A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia

Qu, Na; He, Yanlin; Wang, Chunmei; Xu, Pingwen; Yang, Yongjie; Cai, Xing; Liu, Hesong; Yu, Kaifan; Zhou, Pei; Hyseni, Ilirjana; Sun, Zheng; Fukuda, Makoto; Li, Yang; Tian, Qing; Xu, Yong

doi:10.1038/s41380-019-0506-1

Cited by 82 publications

(94 citation statements)

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“…This anorectic effect was blocked by the MC4R antagonist. As stress increases the activity of ARC POMC neurons (Liu et al, 2007;Qu et al, 2020) and MC4Rs in the MeA contribute to stress-induced behavior and hypophagia (Liu et al, 2013), the ARC POMC →MeA pathway that we identified may contribute to stress-induced short-term hypophagia.…”

Section: Discussionmentioning

confidence: 79%

“…It is known that fear and stress actively suppress eating. Chronic stress results in reduced body weight and anorexia that is associated with increased ARC POMC neuron activity (Qu et al, 2020 ). This anorectic effect in response to stress appears to be mediated through inhibition by opioids of dopamine-expressing neurons in the ventral tegmental area (VTA; Qu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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Activation of the ARCPOMC→MeA Projection Reduces Food Intake

Kwon

2020

Front. Neural Circuits

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Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) plays an essential role in the control of food intake and energy expenditure. Melanocortin-4 receptors (MC4Rs) are expressed in key areas that are implicated in regulating energy homeostasis. Although the importance of MC4Rs in the paraventricular hypothalamus (PVH) has been well documented, the role of MC4Rs in the medial amygdala (MeA) on feeding remains controversial. In this study, we specifically examine the role of a novel ARC POMC →MeA neural circuit in the regulation of short-term food intake. To map a local melanocortinergic neural circuit, we use monosynaptic anterograde as well as retrograde viral tracers and perform double immunohistochemistry to determine the identity of the neurons receiving synaptic input from POMC neurons in the ARC. To investigate the role of the ARC POMC →MeA projection on feeding, we optogenetically stimulate channelrhodopsin-2 (ChR2)-expressing POMC fibers in the MeA. Anterograde viral tracing studies reveal that ARC POMC neurons send axonal projections to estrogen receptor-α (ER-α)-and MC4R-expressing neurons in the MeA. Retrograde viral tracing experiments show that the neurons projecting to the MeA is located mainly in the lateral part of the ARC. Optogenetic stimulation of the ARC POMC →MeA pathway reduces short-term food intake. This anorectic effect is blocked by treatment with the MC4R antagonist SHU9119. In addition to the melanocortinergic local circuits within the hypothalamus, this extrahypothalamic ARC POMC →MeA neural circuit would play a role in regulating short-term food intake.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Activation of the ARCPOMC→MeA Projection Reduces Food Intake

Kwon

2020

Front. Neural Circuits

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“…ChR2-assisted circuit mapping. We performed the WGA-ChR2-assisted circuit mapping [46][47][48] in order to demonstrate the connectivity of ERα vlVMH neurons and their downstream target neurons in various brain regions. Briefly, 12-week-old Esr1-Cre female mice were anesthetized by isoflurane and received stereotaxic injections of Ad-iN/WED (200 nl, 6.1 × 10 12 VP per ml) and AAV-EF1α-DIO hChR2(H134R)-EYFP (200 nl, 6.2 × 10 12 VP per ml) into the vlVMH.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance

Wang

et al. 2020

Nat Commun

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Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα vlVMH) or glucose-excited neurons (GE-ERα vlVMH). Hypoglycemia activates GI-ERα vlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERα vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα vlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα vlVMH to mpARH circuit and inhibition of ERα vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERα vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.

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“…Primary study showed that the mice exhibited depression-like behavior when POMC neurons in the arcuate nucleus were inhibited. 24 Studies have pointed out that heroin addicts treated with intravenous diacetylmorphine could cause an POMC promoter methylation and reduce the level of stress hormone in the patient's body, thus playing a role in emotional regulation of treatment. 25 In alcohol dependence, POMC promoter methylation is associated with craving.…”

Section: Introductionmentioning

confidence: 99%