of intersectional SIM1 and ERα expression, Xu and colleagues selectively deleted Esr1 from SIM1-expressing neurons (S...

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SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit

Li,

Kim,

Jiang

et al. 2024

Advanced Science

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SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction‐associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron‐specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1‐null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1‐expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic‐onset or adult‐onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN‐projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN‐projecting PVHSH2B1 neurons protects against diet‐induced obesity. SH2B1 binds to TrkB and enhances brain‐derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.

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Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice

Cited by 109 publications

References 52 publications

Estrogen receptor–α in medial amygdala neurons regulates body weight

Estrogen receptor–α in medial amygdala neurons regulates body weight

Hypoactivity following perturbed estrogen signaling in the medial amygdala

SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit

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