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Nat Neurosci. 2014 Dec;17(12):1744-1750. doi: 10.1038/nn.3861. Epub 2014 Nov 10.

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

Author information

1
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
2
Center for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
3
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, and Department of Pharmacology, University of Cambridge, Cambridge, UK.
4
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
5
Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
6
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
7
Kovler Diabetes Center, University of Chicago, Chicago, IL, USA.
8
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
#
Contributed equally

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.

PMID:
25383904
PMCID:
PMC4255234
DOI:
10.1038/nn.3861
[Indexed for MEDLINE]
Free PMC Article

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