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Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5\u2032 AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together, these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic paradigm but requires FGF21 for reduction in adiposity.<\/jats:p>","DOI":"10.1172\/jci.insight.123130","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T11:02:59Z","timestamp":1551870179000},"source":"Crossref","is-referenced-by-count":217,"title":["SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms"],"prefix":"10.1172","volume":"4","author":[{"given":"Soravis","family":"Osataphan","sequence":"first","affiliation":[{"name":"Section of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA."},{"name":"Harvard Medical School, Boston, Massachusetts, USA."},{"name":"Department of Pathology, Srinakharinwirot University, Bangkok, 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