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Obesity, aging and related metabolic diseases have become common health problems in modern society.
It is generally believed that metabolic dysfunction is caused by both internal and external environmental factors: mutations and sexual dimorphisms of obesity-related genes are considered to be the most important internal causes affecting metabolism; intestinal flora imbalance, chronic stress and microenvironment Inflammation is considered to be an external cause.
At the same time, metabolism and aging affect each other.
During the aging process, the metabolism of the human body undergoes tremendous changes, and the hypothalamus greatly affects the aging process of the body.
All the above reminds us that the hypothalamus plays an extremely critical role in the regulation of metabolism and aging.
Therefore, a thorough understanding of how the brain, especially the hypothalamus is affected by other factors in metabolic regulation, is essential for the treatment and prevention of metabolic diseases and the maintenance of human metabolic health.
On April 7, 2020, Professor Liu Tiemin from Fudan University, Professor Xu Yong from Baylor College of Medicine in the United States, Professor Yi Chunxia from the University of Amsterdam in the Netherlands, Professor Tong Qingchun from the University of Texas Health Science Research Center in Houston, and Professor Cai Dongsheng from the Albert Einstein College of Medicine in Protein&Cell Published a review paper entitled The hypothalamus for whole-body physiology: from metabolism to aging, which comprehensively summarizes the most important central regulatory metabolic factors: genes, gender, brain glial cells, intestinal flora and external pressure And analyze the neural circuits and molecular mechanisms involved; at the same time explore the role of the hypothalamus in the metabolism and aging process (Figure 1).
Figure 1 Genes, gender, brain glial cells, intestinal flora and external pressure participate in the regulation of metabolism by the central nervous system; at the same time, the hypothalamus affects the aging process of the organism, and aging affects the metabolism of the organism.
A genetic basis of obesity, GWAS results indicate that the expression of many mutant genes related to body mass factor (BMI) is enriched in the brain.
The currently identified obesity-related genes can be roughly divided into three categories.
The first type of genes are involved in the regulation of the leptin-melanocortin pathway, such as the leptin receptor gene (LEPR), melanocorticotropin gene (POMC), melanocortin 4 receptor gene (MC4R), SIM1 gene, Arene receptor nuclear transporter 2 gene (ARNT2) and so on.
These genes are expressed in high abundance in the hypothalamus, and mutations in these genes are found in obese patients; in mice, there are mutant phenotypes such as increased eating, obesity, or hyperglycemia.
The second type of obesity-related genes are primary cilia-related genes.
Primary cilia are generally considered to be involved in cell signal transduction.
However, in recent years, it has been discovered that ciliary protein centrosome protein 19 (CEP19), adenylate cyclase 3 (ADCY3) and other ciliary proteins have lost function and are associated with obesity, hyperappetite and other Metabolic abnormalities are related.
In addition to the above two types of genes, there are also some mutations related to obesity, such as α-ketoglutarate-dependent dioxygenase gene (FTO), phospholipid transcription factor 1-like protein gene (MYT1L) and SH2B linkage Protein 1 gene (SH2B1).
These genes are widely expressed in the brain, and their mutations are related to human obesity, but the underlying mechanism is still unclear.
Two gender differences in metabolic regulation There are gender differences in the feeding behavior and energy homeostasis regulation of rodents.
In animal experiments, male rats consume more energy than females and are more susceptible to obesity induced by high-fat diet (HFD) feeding And insulin resistance.
Most of the research on this gender difference focuses on sex chromosomes and gonadal hormones: studies have shown that some X-linked genes are involved in regulating energy balance, such as 5-hydroxytryptamine 2C receptor gene (5-TH2CR), transient receptor potential Channel 5 gene (TrpC5) and O-GlcNAc transferase gene (OGT).
Changing the expression of these genes in hypothalamic neurons can produce gender-dependent metabolic changes.
Estrogen and testosterone are also involved in metabolic regulation.
Knockout of estrogen receptor 1 (Esr1/ERα) or androgen receptor (AR) will cause changes in the weight of mice.
In recent years, it has also been discovered that some autosomal gene expression proteins, such as kisseptin (Kiss1) and its receptor and SRC-1, can indirectly lead to sexual dimorphism in the metabolic process by regulating estrogen/estrogen receptors.
