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Written by Yin Kaili and Zhang Guo, edited by Guo Sizhen Wang Currently, obesity has become a global public health problem, and the reasons for its occurrence need to be clarified urgently
.
The central nervous system, especially the hypothalamus, is closely related to the regulation of animal energy balance
.
The subgroups of neurons in the hypothalamus, including neurons that produce Agouti-related peptide (AgRP), are all involved in this process [1, 2]
.
On the other hand, maintaining the homeostasis of calcium ions in cells is necessary for cells to perform normal functions [3-5], and store-operated calcium entry (SOCE) [6] plays a role in it.
The key role
.
Previous studies have shown that the disorder of SOCE is closely related to immune, cardiovascular and central nervous system diseases [7]
.
However, the role of SOCE in neurons, especially hypothalamic neurons, in the formation of obesity is still unclear
.
Recently, the team of Professor Zhang Guo and Professor Lu Yisheng from Huazhong University of Science and Technology jointly published a research paper entitled "Deficiency of ER Ca2+ sensor STIM1 in AgRP neurons confers protection against dietary obesity" in Cell Reports
.
Using experimental animal models, the team found that the disorder of calcium ion concentration in hypothalamic neurons is closely related to systemic nutrition; inhibits SOCE in the central nervous system, or inhibits the calcium-sensing molecule Stim1 (Stromal interacting molecule in AgRP neurons).
1) It can effectively resist obesity caused by high-fat food feeding
.
This study revealed a new mechanism for the formation of nutritional obesity
.
The hypothalamus plays a key role in energy balance and the development of obesity
.
So, first of all, is the calcium-sensing molecule Stim1 of SOCE expressed in the hypothalamus? And does the inhibition of SOCE affect the development of nutritional obesity in mice? The team’s research shows that the administration of SOCE inhibitors in the central nervous system of mice can significantly alleviate the excessive weight gain caused by high-fat food feeding, suggesting that central SOCE may play an important role in the formation of obesity
.
In addition, it is known that Stim1 is a key sensor molecule of endoplasmic reticulum calcium ions
.
The team found that the Stim1 protein is expressed in mouse hypothalamic AgRP neurons, and the deletion of the Stim1 gene attenuated the increase in Ca2+ concentration in AgRP neurons caused by overnight fasting (Figure 1)
.
Figure 1.
Loss of Stim1 attenuates the increase in Ca2+ concentration in AgRP neurons caused by overnight fasting (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Based on the above results, the team further studied the induction of Stim1 in AgRP neurons The role of obesity
.
The results showed that destroying Stim1 in AgRP neurons can make mice resistant to obesity induced by high-fat food and alleviate obesity-related abnormal glucose and lipid metabolism (Figure 2)
.
Conversely, activation of Stim1 in AgRP neurons of normal-weight mice can lead to obesity-like phenotypes, including excessive increase in body weight and body fat, and impaired glucose tolerance
.
Figure 2 AgRP neuron deletion Stim1 makes mice resistant to nutritional obesity and related comorbidities (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Figure 3 SOCE and Stim1 regulate the synthesis of peptides in neurons (Figure Source: Zhuo Chen, et al.
, Cell Reports, 2021) The endoplasmic reticulum stress of the hypothalamus plays an important role in the formation of nutritional obesity [8]
.
Excessive protein synthesis, especially the subsequent accumulation of unfolded or misfolded proteins, will induce the endoplasmic reticulum stress response [9]
.
At the same time, both Stim1 and ribosomes are located in the endoplasmic reticulum
.
So, next, whether SOCE or Stim1 will affect specific translation mechanisms, thereby affecting the formation and development of obesity
.
The team’s research shows that SOCE and Stim1 can regulate the expression of ribosomal protein mRNA and rRNA in neurons, thereby realizing the regulation of RNA translation (Figure 3); inhibiting SOCE can activate Oas3 (2′,5′-Oligoadenylate synthetase 3) ) -RNase L signal pathway
.
Finally, the use of virus-mediated genetic manipulation to up-regulate Oas3 in AgRP neurons can make mice significantly resistant to obesity induced by high-fat food (Figure 4)
.
In turn, inhibiting the activity of RNase L in AgRP neurons can significantly reduce the weight loss effect of Stim1 knockout (Figure 4)
.
