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Editor | Xi Excessive eating is a major cause of obesity.
In the past 50 years, with the changes in people's diet and life>
However, due to the genetic diversity of the population, there seems to be a group of "thin people who will never gain weight" around us, suggesting the existence of "obese genes".
The strongest genetic risk factor currently known to be associated with obesity in the population is single nucleotide polymorphisms (SNPs) located in the non-coding region of the FTO gene.
Two breakthrough papers published around 2014 link FTO to the neighboring IRX3 and IRX5 genes: In human brains and fat cells, the FTO gene locus and the IRX3 and IRX5 gene locus have long-distance interactions in the three-dimensional chromosomal structure.
At the same time, Irx3-deficient mice have phenotypes such as thin body, low fat content, and high energy consumption [1,2].
These results suggest that Irx3 and Irx5 are functional "obesity genes" that regulate body composition and energy metabolism.
However, how they regulate energy metabolism is currently unclear.
On the other hand, these studies also found that Irx3 is highly expressed in the arcuate nucleus and arcuate nucleus-median eminence (ARC-ME) of the hypothalamus, the regulating center of energy metabolism.
This rice-sized area not only contains important neurons that can regulate appetite, such as AgRP/NPY and POMC/CART neurons, but also because it is adjacent to the third ventricle (3V) and can come in contact with the circulatory system A variety of hormones, such as leptin (leptin) and so on.
During the growth and development of mice, the neurogenesis of the hypothalamus reaches its peak around E12.
5 days of embryonic stage, and more and more studies have shown that there are a large number of new neurons in this area within 4 weeks after birth.
Produce and participate in the remodeling of the arcuate nucleus of the hypothalamus [3], thereby affecting the regulation of eating and energy metabolism [5].
This phenomenon is believed to be related to a specially differentiated glial cell called tanycyte [4], but the specific mechanism involved still needs further exploration.
Recently, the Chi-Chung Hui research group from the University of Toronto and the Toronto Sick Children’s Hospital published a research paper titled lrx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin response on Nature Metabolism, and discovered the effects of Irx3 and Irx5 The body's response to leptin and the regulation of eating have revealed an important connection with Irx3 and Irx5 in the regulation of postnatal neurogenesis in the hypothalamus.
Irx3 and Irx5 are members of the same transcription factor family, and they have important and partially overlapping roles in the development of multiple organs in mice.
Therefore, mice lacking Irx3 or Irx5 are physically weak, making these mice not the best model for studying the role of Irx3 or Irx5 in energy metabolism.
This paper established for the first time that a double-heterozygous mouse (Irx3/5 double-heterozygous, Irx3/5dHet) with Irx3 and Irx5 knocked out on the same chromosome simulates the state of low IRX3 and IRX5 expression in the population.
The author found that Irx3/5dHet mice had a lighter body weight and lower body fat content than the wild type without significant developmental delay.
This phenomenon is mainly derived from two aspects: the increase in energy consumption and the decrease in food intake-the former is caused by fat thermogenesis, and the latter is related to the susceptibility to leptin.
It is worth noting that leptin tolerance and strong appetite are one of the main symptoms in obese patients.
At the same time, the authors found that in the arcuate nucleus region of the hypothalamus of adult Irx3/5dHet mice, the number of neurons that respond to leptin and control appetite increased significantly compared to wild-type, and revealed that this is in contrast to more neuronal production after birth related.
Irx3 and Irx5 are expressed in a layer of cells close to the edge of the third ventricle.
Therefore, the author further used Ins2-Cre, which can specifically label these cells, to explore the functions of Irx3 and Irx5.
Through lineage tracking and single-cell RNA sequencing experiments, the author discovered a new type of radial glia-like cells in the hypothalamus.
It is worth noting that these radial glial cells not only highly express Irx3 and Irx5, but are also highly similar to the known neural stem cells in the subventricular zone (SVZ) of the lateral ventricle.
At the same time, single-cell RNA sequencing analysis methods such as RNA velocity also show that this kind of radial glial cells have the potential to continue to differentiate into stretched cells and neurons, suggesting that Irx3 and Irx5 are the key factors affecting the process of differentiation into neurons.
.
In order to study the effect of Irx3 function in radial glial cells on postnatal neurogenesis and energy metabolism, the authors constructed a mouse model that specifically knocked out Irx3 in Ins2-Cre-labeled cells (Ins2-Cre; Irx3KO) .
