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Written by Qian Shuwen, edited by Qian Shuwen, Wang Sizhen Beige adipose is a type of fat with thermogenesis function, which can convert the energy produced by nutrient metabolism into heat energy, which is used to maintain body temperature
.
Beige fat is widely distributed in adults and is activated under certain conditions (such as cold stimulation and exercise)
.
Adipose tissue contains many types of cells, among which sympathetic nerves synthesize and release norepinephrine (norepinephrine, NE).
NE binds to β3 adrenergic receptors (β3-AR) on the surface of fat cells to activate downstream protein kinase A ( PKA)
.
PKA activates hormone-sensitive esterase (HSL) to promote lipolysis, while activating uncoupling protein (UCP1) to promote thermogenesis
.
Adipose tissue macrophages (ATMs) play an important role in regulating the metabolism of adipose tissue
.
Macrophages can be divided into inflammatory M1-like macrophages and anti-inflammatory M2-like macrophages
.
The activation of beige fat is accompanied by an increase in M2-like macrophages [1-3].
There have been studies suggesting that macrophages promote the activity of beige fat by secreting catecholamines [4], but it was quickly denied by another study [5] ]
.
Therefore, although the positive correlation between M2 macrophage activation and beige fat activation is clear, there is little direct evidence of how macrophages act on other cells
.
On November 15, 2021, the cooperative team of Tang Qiqun and Qian Shuwen of Fudan University published an online report entitled "Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue" on Nature Metabolism.
The research results put forward a new beige fat activation mechanism of M2 macrophage/Slit3/sympathetic nerve/adipocyte axis
.
Wang Yina is the first author of the paper, and Qian Shuwen and Tang Qqun are the co-corresponding authors of the paper
.
The study found that M2 macrophages in adipose tissue secrete Slit3 protein, which binds to the receptor Robo1 on the sympathetic nerve, activates the Ca2+/CaMKⅡ pathway to promote norepinephrine secretion, thereby increasing fat cell catabolism and heat production, and improving mice The cold tolerance
.
The team’s previous research results found that the conditioned medium of M2 macrophages can promote the expression of adipose tissue thermogenesis gene UCP1, angiogenesis and other beige fat activation characteristics; in addition, transplantation of M2 macrophages into the body can also promote whiteness.
The fat becomes beige and increases the overall metabolic rate of mice [3]
.
The above results suggest that macrophages can influence other cells through paracrine action and play a role in the activation of beige fat
.
In order to explore this problem, it is first necessary to screen the secretory factors of macrophages
.
In order to screen out secreted factors that meet physiological changes, the research team returned to the body to look for genes that change differentially in fat tissue macrophages during cold adaptation
.
They separated the subcutaneous adipose tissues of mice reared at 4℃ cold exposure for 3 days and room temperature, used flow cytometry to sort the M2 macrophages, performed RNA sequencing detection, and then compared the two groups of differentially expressed genes.
The KEGG analysis has The significant change in the signaling pathway is axon guidance.
Some of the proteins expressed by genes are secreted proteins.
The team focused on the highest expressed secretory protein Slit3 (slit guidance ligand 3) (Figure 1ae)
.
Further by detecting the protein level of Slit3 in M2 macrophages and in the culture supernatant (Figure 1 fj), the function of M2 macrophages to produce and secrete Slit3 induced by cold stimulation was confirmed
.
Figure 1 Cold stimulation induces M2 macrophages to express and secrete Slit3 (Source: Wang, YN.
et al.
, Nat Metab, 2021) In order to study the function of macrophage-derived Slit3, the research team will overexpress Slit3 M2 macro Phage cells were transplanted into the subcutaneous adipose tissue, and it was found (Figure 2) that the expression of lipolytic genes and UCP1 in the adipose tissue increased; the expression of tyrosine hydroxylase that catalyzes the production of NE increased; the oxygen consumption of adipose tissue increased; the overall metabolism of the mouse Increased levels; increased heat production
.