Figure 4 Overexpression of Oas3 in AgRP neurons can resist diet-induced obesity; inhibition of RNase L in AgRP neurons eliminates the weight loss effect of ASKO (AgRP, Stim1 Knockout) (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Figure 5 Work summary diagram: The role of Stim1-Oas3 signaling pathway in hypothalamic AgRP neurons in the formation of nutritional obesity in mice (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Article conclusions and Discussion, inspiration and outlook The research suggests that targeting hypothalamic SOCE may be a new way of weight loss intervention
.
Of course, this requires further research in the future
.
Such as experiments in primates, and clinical trials
.
In addition, in addition to the Stim protein, the SOCE Ca2+ channel protein Orai, which is located on the cell membrane, is more likely to be a direct target for intervention
.
These all require more in-depth research
.
In summary, the above results indicate that the Stim1-Oas3 signaling pathway in AgRP neurons of the hypothalamus is closely related to nutritional obesity and related metabolic disorders (Figure 5); inhibition of SOCE in the central nervous system can have a similar effect, suggesting that Targeting the central nervous system, including SOCE in AgRP neurons, may be an effective way to lose weight
.
Original link: https://doi.
org/10.
1016/j.
celrep.
2021.
109868 Professor Wang Youjun from Beijing Normal University, Professor Li Juxue from Nanjing Medical University, and Researcher Tang Yizhe from Shenzhen Second People's Hospital provided strong support for this research
.
The research was funded by the National Natural Science Foundation of China and other units
.
Selected articles from previous issues [1] Science︱ is the first to prove in humans that a variety of neurodegenerative diseases can affect the neurogenesis of the hippocampal dentate gyrus [2] Neuron︱ new discovery! The hippocampus playback in the awake state promotes memory function by storing and updating specific past experiences [3] Mol Psychiatry︱ A new discovery of biomarkers for depression-mitochondrial proteins in exosomes [4] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [5] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional heterogeneity of the cerebellar nucleus to thalamus projection [6] J Neurosci︱ Cao Junli’s research group Revealing the loop mechanism of the anterior cingulate gyrus to regulate mirror pain [7] Nat Commun︱Non-human primate (monkey marmoset) autism model reveals the biological abnormalities in the early development of human diseases [8] Cell Discovery︱ Ma Yuanwu/Shen Bin’s team realized the precise editing of rat mitochondrial DNA for the first time [9] Dev Cell︱ Lactic acid promotes peripheral nerve damage and repair B side: Long-term lactic acid metabolism of axons can lead to oxidative stress and axon degeneration [10] Nat Commun︱ Selective inhibition of microglia activation is expected to alleviate pathological α-syn transmission [11] Mol Psychiatry︱ Gao Tianming's research group reveals the different roles of astrocytes and neurons in synaptic plasticity and memory [12] Sci Transl Med︱ Xiang Xianyuan et al.
Reveal the crazy sugar phagocytosis of brain immune cells to help early diagnosis of neurodegenerative diseases [13] A new mechanism of Mol Cell︱ Alzheimer’s disease: Tau protein oligomerization induces RNA-binding protein HNRNPA2B1 nuclear cell transport It also mediates the enhancement of m6A-RNA modification [14] Cereb Cortex | Li Tao's group reported the abnormality of the cortical myelin covariation network with the deep characteristics of the cerebral cortex in schizophrenia [14] Cell︱ holds hands, advances and retreats together! Microglia form a cellular connection network and work together to degrade pathological α-syn.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ Near-infrared brain function data processing class (online: 11.
1~11.
14) [2] Data map help guide! How good is it to learn these software? 【3】JAMA Neurol︱Attention! Young people are more likely to suffer from "Alzheimer's disease"? [4] Patch clamp and optogenetics and calcium imaging technology seminar (October 30-31) References (slide up and down to view) [1] Gautron L, Elmquist JK, Williams KW.
Neural control of energy balance: translating circuits to therapies.
Cell.
2015; 161:133-145.
[2] Morton GJ, Meek TH, Schwartz MW.
Neurobiology of food intake in health and disease.
Nat Rev Neurosci.
2014; 15:367-78.
[3] Arruda AP, Hotamisligil GS.
Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes.
Cell Metab.
2015; 22:381-97.
[4] Berridge MJ, Lipp P, Bootman MD.
The versatility and universality of calcium signalling.
Nat Rev Mol Cell Biol.
2000; 1:11-21.
[5] Schrank S, Barrington N, Stutzmann GE.
Calcium-Handling Defects and Neurodegenerative Disease.
Cold Spring Harb Perspect Biol.
2020; 12:a035212.
[6] Putney JW Jr.
A model for receptor-regulated calcium entry.
