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Child overweight and obesity are public health issues that cannot be ignored worldwide-it not only affects the normal development of the body, but also increases the occurrence of chronic diseases including type II diabetes
.
Although childhood obesity is closely related to environmental factors such as diet and life>
.
For example, loss-of-function mutations in human SIM1 can cause severe hyperphagia and obesity in children [1]
.
The paraventricular nucleus of the hypothalamus (PVH) contains a complex and diverse group of neurons, which is one of the important centers for regulating eating
.
SIM1 is not only highly expressed in this area, it plays a key role in the development of neurons, but also regulates appetite and eating
.
In mice, insufficient Sim1 haploid dose (Sim1Het mice) will destroy the original neuronal groups of PVH, and the mice will show such traits as binge drinking and binge eating [2]
.
However, we still know very little about the mechanism behind the functional loss of SIM1: Does SIM1 have a synergistic effect with other obesity factors? How does SIM1 regulate eating? How does SIM1 affect the development of PVH neurons? Wait, they are all unresolved issues
.
Recently, the Chi-Chung Hui research group from the University of Toronto and the Toronto Sick Children’s Hospital published an article titled Ectopic expression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to defects in Sim1 haploinsufficiency on Science Advances.
The cellular transcriptome level expounds the diversity of PVH neuronal groups, revealing that the ectopic expression of "obesity factors" Irx3 and Irx5 in PVH is the key mechanism of overeating and obesity in Sim1 haploid mice
.
In order to understand the role of Sim1 in PVH, the researchers systematically described a neuron "map" of PVH in mice
.
Through single-cell RNA sequencing, they found that the Sim1-Cre lineage neurons in PVH can be divided into two major groups-the "Neuron1" group with unknown function and the "Neuron2" group involved in feeding regulation
.
Interestingly, the two have different "responses" to the lack of Sim1 haploid doses: In Sim1Het mice, the number of neurons in the "Neuron1" group that express Cartpt and other genes increased significantly, while the number of neurons marked by Avp, Nos1, etc.
Neuron2" group of neurons is greatly reduced (Figure 1)
.
This discovery not only confirms that Sim1 plays an important role in the development of PVH neurons, but also explains the new mechanism of the lack of Sim1 haploid dosage leading to polyphagia and obesity
.
Figure 1.
Single-cell RNA sequencing of the Sim1-Cre lineage revealed the presence of two main neuronal groups in PVH.
On the other hand, the article found that Irx3 and Irx5 were ectopically expressed in PVH in Sim1Het mice
.
Previous studies have shown that Irx3 and Irx5 are important "obesity factors"
.
Both are usually expressed in the arcuate nucleus and arcuate nucleus-median eminence (ARC-ME) of the hypothalamus, regulating body weight and body fat rate, eating and energy metabolism, leptin response and postnatal neurogenesis, etc.
[3 , 4]
.
Therefore, researchers speculate that the ectopic expression of Irx3 and Irx5 in PVH may be the cause of polyphagia and obesity caused by insufficient Sim1 haploid dose
.
By reducing the expression of Irx3 and Irx5 in Sim1Het mice, they found that the phenotypes such as polyphagia and obesity of Sim1Het mice could be significantly suppressed, and the proportion of disordered neuron groups in PVH was also restored
.
At the same time, specifically knocking out Irx3 in the PVH of Sim1Het mice can "rescue" the abnormalities caused by the insufficient dose of Sim1 haplotypes in terms of PVH neuron groups, food intake, and body weight (Figure 2)
.
This series of results further revealed that Irx3 and Irx5 are key factors involved in feeding regulation and neuronal development, providing new ideas for obesity treatment
.
Figure 2.
In the PVH of mice with insufficient Sim1 haploid dose, the ectopic expression of Irx3 and Irx5 is a key factor in triggering neuronal development disorders and the appearance of polyphagia, obesity and other traits in mice.
This paper is from Chi-Chung Hui's research group Following the publication of Irx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin sensitivity in Nature Metabolism in early 2021, this is another important achievement in the field of energy metabolism
.
Postdoctoral fellow Joe Eun Son is the first author of this article, Professor Jacques L.
Michaud from the University of Montreal and CHU Ste-Justine Research Center, Professor Xi Huang from the University of Toronto and Toronto Sick Children, Central South University Xiangya Hospital, Hunan Brain Tumor International Technology Professor Li Xuejun, Dr.
Wang Gou Siyi and their team made important contributions to the research
.
Article link: https:// Platemaker: 11 References 1.
A.
Bonnefond, et al.
(2013) Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
J Clin Invest 123, 3037–3041.
2.
JL Michaud, et al.
(2001) Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus.
Hum Mol Genet 10, 1466-14733 .
JE Son, et al.
(2021) Irx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin sensitivity.
Nat Metab 3, 701-713.
4.
Z.
, Dou, JE Son, C.
-C.
Hui.
( 2021) Irx3 and Irx5-Novel regulatory factors of postnatal neurogenesis.