3.
Changes in hypothalamic glial cell immunity and metabolism in obesity and diabetes.
Microglia are the innate immune cells in the brain, which mainly remove cell debris and pathogens to maintain brain tissue homeostasis.
When animals were exposed to HFD, the microglia in the midbasal hypothalamus (MBH, a brain area lacking the blood-brain barrier) showed significantly faster and higher reactivity than other hypothalamic areas.
The activated microglia in MBH may have both pro-inflammatory (M1) and anti-inflammatory (M2) characteristics.
In the early stage of HFD feeding, the hypothalamic microglia produced more mitochondrial uncoupling protein 2 (UCP2, one of the M2 phenotypic characteristics), and the loss of UCP2 can increase the leptin sensitivity of POMC neurons and help Resist high fat-induced obesity.
This shows that the reprogramming changes of the immune metabolism of microglia are essential for the resistance to HFD-induced obesity.
Similar to microglia, HFD-fed mice increased the number of astrocytes and the astrocyte-derived cytokine interleukin 6 (IL-6) downstream of the nuclear factor kappa B (NF-κB) pathway.
Insulin and leptin receptors are highly expressed in astrocytes.
The absence of these two receptors will not only change the morphology of astrocytes, but also affect the electrical activity of hypothalamic melanocortin neurons.
Four intestinal microbes and brain regulation metabolism The intestinal flora is highly correlated with human metabolic health.
The composition of the microbial community of obese and diabetic patients has undergone tremendous changes.
In lean people, anti-inflammatory microbial species (such as Faecalibacterium prausnitzii) are more abundant, while the enrichment of bacterial Bacteroides and Kiwifruit is more closely related to obese individuals. The latest research proves that the gut microbiota is widely involved in various metabolic aspects through the brain-gut axis.
Short-chain fatty acids (SCFA) and bile acids (BAs) are metabolites related to the gut microbiota.
On the one hand, SCFAs and BAs can directly enter the brain through the blood-brain barrier, and on the other hand, they can promote glucagon-like peptide (GLP-1), peptide YY (PYY) and fibroblasts by binding to receptors on small intestinal L cells Growth factor 19 (FGF19) is produced, which then passes through the BBB through the endocrine system to act on hypothalamic neurons.
The influence of SCFAs on metabolism can also act through the vagus nerve.
In addition, the bacterial protein casein protease B (ClpB) was found to mimic the effect of α-MSH, reducing food intake by acting on the brain.
Five stress, eating and obesity stress are mental or emotional stress or tension caused by unfavorable environments.
Stress-induced affective eating links anxiety/depression and obesity through changes in cortisol and brain reward circuits, leading to compulsive overeating.
On the contrary, eating disorders are usually accompanied by emotional changes, including stress, anxiety, and aggression.
The treatment of some mental illnesses is usually accompanied by the development of obesity.
Corticotropin-releasing hormone (CRH) neurons are widely distributed in the brain and are considered to be one of the first responders to coordinate behavior and hormonal responses to stress.
Hypothalamic CRH neurons are a major subset of CRH neurons in the brain.
They are located in PVH (a key brain area for feeding and weight regulation) and cause neuroendocrine responses through the autonomic nervous system and the hypothalamic-pituitary-adrenal axis (HPA).
In addition, studies have shown that many eating-related neurons change the amount of food consumed while also changing the state of anxiety and stress in mice.
This indicates that the emotions related to eating and stress are likely to be regulated by a common neural circuit, which is also evolutionary.
Conservative.
6.
Central Nervous System Regulation of Aging A significant physiological feature in the process of aging is the change of energy homeostasis.
The hypothalamic ARC brain area is an important brain area that regulates eating and energy balance.
The activity of POMC neurons in aged mice was significantly reduced.
Overexpression of Pomc gene in ARC can reduce the age-dependent metabolic changes in aged rats; the levels of NPY protein and NPY receptor in the hypothalamic region of aged rats will also decrease.
Hypothalamic atrophy is found in aging-related neurodegenerative diseases; middle-aged rodents with increased hypothalamic NF-κB activity show symptoms of accelerated aging and reduced lifespan, while inhibiting NF-κB signaling in the hypothalamus Enough to cause a slowdown in aging and an increase in lifespan.
