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By | Qi The central regulation of blood sugar and pancreatic secretion has been known for over a century
.
Insulin secretion is thought to be centrally controlled, with initial evidence from classical Pavlovian conditioning experiments, followed by brain injury or electrical stimulation experiments in rats and dogs showing that many brain regions appear to be involved in the regulation of insulin levels
.
It has been found that glucose-sensing neurons, mainly located in the hypothalamus, respond to hyperglycemia or hypoglycemia [1] and can regulate insulin secretion, but the neuroanatomy and function of specific neuronal populations in the brain and pancreatic beta cells Intercellular communication remains unknown
.
On February 1, 2022, Sushil G.
Rane's team from the NIH in the United States published an article entitled A distinct hypothalamus-to-β cell circuit modulates insulin secretion in the journal Cell Metabolism.
A functional transneuronal circuit connecting to mouse beta cells originating in a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT) and reaching via sympathoautonomic branches Endocrine islets of the pancreas to innervate beta cells
.
Stimulation of PVNOXT neurons rapidly inhibits insulin secretion and leads to hyperglycemia
.
Instead, silencing of these neurons elevates insulin levels and induces hypoglycemia by dysregulating neuronal signaling and secretion pathways in beta cells
.
Furthermore, PVNOXT neuronal activity is triggered by glucose deprivation
.
In conclusion, this study demonstrates that a subset of PVNOXT neurons form functional polysynaptic circuits with beta cells in mice to regulate insulin secretion, and their function is required for beta cell responses to hypoglycemia
.
To identify neuronal populations in the brain that are synapsically connected to beta cells, the authors devised an in vivo tracking method in which the retrograde tracer Beta2017 was injected into the pancreas of Ins1-Cre mice expressing Cre recombinase only in beta cells In the tube, viral EGFP+ fluorescence was detected in islets, especially beta cells, within 24 to 48 hours after injection, and by 72 hours, the first EGFP+ cells appeared in the intermediolateral nucleus of the spinal cord and the hypothalamus, and were almost completely Located in the PVN, suggesting the existence of a transneuronal circuit connecting a subset of PVN neurons to pancreatic beta cells
.
The two main subpopulations of PVN neurons projecting to the thoracic segment of the spinal cord are oxytocinergic or vasopressinergic neurons, and in the tracking experiments described above, a group of EGFP+ cells were also positive for the neuropeptide oxytocin, so the authors wanted to verify the link between PVNOXT neurons and the regulation of glucose homeostasis
.
The authors stereotaxically injected AAV-DIO-hM3Dq or AAVDIO-mCherry virus in the PVN of OXT-ires-Cre mice [2] to induce expression of hM3Dq receptor or mCherry fluorescent reporter gene only in PVNOXT neurons, followed by small Mice were injected intraperitoneally with glucose or glucose and the hM3Dq receptor agonist CNO
.
Mouse pancreas were harvested 10 min after CNO stimulation and electron microscopy was performed using the latest intact pancreas slicing protocol [3] to demonstrate the effect of neurons on β-cell insulin granule motility
.
Normally, about 10% of granules are retained on the plasma membrane, and only a small fraction are released immediately after stimulation [4], while stimulation of PVNOXT neurons results in a significant reduction in granules on the plasma membrane, suggesting that PVNOXT neurons Metaactivation signals beta cells to inhibit insulin release by targeting granule trafficking
.
The authors also monitored using an in vivo glucose monitoring telemetry system [5].
Activation of PVNOXT neurons during hyperglycemic stimulation resulted in a significant increase in blood glucose levels, and this effect persisted for at least the first 30 minutes after glucose administration
.
This finding is consistent with the role of PVNOXT neurons in inhibiting insulin secretion
.
The PVN is the only brain region that contains oxytocin neurons projecting to the spinal cord.
To confirm whether this circuit involves sympathetic preganglionic neurons, the authors injected OXT-ires-Cre mice into the thoracic segments 9-13 of the spinal cord.
