SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms.
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.
['Osataphan|Soravis|S|', 'Macchi|Chiara|C|', 'Singhal|Garima|G|', 'Chimene-Weiss|Jeremy|J|', 'Sales|Vicencia|V|', 'Kozuka|Chisayo|C|', 'Dreyfuss|Jonathan M|JM|', 'Pan|Hui|H|', 'Tangcharoenpaisan|Yanin|Y|', 'Morningstar|Jordan|J|', 'Gerszten|Robert|R|', 'Patti|Mary-Elizabeth|ME|']
D055372:AMP-Activated Protein Kinases D050154:Adiposity D000818:Animals D001786:Blood Glucose D000068896:Canagliflozin D065150:Cellular Reprogramming D003924:Diabetes Mellitus, Type 2 D004075:Diglycerides D004734:Energy Metabolism D005215:Fasting D005234:Fatty Liver D005346:Fibroblast Growth Factors D007328:Insulin D007659:Ketones D050356:Lipid Metabolism D008055:Lipids D008099:Liver D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009765:Obesity D015398:Signal Transduction D020123:Sirolimus D051297:Sodium-Glucose Transporter 2 D000077203:Sodium-Glucose Transporter 2 Inhibitors
Metabolism Obesity Fatty acid oxidation Hepatology Intermediary metabolism