Front Neurosci 15.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Violators Must be investigated
.
.
Although childhood obesity is closely related to environmental factors such as diet and life>
.
For example, loss-of-function mutations in human SIM1 can cause severe hyperphagia and obesity in children [1]
.
The paraventricular nucleus of the hypothalamus (PVH) contains a complex and diverse group of neurons, which is one of the important centers for regulating eating
.
SIM1 is not only highly expressed in this area, it plays a key role in the development of neurons, but also regulates appetite and eating
.
In mice, insufficient Sim1 haploid dose (Sim1Het mice) will destroy the original neuronal groups of PVH, and the mice will show such traits as binge drinking and binge eating [2]
.
However, we still know very little about the mechanism behind the functional loss of SIM1: Does SIM1 have a synergistic effect with other obesity factors? How does SIM1 regulate eating? How does SIM1 affect the development of PVH neurons? Wait, they are all unresolved issues
.
Recently, the Chi-Chung Hui research group from the University of Toronto and the Toronto Sick Children’s Hospital published an article titled Ectopic expression of Irx3 and Irx5 in the paraventricular nucleus of the hypothalamus contributes to defects in Sim1 haploinsufficiency on Science Advances.
The cellular transcriptome level expounds the diversity of PVH neuronal groups, revealing that the ectopic expression of "obesity factors" Irx3 and Irx5 in PVH is the key mechanism of overeating and obesity in Sim1 haploid mice
.
In order to understand the role of Sim1 in PVH, the researchers systematically described a neuron "map" of PVH in mice
.
Through single-cell RNA sequencing, they found that the Sim1-Cre lineage neurons in PVH can be divided into two major groups-the "Neuron1" group with unknown function and the "Neuron2" group involved in feeding regulation
.
Interestingly, the two have different "responses" to the lack of Sim1 haploid doses: In Sim1Het mice, the number of neurons in the "Neuron1" group that express Cartpt and other genes increased significantly, while the number of neurons marked by Avp, Nos1, etc.
Neuron2" group of neurons is greatly reduced (Figure 1)
.
This discovery not only confirms that Sim1 plays an important role in the development of PVH neurons, but also explains the new mechanism of the lack of Sim1 haploid dosage leading to polyphagia and obesity
.
Figure 1.
Single-cell RNA sequencing of the Sim1-Cre lineage revealed the presence of two main neuronal groups in PVH.
On the other hand, the article found that Irx3 and Irx5 were ectopically expressed in PVH in Sim1Het mice
.
Previous studies have shown that Irx3 and Irx5 are important "obesity factors"
.
Both are usually expressed in the arcuate nucleus and arcuate nucleus-median eminence (ARC-ME) of the hypothalamus, regulating body weight and body fat rate, eating and energy metabolism, leptin response and postnatal neurogenesis, etc.
[3 , 4]
.
Therefore, researchers speculate that the ectopic expression of Irx3 and Irx5 in PVH may be the cause of polyphagia and obesity caused by insufficient Sim1 haploid dose
.
By reducing the expression of Irx3 and Irx5 in Sim1Het mice, they found that the phenotypes such as polyphagia and obesity of Sim1Het mice could be significantly suppressed, and the proportion of disordered neuron groups in PVH was also restored
.
At the same time, specifically knocking out Irx3 in the PVH of Sim1Het mice can "rescue" the abnormalities caused by the insufficient dose of Sim1 haplotypes in terms of PVH neuron groups, food intake, and body weight (Figure 2)
.
This series of results further revealed that Irx3 and Irx5 are key factors involved in feeding regulation and neuronal development, providing new ideas for obesity treatment
.
Figure 2.
In the PVH of mice with insufficient Sim1 haploid dose, the ectopic expression of Irx3 and Irx5 is a key factor in triggering neuronal development disorders and the appearance of polyphagia, obesity and other traits in mice.
This paper is from Chi-Chung Hui's research group Following the publication of Irx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin sensitivity in Nature Metabolism in early 2021, this is another important achievement in the field of energy metabolism
.
Postdoctoral fellow Joe Eun Son is the first author of this article, Professor Jacques L.
Michaud from the University of Montreal and CHU Ste-Justine Research Center, Professor Xi Huang from the University of Toronto and Toronto Sick Children, Central South University Xiangya Hospital, Hunan Brain Tumor International Technology Professor Li Xuejun, Dr.
Wang Gou Siyi and their team made important contributions to the research
.
Article link: https:// Platemaker: 11 References 1.
A.
Bonnefond, et al.
(2013) Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features.
J Clin Invest 123, 3037–3041.
2.
JL Michaud, et al.
(2001) Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus.
Hum Mol Genet 10, 1466-14733 .
JE Son, et al.
(2021) Irx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin sensitivity.
Nat Metab 3, 701-713.
4.
Z.
, Dou, JE Son, C.
-C.
Hui.
( 2021) Irx3 and Irx5-Novel regulatory factors of postnatal neurogenesis.
Front Neurosci 15.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights.
Violators Must be investigated
.