On the other hand, if Slit3 (Slit3f/f lyz2cre) is knocked out in macrophages (Figure 3), the above-mentioned series of changes from the molecular level to the overall level are reduced, which also supports the secretion of Slit3 by macrophages to activate beige fat.
One conclusion
.
Figure 2 Transplanting M2 macrophages expressing Slit3 into adipose tissue can activate sympathetic nerves and promote thermogenesis (Source: Wang, YN.
et al.
, Nat Metab, 2021) Figure 3 Myeloid knockout Slit3 inhibits mouse adipose tissue Sympathetic activity and thermogenesis (Source: Wang, YN.
et al.
, Nat Metab, 2021) To determine whether Slit3 activates beige fat through sympathetic nerves
.
The team researchers treated the cultured adipocytes (Figure 4 a, b) or sympathetic nerve cells (Figure 4 ce) with recombinant Slit3 protein or macrophage conditioned medium overexpressing Slit3, and found that Slit3 can regulate sympathetic nerves, but No obvious effect on fat cells
.
The effect of Slit3 in promoting thermogenesis in the body can be blocked by the operation of denervation (Figure 4 fn)
.
These results indicate that Slit3 activates beige fat through sympathetic nerves
.
Figure 4 Slit3 promotes fat thermogenesis by activating sympathetic nerves (Source: Wang, YN.
et al.
, Nat Metab, 2021) So how does Slit3 activate sympathetic nerves? The study found that the sympathetic nerve cell line PC12 expresses Slit3 receptor Robo1 (Figure 5 ad), and that Robo1 and the sympathetic nerve characteristically expressed tyrosine hydroxylase (TH) co-localize in mouse subcutaneous fat (Figure 5 e) )
.
If Robo1 is knocked down locally in adipose tissue, the function of Slit3 to promote thermogenesis is inhibited (Figure 5 fl)
.
Therefore, Slit3 activates Ca2+/CaMKⅡ through Robo1 receptor, which in turn activates TH phosphorylation and promotes the synthesis and secretion of norepinephrine
.
Figure 5 Slit3 binds to the receptor Robo1 on the sympathetic nerve to activate the Ca2+/CaMKⅡ pathway to promote the synthesis of norepinephrine (Source: Wang, YN.
et al.
, Nat Metab, 2021) Figure 6 Model diagram: Beige fat activation mechanism- M2 macrophage/Slit3/sympathetic nerve/adipocyte axis (Source: Wang, YN.
et al.
, Nat Metab, 2021) Conclusion and discussion, inspiration and outlook The macrophage secretion protein Slit3 was screened out.
Cell models and animal models were used to prove that Slit3 activates TH through the receptor Robo1 and Ca2+/CaMKⅡ pathways on the sympathetic nerve, thereby promoting the synthesis and secretion of norepinephrine
.
Play a role in the production of heat in adipose tissue
.
This study provides direct evidence of cross talk between immune cells (macrophages) and nerve cells (sympathetic nerves), and partially solves the mechanism by which macrophages activate beige fat
.
The proliferation of macrophages provides a long-term way to activate sympathetic nerves, which is a mechanism of chronic cold adaptation
.
Moreover, because macrophages only proliferate locally in adipose tissue, the activation of sympathetic nerves and the release of norepinephrine are also limited to the local area, so as to prevent norepinephrine from putting pressure on other body tissues such as cardiovascular or muscles
.
So how do macrophages perceive temperature to be activated and proliferate? This problem has not been solved in this study, and it is worthy of further exploration
.
Original link: https://doi.
org/10.
