POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels

  1. Alexandre Caron
  2. Heather M Dungan Lemko
  3. Carlos M Castorena
  4. Teppei Fujikawa
  5. Syann Lee
  6. Caleb C Lord
  7. Newaz Ahmed
  8. Charlotte E Lee
  9. William L Holland
  10. Chen Liu
  11. Joel K Elmquist  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Howard Community College, United States
  3. University of Texas Health Science Center at San Antonio, United States

Abstract

Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin's actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin's effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.

Article and author information

Author details

  1. Alexandre Caron

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6939-6136
  2. Heather M Dungan Lemko

    Howard Community College, Columbia, United States
    Competing interests
    No competing interests declared.
  3. Carlos M Castorena

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. Teppei Fujikawa

    Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    No competing interests declared.
  5. Syann Lee

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Caleb C Lord

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  7. Newaz Ahmed

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  8. Charlotte E Lee

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  9. William L Holland

    Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  10. Chen Liu

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  11. Joel K Elmquist

    Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Joel.Elmquist@utsouthwestern.edu
    Competing interests
    Joel K Elmquist, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6929-6370

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R37DK053301)

  • Joel K Elmquist

Canadian Diabetes Association (NOD_PF-3-15-4756-AC)

  • Alexandre Caron

American Heart Association (14SDG17950008)

  • Teppei Fujikawa

National Institute of Diabetes and Digestive and Kidney Diseases (K01DK11164401)

  • Carlos M Castorena

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK114036)

  • Chen Liu

American Heart Association (16SDG27260001)

  • Chen Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal work described in this manuscript has been approved and conducted under the oversight of the UT Southwestern Institutional Animal Care and Use Committee (IACUC, APN 2015-101301 and APN 2015-101263).

Reviewing Editor

  1. Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States

Publication history

  1. Received: November 20, 2017
  2. Accepted: March 8, 2018
  3. Accepted Manuscript published: March 12, 2018 (version 1)
  4. Version of Record published: March 23, 2018 (version 2)

Copyright

© 2018, Caron et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Alexandre Caron
  2. Heather M Dungan Lemko
  3. Carlos M Castorena
  4. Teppei Fujikawa
  5. Syann Lee
  6. Caleb C Lord
  7. Newaz Ahmed
  8. Charlotte E Lee
  9. William L Holland
  10. Chen Liu
  11. Joel K Elmquist
(2018)
POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels
eLife 7:e33710.
https://doi.org/10.7554/eLife.33710

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