Other studies have shown that there are hypothalamic neural stem/progenitor cells (htNSCs) in adult mice.
The age-dependent loss of these cells is the cause of accelerated aging.
The underlying mechanism is related to the secretion of miRNA exosomes by these cells.
The new endocrine function is closely related.
In short, the exploration of the role of hypothalamic inflammation and stem cells can serve as a new direction for the study of aging mechanisms.
7.
Outlook Research in the past few decades, especially emerging technologies that have emerged recently, has revealed that many brain regions and neurons in the brain are related to eating and possible weight regulation.
However, for the treatment of obesity and metabolic diseases, current research is still in the ascendant.
For the further development of this field, we propose the following research directions and expectations: 1.
Single-cell sequencing can more finely divide neuronal subtypes and brain regions, and how to develop new technologies to label and manipulate these neuronal subgroups; 2.
It is necessary to combine human metabolism research with basic neuroendocrinology to explain the role of genes and neuroendocrine in human metabolic homeostasis; 3.
Pharmacological and genetic studies of energy balance differences need to cover both male and female mice as much as possible; 4.
Study on the mechanism of how microglia and astrocytes respond to diet-induced metabolic stress and how they interact; 5.
Study on the systemic mechanism of how intestinal flora respond to the microenvironment and act on the central nervous system, vagus nerve How to connect the intestinal flora and central metabolic regulation and the necessity of verification of the reproducibility of the research results in the population cohort; the comparison of the mechanisms of chronic stress and HFD on the brain nerves regulating eating and body weight, and the regulation of stress stress and HFD- The precise distinction of obese brain area/nerve circuit function; 6.
Explore the deep relationship between hypothalamic dysfunction, aging and metabolic syndrome, explore new anti-aging mechanisms that target aging-related micro-inflammation and neuroinflammation . Original link: https://link.
springer.
com/article/10.
1007/s13238-021-00834-x Platemaker: Instructions for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is allowed, the author has all legal rights, and offenders must be investigated.
It is generally believed that metabolic dysfunction is caused by both internal and external environmental factors: mutations and sexual dimorphisms of obesity-related genes are considered to be the most important internal causes affecting metabolism; intestinal flora imbalance, chronic stress and microenvironment Inflammation is considered to be an external cause.
At the same time, metabolism and aging affect each other.
During the aging process, the metabolism of the human body undergoes tremendous changes, and the hypothalamus greatly affects the aging process of the body.
All the above reminds us that the hypothalamus plays an extremely critical role in the regulation of metabolism and aging.
Therefore, a thorough understanding of how the brain, especially the hypothalamus is affected by other factors in metabolic regulation, is essential for the treatment and prevention of metabolic diseases and the maintenance of human metabolic health.
On April 7, 2020, Professor Liu Tiemin from Fudan University, Professor Xu Yong from Baylor College of Medicine in the United States, Professor Yi Chunxia from the University of Amsterdam in the Netherlands, Professor Tong Qingchun from the University of Texas Health Science Research Center in Houston, and Professor Cai Dongsheng from the Albert Einstein College of Medicine in Protein&Cell Published a review paper entitled The hypothalamus for whole-body physiology: from metabolism to aging, which comprehensively summarizes the most important central regulatory metabolic factors: genes, gender, brain glial cells, intestinal flora and external pressure And analyze the neural circuits and molecular mechanisms involved; at the same time explore the role of the hypothalamus in the metabolism and aging process (Figure 1).
Figure 1 Genes, gender, brain glial cells, intestinal flora and external pressure participate in the regulation of metabolism by the central nervous system; at the same time, the hypothalamus affects the aging process of the organism, and aging affects the metabolism of the organism.
A genetic basis of obesity, GWAS results indicate that the expression of many mutant genes related to body mass factor (BMI) is enriched in the brain.
The currently identified obesity-related genes can be roughly divided into three categories.
The first type of genes are involved in the regulation of the leptin-melanocortin pathway, such as the leptin receptor gene (LEPR), melanocorticotropin gene (POMC), melanocortin 4 receptor gene (MC4R), SIM1 gene, Arene receptor nuclear transporter 2 gene (ARNT2) and so on.
