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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Female
  • Hypoglycemia / metabolism*
  • Leptin / pharmacology*
  • Leptin / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / metabolism*
  • Organ Culture Techniques
  • Parabrachial Nucleus / drug effects
  • Parabrachial Nucleus / metabolism*
  • Receptors, Leptin / metabolism

Substances

  • Blood Glucose
  • Leptin
  • Receptors, Leptin
  • leptin receptor, mouse