.
The central nervous system, especially the hypothalamus, is closely related to the regulation of animal energy balance
.
The subgroups of neurons in the hypothalamus, including neurons that produce Agouti-related peptide (AgRP), are all involved in this process [1, 2]
.
On the other hand, maintaining the homeostasis of calcium ions in cells is necessary for cells to perform normal functions [3-5], and store-operated calcium entry (SOCE) [6] plays a role in it.
The key role
.
Previous studies have shown that the disorder of SOCE is closely related to immune, cardiovascular and central nervous system diseases [7]
.
However, the role of SOCE in neurons, especially hypothalamic neurons, in the formation of obesity is still unclear
.
Recently, the team of Professor Zhang Guo and Professor Lu Yisheng from Huazhong University of Science and Technology jointly published a research paper entitled "Deficiency of ER Ca2+ sensor STIM1 in AgRP neurons confers protection against dietary obesity" in Cell Reports
.
Using experimental animal models, the team found that the disorder of calcium ion concentration in hypothalamic neurons is closely related to systemic nutrition; inhibits SOCE in the central nervous system, or inhibits the calcium-sensing molecule Stim1 (Stromal interacting molecule in AgRP neurons).
1) It can effectively resist obesity caused by high-fat food feeding
.
This study revealed a new mechanism for the formation of nutritional obesity
.
The hypothalamus plays a key role in energy balance and the development of obesity
.
So, first of all, is the calcium-sensing molecule Stim1 of SOCE expressed in the hypothalamus? And does the inhibition of SOCE affect the development of nutritional obesity in mice? The team’s research shows that the administration of SOCE inhibitors in the central nervous system of mice can significantly alleviate the excessive weight gain caused by high-fat food feeding, suggesting that central SOCE may play an important role in the formation of obesity
.
In addition, it is known that Stim1 is a key sensor molecule of endoplasmic reticulum calcium ions
.
The team found that the Stim1 protein is expressed in mouse hypothalamic AgRP neurons, and the deletion of the Stim1 gene attenuated the increase in Ca2+ concentration in AgRP neurons caused by overnight fasting (Figure 1)
.
Figure 1.
Loss of Stim1 attenuates the increase in Ca2+ concentration in AgRP neurons caused by overnight fasting (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Based on the above results, the team further studied the induction of Stim1 in AgRP neurons The role of obesity
.
The results showed that destroying Stim1 in AgRP neurons can make mice resistant to obesity induced by high-fat food and alleviate obesity-related abnormal glucose and lipid metabolism (Figure 2)
.
Conversely, activation of Stim1 in AgRP neurons of normal-weight mice can lead to obesity-like phenotypes, including excessive increase in body weight and body fat, and impaired glucose tolerance
.
Figure 2 AgRP neuron deletion Stim1 makes mice resistant to nutritional obesity and related comorbidities (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Figure 3 SOCE and Stim1 regulate the synthesis of peptides in neurons (Figure Source: Zhuo Chen, et al.
, Cell Reports, 2021) The endoplasmic reticulum stress of the hypothalamus plays an important role in the formation of nutritional obesity [8]
.
Excessive protein synthesis, especially the subsequent accumulation of unfolded or misfolded proteins, will induce the endoplasmic reticulum stress response [9]
.
At the same time, both Stim1 and ribosomes are located in the endoplasmic reticulum
.
So, next, whether SOCE or Stim1 will affect specific translation mechanisms, thereby affecting the formation and development of obesity
.
The team’s research shows that SOCE and Stim1 can regulate the expression of ribosomal protein mRNA and rRNA in neurons, thereby realizing the regulation of RNA translation (Figure 3); inhibiting SOCE can activate Oas3 (2′,5′-Oligoadenylate synthetase 3) ) -RNase L signal pathway
.
Finally, the use of virus-mediated genetic manipulation to up-regulate Oas3 in AgRP neurons can make mice significantly resistant to obesity induced by high-fat food (Figure 4)
.
In turn, inhibiting the activity of RNase L in AgRP neurons can significantly reduce the weight loss effect of Stim1 knockout (Figure 4)
.
Figure 4 Overexpression of Oas3 in AgRP neurons can resist diet-induced obesity; inhibition of RNase L in AgRP neurons eliminates the weight loss effect of ASKO (AgRP, Stim1 Knockout) (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Figure 5 Work summary diagram: The role of Stim1-Oas3 signaling pathway in hypothalamic AgRP neurons in the formation of nutritional obesity in mice (Source: Zhuo Chen, et al.