These genes are expressed in high abundance in the hypothalamus, and mutations in these genes are found in obese patients; in mice, there are mutant phenotypes such as increased eating, obesity, or hyperglycemia.
The second type of obesity-related genes are primary cilia-related genes.
Primary cilia are generally considered to be involved in cell signal transduction.
However, in recent years, it has been discovered that ciliary protein centrosome protein 19 (CEP19), adenylate cyclase 3 (ADCY3) and other ciliary proteins have lost function and are associated with obesity, hyperappetite and other Metabolic abnormalities are related.
In addition to the above two types of genes, there are also some mutations related to obesity, such as α-ketoglutarate-dependent dioxygenase gene (FTO), phospholipid transcription factor 1-like protein gene (MYT1L) and SH2B linkage Protein 1 gene (SH2B1).
These genes are widely expressed in the brain, and their mutations are related to human obesity, but the underlying mechanism is still unclear.
Two gender differences in metabolic regulation There are gender differences in the feeding behavior and energy homeostasis regulation of rodents.
In animal experiments, male rats consume more energy than females and are more susceptible to obesity induced by high-fat diet (HFD) feeding And insulin resistance.
Most of the research on this gender difference focuses on sex chromosomes and gonadal hormones: studies have shown that some X-linked genes are involved in regulating energy balance, such as 5-hydroxytryptamine 2C receptor gene (5-TH2CR), transient receptor potential Channel 5 gene (TrpC5) and O-GlcNAc transferase gene (OGT).
Changing the expression of these genes in hypothalamic neurons can produce gender-dependent metabolic changes.
Estrogen and testosterone are also involved in metabolic regulation.
Knockout of estrogen receptor 1 (Esr1/ERα) or androgen receptor (AR) will cause changes in the weight of mice.
In recent years, it has also been discovered that some autosomal gene expression proteins, such as kisseptin (Kiss1) and its receptor and SRC-1, can indirectly lead to sexual dimorphism in the metabolic process by regulating estrogen/estrogen receptors.
3.
Changes in hypothalamic glial cell immunity and metabolism in obesity and diabetes.
Microglia are the innate immune cells in the brain, which mainly remove cell debris and pathogens to maintain brain tissue homeostasis.
When animals were exposed to HFD, the microglia in the midbasal hypothalamus (MBH, a brain area lacking the blood-brain barrier) showed significantly faster and higher reactivity than other hypothalamic areas.
The activated microglia in MBH may have both pro-inflammatory (M1) and anti-inflammatory (M2) characteristics.
In the early stage of HFD feeding, the hypothalamic microglia produced more mitochondrial uncoupling protein 2 (UCP2, one of the M2 phenotypic characteristics), and the loss of UCP2 can increase the leptin sensitivity of POMC neurons and help Resist high fat-induced obesity.
This shows that the reprogramming changes of the immune metabolism of microglia are essential for the resistance to HFD-induced obesity.
Similar to microglia, HFD-fed mice increased the number of astrocytes and the astrocyte-derived cytokine interleukin 6 (IL-6) downstream of the nuclear factor kappa B (NF-κB) pathway.
Insulin and leptin receptors are highly expressed in astrocytes.
The absence of these two receptors will not only change the morphology of astrocytes, but also affect the electrical activity of hypothalamic melanocortin neurons.
Four intestinal microbes and brain regulation metabolism The intestinal flora is highly correlated with human metabolic health.
The composition of the microbial community of obese and diabetic patients has undergone tremendous changes.
In lean people, anti-inflammatory microbial species (such as Faecalibacterium prausnitzii) are more abundant, while the enrichment of bacterial Bacteroides and Kiwifruit is more closely related to obese individuals. The latest research proves that the gut microbiota is widely involved in various metabolic aspects through the brain-gut axis.
Short-chain fatty acids (SCFA) and bile acids (BAs) are metabolites related to the gut microbiota.
