SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms

• DOI: 10.1172/jci.insight.123130
• Publication Date: 2019-03-06T16:02:59Z
• Authors: Soravis Osataphan; Chiara Macchi; Garima Singhal; Jeremy Chimene-Weiss; Vicencia Sales; Chisayo Kozuka; Jonathan M. Dreyfuss; Hui Pan; Yanin Tangcharoen...; Jordan Morningstar; Robert Gerszten; Mary-Elizabeth Patti
• Keywords: Blood Glucose; Male; 0303 health sciences; Fasting; AMP-Activated Protein Kinases; Ketones; Cellular Reprogramming; Lipid Metabolism; Lipids; 3. Good health; Diglycerides; Fatty Liver; Fibroblast Growth Factors; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Diabetes Mellitus, Type 2; Liver; Animals; Insulin; SGL-T2; Canagliflozin; Energy Metabolism; Adiposity

Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic effects is required. 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' 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.