These mice are also lean and have a low body fat rate, eat less food and are more susceptible to leptin.
The most important thing is that they also have more neurons produced after birth, which further illustrates the Irx3 in radial glial cells.
It is essential for the neurogenesis of the hypothalamus after birth.
In summary, the author elaborated on the regulatory role of Irx3 and Irx5 as functional "obesity genes" in hypothalamic neurogenesis-reducing their expression will promote postnatal neurogenesis in the hypothalamus and produce more responsive leptin The neurons in the body ultimately affect the body’s eating and energy metabolism (below).
At the same time, the study found for the first time a new type of radial glial cells expressing Irx3 and Irx5 in the hypothalamus, which also provides a new research basis and direction for the in-depth exploration of the functional molecular mechanisms of the two in the future.
Joe Eun Son and Zhengchao Dou are the co-first authors of this article.
The research team of Chi-Chung Hui published Obesity-associated variants within FTO form long-range functional connections with IRX3 in Nature in 2014 and Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation in Cell Research in 2017.
of macrophage, another important achievement in the field of energy metabolism research.
Professor Xi Huang from the University of Toronto and Toronto Sick Children's Hospital, Professor Li Xuejun, Dr.
Wang Gou Siyi, and the team from Central South University and Hunan Brain Tumor International Technology Innovation Cooperation Base have made important contributions to the research. Original link: https://doi.
org/10.
1038/s42255-021-00382-y Platemaker: 11 References 1.
Smemo, S.
et al.
Obesity-associated variants within FTO form long-range functional connections with IRX3 Nature 507, 371-375 (2014) 2.
Claussnitzer, M.
et al.
FTO obesity variant circuitry and adipocyte browning in humans.
N.
Engl.
J.
Med.
373, 895–907 (2015) 3.
McNay , DE et al.
Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice.
J.
Clin.
Invest.
122, 142–152 (2012).
4.
Lee, DA et al.
Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.
Nat.
Neurosci.
15, 700–702 (2012).
5.
Kokoeva, MV et al.
Neurogenesis in the hypothalamus of adult mice: potential role in energy balance.
Science 310, 679–683 (2005 ).
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 and offenders must be investigated.
In the past 50 years, with the changes in people's diet and life>
However, due to the genetic diversity of the population, there seems to be a group of "thin people who will never gain weight" around us, suggesting the existence of "obese genes".
The strongest genetic risk factor currently known to be associated with obesity in the population is single nucleotide polymorphisms (SNPs) located in the non-coding region of the FTO gene.
Two breakthrough papers published around 2014 link FTO to the neighboring IRX3 and IRX5 genes: In human brains and fat cells, the FTO gene locus and the IRX3 and IRX5 gene locus have long-distance interactions in the three-dimensional chromosomal structure.
At the same time, Irx3-deficient mice have phenotypes such as thin body, low fat content, and high energy consumption [1,2].
These results suggest that Irx3 and Irx5 are functional "obesity genes" that regulate body composition and energy metabolism.
However, how they regulate energy metabolism is currently unclear.
On the other hand, these studies also found that Irx3 is highly expressed in the arcuate nucleus and arcuate nucleus-median eminence (ARC-ME) of the hypothalamus, the regulating center of energy metabolism.
This rice-sized area not only contains important neurons that can regulate appetite, such as AgRP/NPY and POMC/CART neurons, but also because it is adjacent to the third ventricle (3V) and can come in contact with the circulatory system A variety of hormones, such as leptin (leptin) and so on.
During the growth and development of mice, the neurogenesis of the hypothalamus reaches its peak around E12.
5 days of embryonic stage, and more and more studies have shown that there are a large number of new neurons in this area within 4 weeks after birth.
Produce and participate in the remodeling of the arcuate nucleus of the hypothalamus [3], thereby affecting the regulation of eating and energy metabolism [5].
This phenomenon is believed to be related to a specially differentiated glial cell called tanycyte [4], but the specific mechanism involved still needs further exploration.
Recently, the Chi-Chung Hui research group from the University of Toronto and the Toronto Sick Children’s Hospital published a research paper titled lrx3 and Irx5 in Ins2-Cre+ cells regulate hypothalamic postnatal neurogenesis and leptin response on Nature Metabolism, and discovered the effects of Irx3 and Irx5 The body's response to leptin and the regulation of eating have revealed an important connection with Irx3 and Irx5 in the regulation of postnatal neurogenesis in the hypothalamus.
