TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling

Abstract

Cholinergic and sympathetic counter-regulatory networks control numerous physiologic functions including learning/memory/cognition, stress responsiveness, blood pressure, heart rate and energy balance. As neurons primarily utilize glucose as their primary metabolic energy source, we generated mice with increased glycolysis in cholinergic neurons by specific deletion of the fructose-2,6-phosphatase protein TIGAR. Steady-state and stable isotope flux analyses demonstrated increased rates of glycolysis, acetyl-CoA production, acetylcholine levels and density of neuromuscular synaptic junction clusters with enhanced acetylcholine release. The increase in cholinergic signaling reduced blood pressure and heart rate with a remarkable resistance to cold-induced hypothermia. These data directly demonstrate that increased cholinergic signaling through the modulation of glycolysis has several metabolic benefits particularly to increase energy expenditure and heat production upon cold exposure.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 3, 4, 5, 7, Figure 1-figure supplement 1, 3, and 6.

Article and author information

Author details

  1. Yan Tang

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1377-422X
  2. Haihong Zong

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Hyokjoon Kwon

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yunping Qiu

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jacob B Pessin

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Licheng Wu

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Katherine A Buddo

    Department of Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ilya Boykov

    Department of Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Cameron A Schmidt

    Department of Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Chien-Te Lin

    Department of Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. P Darrell Neufer

    Department of Physiology, East Carolina University, Greenville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Gary J Schwartz

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Irwin J Kurland

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Jeffrey Pessin

    Department of Medicine, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    jeffrey.pessin@einstein.yu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2041-2726

Funding

National Institutes of Health (DK033823)

  • Jeffrey Pessin

National Institutes of Health (DK020541)

  • Jeffrey Pessin

S10 SIG Award for the Sciex 6500+QTRAP (1S10OD021798)

  • Irwin J Kurland

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

Reviewing Editor

  1. Joel K Elmquist, University of Texas Southwestern Medical Center, United States

Ethics

Animal experimentation: All studies were performed in accordance with protocols approved by the Einstein Institutional Animal Care and Use Committee. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (0000-1041, 0000-1061, and 0000-1389) of the Albert Einstein College of Medicine.

Version history

  1. Received: August 25, 2021
  2. Preprint posted: September 30, 2021 (view preprint)
  3. Accepted: March 2, 2022
  4. Accepted Manuscript published: March 7, 2022 (version 1)
  5. Version of Record published: March 23, 2022 (version 2)

Copyright

© 2022, Tang 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. Yan Tang
  2. Haihong Zong
  3. Hyokjoon Kwon
  4. Yunping Qiu
  5. Jacob B Pessin
  6. Licheng Wu
  7. Katherine A Buddo
  8. Ilya Boykov
  9. Cameron A Schmidt
  10. Chien-Te Lin
  11. P Darrell Neufer
  12. Gary J Schwartz
  13. Irwin J Kurland
  14. Jeffrey Pessin
(2022)
TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling
eLife 11:e73360.
https://doi.org/10.7554/eLife.73360

Share this article

https://doi.org/10.7554/eLife.73360

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