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 journalArticlepeer-review

88 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
Early online date10 Nov 2014
DOIs
Publication statusPublished - Dec 2014

Bibliographical note

We thank AstraZeneca Pharmaceuticals for the generous gift of leptin, B. Roth (University of North Carolina, Chapel Hill) for CNO and members of the labs of M.G.M. and L.K.H. for helpful discussions. Research support was provided by the Animal Phenotyping Core of the Michigan Diabetes Research Center (US National Institutes of Health (NIH) grant P30 DK020572) and the Michigan Nutrition and Obesity Research Center (P30 DK089503), the American Diabetes Association, the American Heart Association, the Marilyn H. Vincent Foundation and the NIH (DK098853) to M.G.M., NIH DK055267 and DK020595 to C.J.R., NIH DK046060 to R.T.K., NIH DK046409 to L.S. and the Wellcome Trust (098012) and Biotechnology and Biological Sciences Research Council (BB/K001418/1) to L.K.H.

Keywords

  • hypothalamus
  • metabolism

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