1038/s42255-021-00482-9 Selected articles from previous issues [1] Nature︱ The neural dynamics behind bird song practice and performance-stereotyped singing with heartbeat [2] PNAS︱ Chen Sijie’s research group developed a new type of aggregation-induced luminescence probe for three-dimensional myelin fluorescence imaging of sciatic nerve and brain tissue [3] Sci Adv | High glucose intake in adolescence is a potential risk factor for the development of mental illness [4] Nat Biotechnol | Li Yulong's laboratory develops a new fluorescent probe to detect the spatiotemporal dynamic changes of endocannabinoids [5] Nat Aging︱ Wang Guohao/Lu Wei/Hou Xianyu found that neurons accumulate lipid peroxides to activate microglia NLRP3 Inflammatory bodies promote demyelination and neuronal degeneration [6] Cell Rep︱ for the first time! A new mechanism by which the axon guide molecule Robo2 affects the function of the hippocampal circuit [7] A new discovery in the Neuron︱ Nobel Prize Laboratory! The olfactory landmarks and paths are integrated to form a cognitive spatial map [8] Nat Neurosci︱ breakthrough! Corticospinal neurons transmit complex motor signals to the spinal cord and striatum loop [9] Science︱ new discovery! The developing adenosine and GABA signaling pathway work together to stabilize GABAergic synapses [10] Mol Psychiatry Frontier Review︱ Li Ming/Li Tao/Hu Zhonghua Joint Review Mental Illness and Tandem Repeats in the Human Genome [11] PNAS︱ Tan Hongtao /Chen Peng's research group collaborated to reveal that dopaminergic neurons regulate chronic stress-induced memory impairment in Drosophila [12] Mol Psychiatry | Gao Tianming's research group reveals the local neural network mechanism of fear memory disappearance [13] Science | Breakthrough! Immune CD4+ T cells are involved in the disease process of Lewy body dementia [14] Cell Rep︱ New research reveals the role of hypothalamic neuronal calcium homeostasis regulators in the formation of obesity [15] Science︱ first confirmed in humans: multiple neurodegeneration Sexual diseases can affect the neurogenesis of the hippocampal dentate gyrus.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) Lectures/conferences/seminars/forums [1] A review of the exciting content of the second phase of the Brain Talk Academician Forum: Axon Regeneration and Neural Stem Cell References (slide up and down to view) 1.
Hui, X.
, et al.
,
.
Beige fat is widely distributed in adults and is activated under certain conditions (such as cold stimulation and exercise)
.
Adipose tissue contains many types of cells, among which sympathetic nerves synthesize and release norepinephrine (norepinephrine, NE).
NE binds to β3 adrenergic receptors (β3-AR) on the surface of fat cells to activate downstream protein kinase A ( PKA)
.
PKA activates hormone-sensitive esterase (HSL) to promote lipolysis, while activating uncoupling protein (UCP1) to promote thermogenesis
.
Adipose tissue macrophages (ATMs) play an important role in regulating the metabolism of adipose tissue
.
Macrophages can be divided into inflammatory M1-like macrophages and anti-inflammatory M2-like macrophages
.
The activation of beige fat is accompanied by an increase in M2-like macrophages [1-3].
There have been studies suggesting that macrophages promote the activity of beige fat by secreting catecholamines [4], but it was quickly denied by another study [5] ]
.
Therefore, although the positive correlation between M2 macrophage activation and beige fat activation is clear, there is little direct evidence of how macrophages act on other cells
.
On November 15, 2021, the cooperative team of Tang Qiqun and Qian Shuwen of Fudan University published an online report entitled "Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue" on Nature Metabolism.
The research results put forward a new beige fat activation mechanism of M2 macrophage/Slit3/sympathetic nerve/adipocyte axis
.
Wang Yina is the first author of the paper, and Qian Shuwen and Tang Qqun are the co-corresponding authors of the paper
.
The study found that M2 macrophages in adipose tissue secrete Slit3 protein, which binds to the receptor Robo1 on the sympathetic nerve, activates the Ca2+/CaMKⅡ pathway to promote norepinephrine secretion, thereby increasing fat cell catabolism and heat production, and improving mice The cold tolerance
.