A retrograde Cre-dependent AAV-hM3Dq virus, and stimulation of these neurons with CNO during fasting-refeeding can result in a significant increase in mealtime glucose levels, suggesting that PVNOXT neurons innervate the pancreas through a circuit involving sympathetic preganglionic neurons
.
During fasting, inhibition of insulin secretion is often required to prevent hypoglycemia and deleterious neuroglycemic effects
.
To assess the role of this group of neurons in fasting-induced insulin suppression, the authors silenced PVNOXT neurons by virus injection.
After 24 hours of fasting, the silenced mice had significantly higher plasma insulin levels than controls, whereas blood glucose levels were significantly reduced
.
During this period, the authors performed RNA-seq on mouse pancreatic islets and found that signaling pathways related to neurotransmission, as well as insulin secretion, related to vesicle trafficking and granule fusion were significantly affected
.
These findings demonstrate that functional PVNOXT neurons are necessary for suppressing insulin secretion and preventing hypoglycemia during chronic fasting
.
Previous studies have reported that the PVN contains preautonomic neurons that are strongly responsive to low glucose levels [6], so are PVNOXT neurons part of the central sensing mechanism against hypoglycemia? The authors injected 2-DG, an unmetabolized glucose analog that elicits a hypoglycemic response, and monitored PVNOXT neuronal activity in response to 2-DG
.
The number of oxytocin neurons in the 2-DG group nearly tripled compared to the control group, and PVNOXT neurons were able to increase their activity within 20 minutes of administration in response to 2-DG injection
.
These results suggest that PVNOXT neurons have a unique role in response to glucose deprivation as part of the brain's perception mechanism for hypoglycemia
.
Collectively, this study uncovers a functional brain-beta cell transneuronal circuit regulating insulin secretion that links central responses to severe hypoglycemia and sympathetic inhibition of insulin secretion
.
However, given the neuroanatomical differences between mice and humans in endocrine pancreatic innervation and islet organization, it remains to be seen whether these findings apply to humans
.
Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
12.
020 Publisher: Eleven References 1.
Routh, VH, Hao, L.
, Santiago, AM, Sheng, Z.
, and Zhou, C.
(2014).
Hypothalamic glucose sensing: making ends meet.
Front.
Syst.
Neurosci.
8, 236.
2.
Wu, Z.
, Xu, Y.
, Zhu, Y.
, Sutton, AK, Zhao, R.
, Lowell, BB, Olson, DP, and Tong, Q.
(2012).
An obligate role of oxytocin neurons in diet induced energy expenditure.
PLoS One 7, e45167.
3.
Fulgenzi, G.
, Hong, Z.
, Tomassoni-Ardori, F .
, Barella, LF, Becker, J.
, Barrick, C.
, Swing, D.
, Yanpallewar, S.
, Croix, BS, Wess, J.
, et al.
(2020).
Novel metabolic role for BDNF in pancreatic beta -cell insulin secretion.
Nat.
Commun.
11, 1950.
4.
Orci, L.
(1985).
The insulin factory: a tour of the plant surroundings and a visit to the assembly line.
The Minkowski lecture 1973 revisited.
Diabetologia 28, 528– 546.
5.
Korstanje, R.
, Ryan, JL, Savage,HS, Lyons, BL, Kane, KG, and Sukoff Rizzo, SJ (2017).
Continuous glucose monitoring in female NOD mice reveals daily rhythms and a negative correlation with body temperature.
Endocrinology 158, 2707–2712.
6.
Melnick, IV, Price, CJ, and Colmers, WF (2011).
Glucosensing in parvocellular neurons of the rat hypothalamic paraventricular nucleus.
Eur.
J.
Neurosci.
34, 272–282.
Instructions for reprinting [Original article] BioArt original article, welcome to forward and share, without Reproduction is prohibited, and the copyright of all works published is owned by BioArtReprint notice [Original article] BioArt's original article, welcome to forward and share personally, it is prohibited to reprint without permission, and the copyright of all works published is owned by BioArtReprint notice [Original article] BioArt's original article, welcome to forward and share personally, it is prohibited to reprint without permission, and the copyright of all works published is owned by BioArt
.
