Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance

Jonathan N Flak; Christa M Patterson; Alastair S Garfield; Giuseppe D'Agostino; Paulette B Goforth; Amy K Sutton; Paige A Malec; Jenny-Marie T Wong; Mark Germani; Justin C Jones; Michael Rajala; Leslie Satin; Christopher J Rhodes; David P Olson; Robert T Kennedy; Lora K Heisler; Martin G Myers Jr

doi:10.1038/nn.3861

Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance

Jonathan N Flak, Christa M Patterson, Alastair S Garfield, Giuseppe D'Agostino, Paulette B Goforth, Amy K Sutton, Paige A Malec, Jenny-Marie T Wong, Mark Germani, Justin C Jones, Michael Rajala, Leslie Satin, Christopher J Rhodes, David P Olson, Robert T Kennedy, Lora K Heisler, Martin G Myers Jr

Division of Diabetes, Endocrinology & Gastroenterology (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.

Original language	English
Pages (from-to)	1744-1750
Number of pages	7
Journal	Nature Neuroscience
Volume	17
Issue number	12
DOIs	https://doi.org/10.1038/nn.3861
Publication status	Published - Dec 2014

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Flak, J. N., Patterson, C. M., Garfield, A. S., D'Agostino, G., Goforth, P. B., Sutton, A. K., Malec, P. A., Wong, J.-M. T., Germani, M., Jones, J. C., Rajala, M., Satin, L., Rhodes, C. J., Olson, D. P., Kennedy, R. T., Heisler, L. K., & Myers Jr, M. G. (2014). Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nature Neuroscience, 17(12), 1744-1750. https://doi.org/10.1038/nn.3861

@article{8260e60446dd4883a4133a2a6b8bd3e2,

title = "Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance",

abstract = "Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.",

author = "Flak, {Jonathan N} and Patterson, {Christa M} and Garfield, {Alastair S} and Giuseppe D'Agostino and Goforth, {Paulette B} and Sutton, {Amy K} and Malec, {Paige A} and Wong, {Jenny-Marie T} and Mark Germani and Jones, {Justin C} and Michael Rajala and Leslie Satin and Rhodes, {Christopher J} and Olson, {David P} and Kennedy, {Robert T} and Heisler, {Lora K} and {Myers Jr}, {Martin G}",

year = "2014",

month = dec,

doi = "10.1038/nn.3861",

language = "English",

volume = "17",

pages = "1744--1750",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Springer Nature",

number = "12",

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Flak, JN, Patterson, CM, Garfield, AS, D'Agostino, G, Goforth, PB, Sutton, AK, Malec, PA, Wong, J-MT, Germani, M, Jones, JC, Rajala, M, Satin, L, Rhodes, CJ, Olson, DP, Kennedy, RT, Heisler, LK & Myers Jr, MG 2014, 'Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance', Nature Neuroscience, vol. 17, no. 12, pp. 1744-1750. https://doi.org/10.1038/nn.3861

TY - JOUR

T1 - Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance

AU - Flak, Jonathan N

AU - Patterson, Christa M

AU - Garfield, Alastair S

AU - D'Agostino, Giuseppe

AU - Goforth, Paulette B

AU - Sutton, Amy K

AU - Malec, Paige A

AU - Wong, Jenny-Marie T

AU - Germani, Mark

AU - Jones, Justin C

AU - Rajala, Michael

AU - Satin, Leslie

AU - Rhodes, Christopher J

AU - Olson, David P

AU - Kennedy, Robert T

AU - Heisler, Lora K

AU - Myers Jr, Martin G

PY - 2014/12

Y1 - 2014/12

N2 - Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.

AB - Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.

U2 - 10.1038/nn.3861

DO - 10.1038/nn.3861

M3 - Article

SN - 1097-6256

VL - 17

SP - 1744

EP - 1750

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 12

ER -

Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance

Abstract

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