, Cell Reports, 2021) Article conclusions and Discussion, inspiration and outlook The research suggests that targeting hypothalamic SOCE may be a new way of weight loss intervention
.
Of course, this requires further research in the future
.
Such as experiments in primates, and clinical trials
.
In addition, in addition to the Stim protein, the SOCE Ca2+ channel protein Orai, which is located on the cell membrane, is more likely to be a direct target for intervention
.
These all require more in-depth research
.
In summary, the above results indicate that the Stim1-Oas3 signaling pathway in AgRP neurons of the hypothalamus is closely related to nutritional obesity and related metabolic disorders (Figure 5); inhibition of SOCE in the central nervous system can have a similar effect, suggesting that Targeting the central nervous system, including SOCE in AgRP neurons, may be an effective way to lose weight
.
Original link: https://doi.
org/10.
1016/j.
celrep.
2021.
109868 Professor Wang Youjun from Beijing Normal University, Professor Li Juxue from Nanjing Medical University, and Researcher Tang Yizhe from Shenzhen Second People's Hospital provided strong support for this research
.
The research was funded by the National Natural Science Foundation of China and other units
.
Selected articles from previous issues [1] Science︱ is the first to prove in humans that a variety of neurodegenerative diseases can affect the neurogenesis of the hippocampal dentate gyrus [2] Neuron︱ new discovery! The hippocampus playback in the awake state promotes memory function by storing and updating specific past experiences [3] Mol Psychiatry︱ A new discovery of biomarkers for depression-mitochondrial proteins in exosomes [4] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [5] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional heterogeneity of the cerebellar nucleus to thalamus projection [6] J Neurosci︱ Cao Junli’s research group Revealing the loop mechanism of the anterior cingulate gyrus to regulate mirror pain [7] Nat Commun︱Non-human primate (monkey marmoset) autism model reveals the biological abnormalities in the early development of human diseases [8] Cell Discovery︱ Ma Yuanwu/Shen Bin’s team realized the precise editing of rat mitochondrial DNA for the first time [9] Dev Cell︱ Lactic acid promotes peripheral nerve damage and repair B side: Long-term lactic acid metabolism of axons can lead to oxidative stress and axon degeneration [10] Nat Commun︱ Selective inhibition of microglia activation is expected to alleviate pathological α-syn transmission [11] Mol Psychiatry︱ Gao Tianming's research group reveals the different roles of astrocytes and neurons in synaptic plasticity and memory [12] Sci Transl Med︱ Xiang Xianyuan et al.
Reveal the crazy sugar phagocytosis of brain immune cells to help early diagnosis of neurodegenerative diseases [13] A new mechanism of Mol Cell︱ Alzheimer’s disease: Tau protein oligomerization induces RNA-binding protein HNRNPA2B1 nuclear cell transport It also mediates the enhancement of m6A-RNA modification [14] Cereb Cortex | Li Tao's group reported the abnormality of the cortical myelin covariation network with the deep characteristics of the cerebral cortex in schizophrenia [14] Cell︱ holds hands, advances and retreats together! Microglia form a cellular connection network and work together to degrade pathological α-syn.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ Near-infrared brain function data processing class (online: 11.
1~11.
14) [2] Data map help guide! How good is it to learn these software? 【3】JAMA Neurol︱Attention! Young people are more likely to suffer from "Alzheimer's disease"? [4] Patch clamp and optogenetics and calcium imaging technology seminar (October 30-31) References (slide up and down to view) [1] Gautron L, Elmquist JK, Williams KW.
Neural control of energy balance: translating circuits to therapies.
Cell.
2015; 161:133-145.
[2] Morton GJ, Meek TH, Schwartz MW.
Neurobiology of food intake in health and disease.
Nat Rev Neurosci.
2014; 15:367-78.
[3] Arruda AP, Hotamisligil GS.
Calcium Homeostasis and Organelle Function in the Pathogenesis of Obesity and Diabetes.
Cell Metab.
2015; 22:381-97.
[4] Berridge MJ, Lipp P, Bootman MD.
The versatility and universality of calcium signalling.
Nat Rev Mol Cell Biol.
2000; 1:11-21.
[5] Schrank S, Barrington N, Stutzmann GE.
Calcium-Handling Defects and Neurodegenerative Disease.
Cold Spring Harb Perspect Biol.
2020; 12:a035212.
[6] Putney JW Jr.
A model for receptor-regulated calcium entry.
