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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.<\/jats:p>","DOI":"10.7554\/elife.73360","type":"journal-article","created":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T04:15:11Z","timestamp":1646626511000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.73360","source":"Crossref","is-referenced-by-count":6,"title":["TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1377-422X","authenticated-orcid":true,"given":"Yan","family":"Tang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05cf8a891","id-type":"ROR","asserted-by":"publisher"}],"name":"Departments of Medicine, Albert Einstein College of Medicine","place":["Bronx, United 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