SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
Articolo
Data di Pubblicazione:
2019
Citazione:
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms / S. Osataphan, C. Macchi, G. Singhal, J. Chimene-Weiss, V. Sales, C. Kozuka, J.M. Dreyfuss, H. Pan, Y. Tangcharoenpaisan, J. Morningstar, R. Gerszten, M. Patti. - In: JCI INSIGHT. - ISSN 2379-3708. - 4:5(2019 Mar 07).
Abstract:
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
SGL-T2
Elenco autori:
S. Osataphan, C. Macchi, G. Singhal, J. Chimene-Weiss, V. Sales, C. Kozuka, J.M. Dreyfuss, H. Pan, Y. Tangcharoenpaisan, J. Morningstar, R. Gerszten, M. Patti
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