Irx3 and Irx5 are members of the same transcription factor family, and they have important and partially overlapping roles in the development of multiple organs in mice.
Therefore, mice lacking Irx3 or Irx5 are physically weak, making these mice not the best model for studying the role of Irx3 or Irx5 in energy metabolism.
This paper established for the first time that a double-heterozygous mouse (Irx3/5 double-heterozygous, Irx3/5dHet) with Irx3 and Irx5 knocked out on the same chromosome simulates the state of low IRX3 and IRX5 expression in the population.
The author found that Irx3/5dHet mice had a lighter body weight and lower body fat content than the wild type without significant developmental delay.
This phenomenon is mainly derived from two aspects: the increase in energy consumption and the decrease in food intake-the former is caused by fat thermogenesis, and the latter is related to the susceptibility to leptin.
It is worth noting that leptin tolerance and strong appetite are one of the main symptoms in obese patients.
At the same time, the authors found that in the arcuate nucleus region of the hypothalamus of adult Irx3/5dHet mice, the number of neurons that respond to leptin and control appetite increased significantly compared to wild-type, and revealed that this is in contrast to more neuronal production after birth related.
Irx3 and Irx5 are expressed in a layer of cells close to the edge of the third ventricle.
Therefore, the author further used Ins2-Cre, which can specifically label these cells, to explore the functions of Irx3 and Irx5.
Through lineage tracking and single-cell RNA sequencing experiments, the author discovered a new type of radial glia-like cells in the hypothalamus.
It is worth noting that these radial glial cells not only highly express Irx3 and Irx5, but are also highly similar to the known neural stem cells in the subventricular zone (SVZ) of the lateral ventricle.
At the same time, single-cell RNA sequencing analysis methods such as RNA velocity also show that this kind of radial glial cells have the potential to continue to differentiate into stretched cells and neurons, suggesting that Irx3 and Irx5 are the key factors affecting the process of differentiation into neurons.
.
In order to study the effect of Irx3 function in radial glial cells on postnatal neurogenesis and energy metabolism, the authors constructed a mouse model that specifically knocked out Irx3 in Ins2-Cre-labeled cells (Ins2-Cre; Irx3KO) .
These mice are also lean and have a low body fat rate, eat less food and are more susceptible to leptin.
The most important thing is that they also have more neurons produced after birth, which further illustrates the Irx3 in radial glial cells.
It is essential for the neurogenesis of the hypothalamus after birth.
In summary, the author elaborated on the regulatory role of Irx3 and Irx5 as functional "obesity genes" in hypothalamic neurogenesis-reducing their expression will promote postnatal neurogenesis in the hypothalamus and produce more responsive leptin The neurons in the body ultimately affect the body’s eating and energy metabolism (below).
At the same time, the study found for the first time a new type of radial glial cells expressing Irx3 and Irx5 in the hypothalamus, which also provides a new research basis and direction for the in-depth exploration of the functional molecular mechanisms of the two in the future.
Joe Eun Son and Zhengchao Dou are the co-first authors of this article.
The research team of Chi-Chung Hui published Obesity-associated variants within FTO form long-range functional connections with IRX3 in Nature in 2014 and Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation in Cell Research in 2017.
of macrophage, another important achievement in the field of energy metabolism research.
Professor Xi Huang from the University of Toronto and Toronto Sick Children's Hospital, Professor Li Xuejun, Dr.
Wang Gou Siyi, and the team from Central South University and Hunan Brain Tumor International Technology Innovation Cooperation Base have made important contributions to the research. Original link: https://doi.
org/10.
1038/s42255-021-00382-y Platemaker: 11 References 1.
Smemo, S.
et al.
Obesity-associated variants within FTO form long-range functional connections with IRX3 Nature 507, 371-375 (2014) 2.
Claussnitzer, M.
et al.
FTO obesity variant circuitry and adipocyte browning in humans.
N.
Engl.
J.
Med.
373, 895–907 (2015) 3.
McNay , DE et al.
Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice.
J.
Clin.
Invest.
122, 142–152 (2012).
4.
Lee, DA et al.
Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.
Nat.
Neurosci.
15, 700–702 (2012).
5.
Kokoeva, MV et al.
Neurogenesis in the hypothalamus of adult mice: potential role in energy balance.
Science 310, 679–683 (2005 ).
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 and offenders must be investigated.
