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

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 languageEnglish
Pages (from-to)1744-1750
Number of pages7
JournalNature Neuroscience
Volume17
Issue number12
DOIs
Publication statusPublished - Dec 2014

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Cholecystokinin
Leptin
Hypoglycemia
Neurons
Ventromedial Hypothalamic Nucleus
Leptin Receptors
Sympathetic Nervous System
Starvation
Glucagon
Glucocorticoids
Glucose
Food
Parabrachial Nucleus
Population
Therapeutics

Cite this

Flak, J. N., Patterson, C. M., Garfield, A. S., D'Agostino, G., Goforth, P. B., Sutton, A. K., ... Myers, 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

Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. / Flak, Jonathan N; Patterson, Christa M; Garfield, Alastair S; D'Agostino, Giuseppe; Goforth, Paulette B; Sutton, Amy K; Malec, Paige A; Wong, Jenny-Marie T; Germani, Mark; Jones, Justin C; Rajala, Michael; Satin, Leslie; Rhodes, Christopher J; Olson, David P; Kennedy, Robert T; Heisler, Lora K; Myers, Martin G.

In: Nature Neuroscience, Vol. 17, No. 12, 12.2014, p. 1744-1750.

Research output: Contribution to journalArticle

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, 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
Flak JN, Patterson CM, Garfield AS, D'Agostino G, Goforth PB, Sutton AK et al. Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nature Neuroscience. 2014 Dec;17(12):1744-1750. https://doi.org/10.1038/nn.3861
Flak, Jonathan N ; Patterson, Christa M ; Garfield, Alastair S ; D'Agostino, Giuseppe ; Goforth, Paulette B ; Sutton, Amy K ; Malec, Paige A ; Wong, Jenny-Marie T ; Germani, Mark ; Jones, Justin C ; Rajala, Michael ; Satin, Leslie ; Rhodes, Christopher J ; Olson, David P ; Kennedy, Robert T ; Heisler, Lora K ; Myers, Martin G. / Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. In: Nature Neuroscience. 2014 ; Vol. 17, No. 12. pp. 1744-1750.
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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.",
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AU - Jones, Justin C

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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.

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