BioArt reserves all legal rights and violators will be held accountable
.
.
Insulin secretion is thought to be centrally controlled, with initial evidence from classical Pavlovian conditioning experiments, followed by brain injury or electrical stimulation experiments in rats and dogs showing that many brain regions appear to be involved in the regulation of insulin levels
.
It has been found that glucose-sensing neurons, mainly located in the hypothalamus, respond to hyperglycemia or hypoglycemia [1] and can regulate insulin secretion, but the neuroanatomy and function of specific neuronal populations in the brain and pancreatic beta cells Intercellular communication remains unknown
.
On February 1, 2022, Sushil G.
Rane's team from the NIH in the United States published an article entitled A distinct hypothalamus-to-β cell circuit modulates insulin secretion in the journal Cell Metabolism.
A functional transneuronal circuit connecting to mouse beta cells originating in a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT) and reaching via sympathoautonomic branches Endocrine islets of the pancreas to innervate beta cells
.
Stimulation of PVNOXT neurons rapidly inhibits insulin secretion and leads to hyperglycemia
.
Instead, silencing of these neurons elevates insulin levels and induces hypoglycemia by dysregulating neuronal signaling and secretion pathways in beta cells
.
Furthermore, PVNOXT neuronal activity is triggered by glucose deprivation
.
In conclusion, this study demonstrates that a subset of PVNOXT neurons form functional polysynaptic circuits with beta cells in mice to regulate insulin secretion, and their function is required for beta cell responses to hypoglycemia
.
To identify neuronal populations in the brain that are synapsically connected to beta cells, the authors devised an in vivo tracking method in which the retrograde tracer Beta2017 was injected into the pancreas of Ins1-Cre mice expressing Cre recombinase only in beta cells In the tube, viral EGFP+ fluorescence was detected in islets, especially beta cells, within 24 to 48 hours after injection, and by 72 hours, the first EGFP+ cells appeared in the intermediolateral nucleus of the spinal cord and the hypothalamus, and were almost completely Located in the PVN, suggesting the existence of a transneuronal circuit connecting a subset of PVN neurons to pancreatic beta cells
.
The two main subpopulations of PVN neurons projecting to the thoracic segment of the spinal cord are oxytocinergic or vasopressinergic neurons, and in the tracking experiments described above, a group of EGFP+ cells were also positive for the neuropeptide oxytocin, so the authors wanted to verify the link between PVNOXT neurons and the regulation of glucose homeostasis
.
The authors stereotaxically injected AAV-DIO-hM3Dq or AAVDIO-mCherry virus in the PVN of OXT-ires-Cre mice [2] to induce expression of hM3Dq receptor or mCherry fluorescent reporter gene only in PVNOXT neurons, followed by small Mice were injected intraperitoneally with glucose or glucose and the hM3Dq receptor agonist CNO
.
Mouse pancreas were harvested 10 min after CNO stimulation and electron microscopy was performed using the latest intact pancreas slicing protocol [3] to demonstrate the effect of neurons on β-cell insulin granule motility
.
Normally, about 10% of granules are retained on the plasma membrane, and only a small fraction are released immediately after stimulation [4], while stimulation of PVNOXT neurons results in a significant reduction in granules on the plasma membrane, suggesting that PVNOXT neurons Metaactivation signals beta cells to inhibit insulin release by targeting granule trafficking
.
The authors also monitored using an in vivo glucose monitoring telemetry system [5].
Activation of PVNOXT neurons during hyperglycemic stimulation resulted in a significant increase in blood glucose levels, and this effect persisted for at least the first 30 minutes after glucose administration
.
This finding is consistent with the role of PVNOXT neurons in inhibiting insulin secretion
.
The PVN is the only brain region that contains oxytocin neurons projecting to the spinal cord.
To confirm whether this circuit involves sympathetic preganglionic neurons, the authors injected OXT-ires-Cre mice into the thoracic segments 9-13 of the spinal cord.
A retrograde Cre-dependent AAV-hM3Dq virus, and stimulation of these neurons with CNO during fasting-refeeding can result in a significant increase in mealtime glucose levels, suggesting that PVNOXT neurons innervate the pancreas through a circuit involving sympathetic preganglionic neurons
.
