Neuronal glucose metabolism sets cholinergic tone and controls thermo-regulated signaling at the neuromuscular junction

Summary 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. Highlights Deficiency of a negative regulator of glycolysis (TIGAR) in cholinergic neurons increases the biosynthesis and content of the neurotransmitter acetylcholine. Increased cholinergic tone reduces blood pressure and heart rate while enhancing signaling at neuromuscular junction. Upregulation of neuromuscular junction activation provides protection against the paralytic curare and cold-induced hypothermia. Modulation of cholinergic neuron glycolysis may provide a novel therapeutic approach for treatment of diseases stemming from reduced acetylcholine signaling such as myasthenia gravis and sarcopenic pre-synaptic dysfunction.