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We identified TANK binding kinase 1 (TBK1) as a nutrient- and inflammation-responsive brake on AMPK signaling in adipocytes. Fasting or pharmacological AMPK activation induced\n                    <jats:italic>Tbk1<\/jats:italic>\n                    transcription via a PGC1\u03b1\/nuclear respiratory factor 1 axis, which, in turn, limited AMPK activity through a phosphorylation cascade to conserve energy. In obesity, this AMPK\/TBK1 axis was disrupted due to chronically elevated basal TBK1, thereby restricting energy expenditure during fasting. Adipocyte-specific TBK1 deletion enhanced fasting-induced AMPK activation, mitochondrial function, and lipolytic gene expression in both lean and obese mice. Pharmacological TBK1 inhibition with amlexanox recapitulated these effects. Combined treatment of mice with amlexanox and the AMPK activator AICAR enhanced weight loss, improved glucose tolerance and insulin sensitivity, and suppressed inflammatory and lipogenic programs in adipose tissue, as well as fibrotic gene expression in the liver. Building on prior clinical observations linking TBK1 inhibition to metabolic health, these findings defined a nutrient-sensitive AMPK\/TBK1 feedback loop that limited adipocyte catabolism and suggested that dual targeting of TBK1 and AMPK may help counteract metabolic adaptation and enhance the durability of obesity therapies.\n                  <\/jats:p>\n                  <jats:p\/>\n                  <jats:p>TBK1 acts as a brake on fat burning during fasting. Combining TBK1 inhibitor with AMPK activator reverses obesity and improves metabolic health in mice.<\/jats:p>","DOI":"10.1172\/jci.insight.200168","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T18:00:48Z","timestamp":1778176848000},"source":"Crossref","is-referenced-by-count":3,"title":["A nutrient-responsive AMPK\/TBK1 circuit restricts adipocyte catabolism"],"prefix":"10.1172","volume":"11","author":[{"given":"Churaibhon","family":"Wisessaowapak","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine and Pharmacology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliya","family":"Skorobogatko","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Medicine and Pharmacology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeonhui","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of 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