During fasting, inhibition of insulin secretion is often required to prevent hypoglycemia and deleterious neuroglycemic effects
.
To assess the role of this group of neurons in fasting-induced insulin suppression, the authors silenced PVNOXT neurons by virus injection.
After 24 hours of fasting, the silenced mice had significantly higher plasma insulin levels than controls, whereas blood glucose levels were significantly reduced
.
During this period, the authors performed RNA-seq on mouse pancreatic islets and found that signaling pathways related to neurotransmission, as well as insulin secretion, related to vesicle trafficking and granule fusion were significantly affected
.
These findings demonstrate that functional PVNOXT neurons are necessary for suppressing insulin secretion and preventing hypoglycemia during chronic fasting
.
Previous studies have reported that the PVN contains preautonomic neurons that are strongly responsive to low glucose levels [6], so are PVNOXT neurons part of the central sensing mechanism against hypoglycemia? The authors injected 2-DG, an unmetabolized glucose analog that elicits a hypoglycemic response, and monitored PVNOXT neuronal activity in response to 2-DG
.
The number of oxytocin neurons in the 2-DG group nearly tripled compared to the control group, and PVNOXT neurons were able to increase their activity within 20 minutes of administration in response to 2-DG injection
.
These results suggest that PVNOXT neurons have a unique role in response to glucose deprivation as part of the brain's perception mechanism for hypoglycemia
.
Collectively, this study uncovers a functional brain-beta cell transneuronal circuit regulating insulin secretion that links central responses to severe hypoglycemia and sympathetic inhibition of insulin secretion
.
However, given the neuroanatomical differences between mice and humans in endocrine pancreatic innervation and islet organization, it remains to be seen whether these findings apply to humans
.
Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
12.
020 Publisher: Eleven References 1.
Routh, VH, Hao, L.
, Santiago, AM, Sheng, Z.
, and Zhou, C.
(2014).
Hypothalamic glucose sensing: making ends meet.
Front.
Syst.
Neurosci.
8, 236.
2.
Wu, Z.
, Xu, Y.
, Zhu, Y.
, Sutton, AK, Zhao, R.
, Lowell, BB, Olson, DP, and Tong, Q.
(2012).
An obligate role of oxytocin neurons in diet induced energy expenditure.
PLoS One 7, e45167.
3.
Fulgenzi, G.
, Hong, Z.
, Tomassoni-Ardori, F .
, Barella, LF, Becker, J.
, Barrick, C.
, Swing, D.
, Yanpallewar, S.
, Croix, BS, Wess, J.
, et al.
(2020).
Novel metabolic role for BDNF in pancreatic beta -cell insulin secretion.
Nat.
Commun.
11, 1950.
4.
Orci, L.
(1985).
The insulin factory: a tour of the plant surroundings and a visit to the assembly line.
The Minkowski lecture 1973 revisited.
Diabetologia 28, 528– 546.
5.
Korstanje, R.
, Ryan, JL, Savage,HS, Lyons, BL, Kane, KG, and Sukoff Rizzo, SJ (2017).
Continuous glucose monitoring in female NOD mice reveals daily rhythms and a negative correlation with body temperature.
Endocrinology 158, 2707–2712.
6.
Melnick, IV, Price, CJ, and Colmers, WF (2011).
Glucosensing in parvocellular neurons of the rat hypothalamic paraventricular nucleus.
Eur.
J.
Neurosci.
34, 272–282.
Instructions for reprinting [Original article] BioArt original article, welcome to forward and share, without Reproduction is prohibited, and the copyright of all works published is owned by BioArtReprint notice [Original article] BioArt's original article, welcome to forward and share personally, it is prohibited to reprint without permission, and the copyright of all works published is owned by BioArtReprint notice [Original article] BioArt's original article, welcome to forward and share personally, it is prohibited to reprint without permission, and the copyright of all works published is owned by BioArt
.
BioArt reserves all legal rights and violators will be held accountable
.
