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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 LepRbCCK neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cckcre-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 LepRbCCK neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.

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Change history

  • 10 December 2014

    In the version of this article initially published, the anteroposterior and dorsoventral stereotaxic injection coordinates in the Online Methods were transposed. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.

Author information

Author notes

    • Jonathan N Flak
    • , Christa M Patterson
    •  & Alastair S Garfield

    These authors contributed equally to this work.

Affiliations

  1. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Jonathan N Flak
    • , Christa M Patterson
    • , Mark Germani
    • , Justin C Jones
    • , Michael Rajala
    •  & Martin G Myers Jr
  2. Center for Integrative Physiology, University of Edinburgh, Edinburgh, UK.

    • Alastair S Garfield
  3. Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.

    • Giuseppe D'Agostino
    •  & Lora K Heisler
  4. Department of Pharmacology, University of Cambridge, Cambridge, UK.

    • Giuseppe D'Agostino
    •  & Martin G Myers Jr
  5. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA.

    • Paulette B Goforth
    •  & Leslie Satin
  6. Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

    • Amy K Sutton
  7. Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.

    • Paige A Malec
    • , Jenny-Marie T Wong
    •  & Robert T Kennedy
  8. Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA.

    • Christopher J Rhodes
  9. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.

    • David P Olson

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Contributions

J.N.F. and C.M.P. produced the data in Figures 1,2,3,4,5 and Supplementary Figures 1,2,3,4,5,6,7,8,9,10, with the exception of the data in Figure 1e–i, which was produced by P.B.G. and L.S., and the measurements of catecholamines, which were performed by P.A.M., J.-M.T.W. and R.T.K. M.G. and M.R. helped produce Supplementary Figures 2, 5 and 10. J.C.J. aided with Figures 2,3,4 and with animal genotyping and husbandry. G.D., A.S.G. and L.K.H. performed the experiments in Figure 6. Adenoviral tracers were produced by A.K.S. and C.J.R. Experimental design, interpretation and manuscript preparation were led by M.G.M., L.K.H., J.N.F., C.M.P., A.S.G. and D.P.O.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lora K Heisler or Martin G Myers Jr.

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DOI

https://doi.org/10.1038/nn.3861

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