TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling
- Albert Einstein College of Medicine, United States
- East Carolina University, United States
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
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
- 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
- Received: August 25, 2021
- Preprint posted: September 30, 2021 (view preprint)
- Accepted: March 2, 2022
- Accepted Manuscript published: March 7, 2022 (version 1)
- 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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TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling
eLife 11:e73360.
https://doi.org/10.7554/eLife.73360
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