On the one hand, SCFAs and BAs can directly enter the brain through the blood-brain barrier, and on the other hand, they can promote glucagon-like peptide (GLP-1), peptide YY (PYY) and fibroblasts by binding to receptors on small intestinal L cells Growth factor 19 (FGF19) is produced, which then passes through the BBB through the endocrine system to act on hypothalamic neurons.
The influence of SCFAs on metabolism can also act through the vagus nerve.
In addition, the bacterial protein casein protease B (ClpB) was found to mimic the effect of α-MSH, reducing food intake by acting on the brain.
Five stress, eating and obesity stress are mental or emotional stress or tension caused by unfavorable environments.
Stress-induced affective eating links anxiety/depression and obesity through changes in cortisol and brain reward circuits, leading to compulsive overeating.
On the contrary, eating disorders are usually accompanied by emotional changes, including stress, anxiety, and aggression.
The treatment of some mental illnesses is usually accompanied by the development of obesity.
Corticotropin-releasing hormone (CRH) neurons are widely distributed in the brain and are considered to be one of the first responders to coordinate behavior and hormonal responses to stress.
Hypothalamic CRH neurons are a major subset of CRH neurons in the brain.
They are located in PVH (a key brain area for feeding and weight regulation) and cause neuroendocrine responses through the autonomic nervous system and the hypothalamic-pituitary-adrenal axis (HPA).
In addition, studies have shown that many eating-related neurons change the amount of food consumed while also changing the state of anxiety and stress in mice.
This indicates that the emotions related to eating and stress are likely to be regulated by a common neural circuit, which is also evolutionary.
Conservative.
6.
Central Nervous System Regulation of Aging A significant physiological feature in the process of aging is the change of energy homeostasis.
The hypothalamic ARC brain area is an important brain area that regulates eating and energy balance.
The activity of POMC neurons in aged mice was significantly reduced.
Overexpression of Pomc gene in ARC can reduce the age-dependent metabolic changes in aged rats; the levels of NPY protein and NPY receptor in the hypothalamic region of aged rats will also decrease.
Hypothalamic atrophy is found in aging-related neurodegenerative diseases; middle-aged rodents with increased hypothalamic NF-κB activity show symptoms of accelerated aging and reduced lifespan, while inhibiting NF-κB signaling in the hypothalamus Enough to cause a slowdown in aging and an increase in lifespan.
Other studies have shown that there are hypothalamic neural stem/progenitor cells (htNSCs) in adult mice.
The age-dependent loss of these cells is the cause of accelerated aging.
The underlying mechanism is related to the secretion of miRNA exosomes by these cells.
The new endocrine function is closely related.
In short, the exploration of the role of hypothalamic inflammation and stem cells can serve as a new direction for the study of aging mechanisms.
7.
Outlook Research in the past few decades, especially emerging technologies that have emerged recently, has revealed that many brain regions and neurons in the brain are related to eating and possible weight regulation.
However, for the treatment of obesity and metabolic diseases, current research is still in the ascendant.
For the further development of this field, we propose the following research directions and expectations: 1.
Single-cell sequencing can more finely divide neuronal subtypes and brain regions, and how to develop new technologies to label and manipulate these neuronal subgroups; 2.
It is necessary to combine human metabolism research with basic neuroendocrinology to explain the role of genes and neuroendocrine in human metabolic homeostasis; 3.
Pharmacological and genetic studies of energy balance differences need to cover both male and female mice as much as possible; 4.
Study on the mechanism of how microglia and astrocytes respond to diet-induced metabolic stress and how they interact; 5.
Study on the systemic mechanism of how intestinal flora respond to the microenvironment and act on the central nervous system, vagus nerve How to connect the intestinal flora and central metabolic regulation and the necessity of verification of the reproducibility of the research results in the population cohort; the comparison of the mechanisms of chronic stress and HFD on the brain nerves regulating eating and body weight, and the regulation of stress stress and HFD- The precise distinction of obese brain area/nerve circuit function; 6.
Explore the deep relationship between hypothalamic dysfunction, aging and metabolic syndrome, explore new anti-aging mechanisms that target aging-related micro-inflammation and neuroinflammation . Original link: https://link.
springer.
com/article/10.
1007/s13238-021-00834-x Platemaker: Instructions for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is allowed, the author has all legal rights, and offenders must be investigated.
