A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia

Alastair S Garfield; Bhavik P Shah; Joseph C Madara; Luke K Burke; Christa M Patterson; Jonathan Flak; Rachael L Neve; Mark L Evans; Bradford B Lowell; Martin G Myers; Lora K Heisler

doi:10.1016/j.cmet.2014.11.006

A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia

Alastair S Garfield, Bhavik P Shah, Joseph C Madara, Luke K Burke, Christa M Patterson, Jonathan Flak, Rachael L Neve, Mark L Evans, Bradford B Lowell, Martin G Myers, Lora K Heisler

The Rowett Institute of Nutrition and Health

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Abstract

Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.

Original language	English
Pages (from-to)	1030-1037
Number of pages	8
Journal	Cell Metabolism
Volume	20
Issue number	6
DOIs	https://doi.org/10.1016/j.cmet.2014.11.006
Publication status	Published - 2 Dec 2014

Bibliographical note

Acknowledgments
This work was supported by the University of Edinburgh Chancellor’s Fellowship (A.S.G.), Wellcome Trust (L.K.H.; WT098012), and National Institutes of Health (B.B.L.; R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, and R37 DK053477) (M.G.M.: R01 DK098853). Catecholamine assays were performed by the VUMC Hormone Assay Core (NIH grants DK059637 and DK020593).

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A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
Final published version, 2.6 MBLicence: CC BY

Lora Heisler
- School of Medicine, Medical Sciences & Nutrition, The Rowett Institute of Nutrition and Health - Chair in Human Nutrition
Person: Academic

Cite this

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title = "A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia",

abstract = "Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.",

author = "Garfield, {Alastair S} and Shah, {Bhavik P} and Madara, {Joseph C} and Burke, {Luke K} and Patterson, {Christa M} and Jonathan Flak and Neve, {Rachael L} and Evans, {Mark L} and Lowell, {Bradford B} and Myers, {Martin G} and Heisler, {Lora K}",

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AU - Patterson, Christa M

AU - Flak, Jonathan

AU - Neve, Rachael L

AU - Evans, Mark L

AU - Lowell, Bradford B

AU - Myers, Martin G

AU - Heisler, Lora K

N1 - Acknowledgments This work was supported by the University of Edinburgh Chancellor’s Fellowship (A.S.G.), Wellcome Trust (L.K.H.; WT098012), and National Institutes of Health (B.B.L.; R01 DK096010, R01 DK089044, R01 DK071051, R01 DK075632, and R37 DK053477) (M.G.M.: R01 DK098853). Catecholamine assays were performed by the VUMC Hormone Assay Core (NIH grants DK059637 and DK020593).

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N2 - Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.

AB - Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCK(LPBN)) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1(VMH)) are the specific target of CCK(LPBN) glucoregulatory neurons. This discrete CCK(LPBN)→SF1(VMH) neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCK(LPBN) neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.

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A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia

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