The team’s previous research results found that the conditioned medium of M2 macrophages can promote the expression of adipose tissue thermogenesis gene UCP1, angiogenesis and other beige fat activation characteristics; in addition, transplantation of M2 macrophages into the body can also promote whiteness.
The fat becomes beige and increases the overall metabolic rate of mice [3]
.
The above results suggest that macrophages can influence other cells through paracrine action and play a role in the activation of beige fat
.
In order to explore this problem, it is first necessary to screen the secretory factors of macrophages
.
In order to screen out secreted factors that meet physiological changes, the research team returned to the body to look for genes that change differentially in fat tissue macrophages during cold adaptation
.
They separated the subcutaneous adipose tissues of mice reared at 4℃ cold exposure for 3 days and room temperature, used flow cytometry to sort the M2 macrophages, performed RNA sequencing detection, and then compared the two groups of differentially expressed genes.
The KEGG analysis has The significant change in the signaling pathway is axon guidance.
Some of the proteins expressed by genes are secreted proteins.
The team focused on the highest expressed secretory protein Slit3 (slit guidance ligand 3) (Figure 1ae)
.
Further by detecting the protein level of Slit3 in M2 macrophages and in the culture supernatant (Figure 1 fj), the function of M2 macrophages to produce and secrete Slit3 induced by cold stimulation was confirmed
.
Figure 1 Cold stimulation induces M2 macrophages to express and secrete Slit3 (Source: Wang, YN.
et al.
, Nat Metab, 2021) In order to study the function of macrophage-derived Slit3, the research team will overexpress Slit3 M2 macro Phage cells were transplanted into the subcutaneous adipose tissue, and it was found (Figure 2) that the expression of lipolytic genes and UCP1 in the adipose tissue increased; the expression of tyrosine hydroxylase that catalyzes the production of NE increased; the oxygen consumption of adipose tissue increased; the overall metabolism of the mouse Increased levels; increased heat production
.
On the other hand, if Slit3 (Slit3f/f lyz2cre) is knocked out in macrophages (Figure 3), the above-mentioned series of changes from the molecular level to the overall level are reduced, which also supports the secretion of Slit3 by macrophages to activate beige fat.
One conclusion
.
Figure 2 Transplanting M2 macrophages expressing Slit3 into adipose tissue can activate sympathetic nerves and promote thermogenesis (Source: Wang, YN.
et al.
, Nat Metab, 2021) Figure 3 Myeloid knockout Slit3 inhibits mouse adipose tissue Sympathetic activity and thermogenesis (Source: Wang, YN.
et al.
, Nat Metab, 2021) To determine whether Slit3 activates beige fat through sympathetic nerves
.
The team researchers treated the cultured adipocytes (Figure 4 a, b) or sympathetic nerve cells (Figure 4 ce) with recombinant Slit3 protein or macrophage conditioned medium overexpressing Slit3, and found that Slit3 can regulate sympathetic nerves, but No obvious effect on fat cells
.
The effect of Slit3 in promoting thermogenesis in the body can be blocked by the operation of denervation (Figure 4 fn)
.
These results indicate that Slit3 activates beige fat through sympathetic nerves
.
Figure 4 Slit3 promotes fat thermogenesis by activating sympathetic nerves (Source: Wang, YN.
et al.
, Nat Metab, 2021) So how does Slit3 activate sympathetic nerves? The study found that the sympathetic nerve cell line PC12 expresses Slit3 receptor Robo1 (Figure 5 ad), and that Robo1 and the sympathetic nerve characteristically expressed tyrosine hydroxylase (TH) co-localize in mouse subcutaneous fat (Figure 5 e) )
.
If Robo1 is knocked down locally in adipose tissue, the function of Slit3 to promote thermogenesis is inhibited (Figure 5 fl)
.
Therefore, Slit3 activates Ca2+/CaMKⅡ through Robo1 receptor, which in turn activates TH phosphorylation and promotes the synthesis and secretion of norepinephrine
.
