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

Yan Tang,Yunping Qiu,Katherine A Buddo,Irwin J Kurland,Cameron A Schmidt,Ilya Boykov,P Darrell Neufer,Haihong Zong,Gary J Schwartz,Licheng Wu,Jacob B Pessin,Chien-Te Lin,Jeffrey E Pessin,Hyokjoon Kwon

doi:10.7554/elife.73360

Yan Tang, Yunping Qiu + Show 12 more

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

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Abstract

Cholinergic and sympathetic counter-regulatory networks control numerous physiological 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.

Highlights

TIGAR (Tp53-induced Glycolysis and Apoptosis Regulator) was originally identified as a p53-inducible protein that functions as a fructose-2,6-bisphosphatase (F2,6P) but subsequently shown to have phosphatase activities for a variety of phosphorylated metabolic intermediates and allosteric regulators including 2,3-bisphospholgycerate (2,3BPG), 2-phosphoglycerate, phosphoglycolate and phosphoenolpyruvate (Bensaad, Tsuruta et al 2006, Rigden 2008, Bolanos 2014, Tang, Chen et al 2021)
We reported that the TIGAR can modulate NF-kB signaling through a direct binding interaction and inhibition of the E3 ligase activity of the linear ubiquitin binding assembly complex, LUBAC in cultured cells (Tang, Kwon et al 2018)
During our phenotypic characterization we observed that the Tigar knockout (TKO) male and female mice both display a remarkable resistance to cold induced-hypothermia

Summary

Introduction

TIGAR (Tp53-induced Glycolysis and Apoptosis Regulator) was originally identified as a p53-inducible protein that functions as a fructose-2,6-bisphosphatase (F2,6P) but subsequently shown to have phosphatase activities for a variety of phosphorylated metabolic intermediates and allosteric regulators including 2,3-bisphospholgycerate (2,3BPG), 2-phosphoglycerate, phosphoglycolate and phosphoenolpyruvate (Bensaad, Tsuruta et al 2006, Rigden 2008, Bolanos 2014, Tang, Chen et al 2021). TIGAR (Tp53-induced Glycolysis and Apoptosis Regulator) was originally identified as a p53-inducible protein that functions as a fructose-2,6-bisphosphatase (F2,6P) but subsequently shown to have phosphatase activities for a variety of phosphorylated metabolic intermediates and allosteric regulators including 2,3-. The dephosphorylation of 2,3BPG to generate 3-phosphoglycerate would be expected to increase glycolysis (Bolanos 2014). The role of TIGAR in regulating carbohydrate metabolism is complicated by the presence of the related phosphofructokinase bis-phosphatase (PFKBP) family that has both F6P 2-kinase as well as F2,6P bisphosphatase activities (Mor, Cheung et al 2011). The biologic readout of TIGAR function is likely to be highly cell context dependent. In this regard, TIGAR has been reported to differentially modulate multiple different pathophysiologic outcomes. TIGAR plays a complex role on the formation and progression of different types of cancer via suppressing aerobic glycolysis and controlling of reactive oxygen species (ROS)

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