Figure 5 Slit3 binds to the receptor Robo1 on the sympathetic nerve to activate the Ca2+/CaMKⅡ pathway to promote the synthesis of norepinephrine (Source: Wang, YN.
et al.
, Nat Metab, 2021) Figure 6 Model diagram: Beige fat activation mechanism- M2 macrophage/Slit3/sympathetic nerve/adipocyte axis (Source: Wang, YN.
et al.
, Nat Metab, 2021) Conclusion and discussion, inspiration and outlook The macrophage secretion protein Slit3 was screened out.
Cell models and animal models were used to prove that Slit3 activates TH through the receptor Robo1 and Ca2+/CaMKⅡ pathways on the sympathetic nerve, thereby promoting the synthesis and secretion of norepinephrine
.
Play a role in the production of heat in adipose tissue
.
This study provides direct evidence of cross talk between immune cells (macrophages) and nerve cells (sympathetic nerves), and partially solves the mechanism by which macrophages activate beige fat
.
The proliferation of macrophages provides a long-term way to activate sympathetic nerves, which is a mechanism of chronic cold adaptation
.
Moreover, because macrophages only proliferate locally in adipose tissue, the activation of sympathetic nerves and the release of norepinephrine are also limited to the local area, so as to prevent norepinephrine from putting pressure on other body tissues such as cardiovascular or muscles
.
So how do macrophages perceive temperature to be activated and proliferate? This problem has not been solved in this study, and it is worthy of further exploration
.
Original link: https://doi.
org/10.
1038/s42255-021-00482-9 Selected articles from previous issues [1] Nature︱ The neural dynamics behind bird song practice and performance-stereotyped singing with heartbeat [2] PNAS︱ Chen Sijie’s research group developed a new type of aggregation-induced luminescence probe for three-dimensional myelin fluorescence imaging of sciatic nerve and brain tissue [3] Sci Adv | High glucose intake in adolescence is a potential risk factor for the development of mental illness [4] Nat Biotechnol | Li Yulong's laboratory develops a new fluorescent probe to detect the spatiotemporal dynamic changes of endocannabinoids [5] Nat Aging︱ Wang Guohao/Lu Wei/Hou Xianyu found that neurons accumulate lipid peroxides to activate microglia NLRP3 Inflammatory bodies promote demyelination and neuronal degeneration [6] Cell Rep︱ for the first time! A new mechanism by which the axon guide molecule Robo2 affects the function of the hippocampal circuit [7] A new discovery in the Neuron︱ Nobel Prize Laboratory! The olfactory landmarks and paths are integrated to form a cognitive spatial map [8] Nat Neurosci︱ breakthrough! Corticospinal neurons transmit complex motor signals to the spinal cord and striatum loop [9] Science︱ new discovery! The developing adenosine and GABA signaling pathway work together to stabilize GABAergic synapses [10] Mol Psychiatry Frontier Review︱ Li Ming/Li Tao/Hu Zhonghua Joint Review Mental Illness and Tandem Repeats in the Human Genome [11] PNAS︱ Tan Hongtao /Chen Peng's research group collaborated to reveal that dopaminergic neurons regulate chronic stress-induced memory impairment in Drosophila [12] Mol Psychiatry | Gao Tianming's research group reveals the local neural network mechanism of fear memory disappearance [13] Science | Breakthrough! Immune CD4+ T cells are involved in the disease process of Lewy body dementia [14] Cell Rep︱ New research reveals the role of hypothalamic neuronal calcium homeostasis regulators in the formation of obesity [15] Science︱ first confirmed in humans: multiple neurodegeneration Sexual diseases can affect the neurogenesis of the hippocampal dentate gyrus.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) Lectures/conferences/seminars/forums [1] A review of the exciting content of the second phase of the Brain Talk Academician Forum: Axon Regeneration and Neural Stem Cell References (slide up and down to view) 1.
Hui, X.
, et al.
,
