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

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Issued Date

2019

Resource Type

Article

File Type

application/pdf

ISSN

23793708

DOI

10.1172/jci.insight.123130

Other identifier(s)

2-s2.0-85062630085

Rights Holder(s)

Scopus

Bibliographic Citation

JCI insight. Vol 4, No.5 (2019)

Suggested Citation

Osataphan S., Macchi C., Singhal G., Chimene-Weiss J., Sales V., Kozuka C., Dreyfuss J.M., Pan H., Tangcharoenpaisan Y., Morningstar J., Gerszten R., Patti M.-E. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI insight. Vol 4, No.5 (2019). doi:10.1172/jci.insight.123130 Retrieved from: https://hdl.handle.net/20.500.14740/5411

Title

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

Author(s)

Osataphan S.
 Macchi C.
 Singhal G.
 Chimene-Weiss J.
 Sales V.
 Kozuka C.
 Dreyfuss J.M.
 Pan H.
 Tangcharoenpaisan Y.
 Morningstar J.
 Gerszten R.
 Patti M.-E.

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.

Subject(s)

Canagliflozin
 Diacylglycerol
 Fibroblast growth factor
 Fibroblast growth factor 21
 Hydroxymethylglutaryl coenzyme A reductase kinase
 Insulin
 Ketone
 Lipid
 Rapamycin
 Slc5a2 protein, mouse
 Sodium glucose cotransporter 2
 Animal
 Blood
 C57BL mouse
 Diet restriction
 Drug effect
 Energy metabolism
 Fatty liver
 Genetics
 Glucose blood level
 Knockout mouse
 Lipid metabolism
 Liver
 Male
 Metabolism
 Mouse
 Non insulin dependent diabetes mellitus
 Nuclear reprogramming
 Obesity
 Pathology
 Pharmacology
 Signal transduction
 Adiposity
 AMP-Activated Protein Kinases
 Animals
 Blood Glucose
 Canagliflozin
 Cellular Reprogramming
 Diabetes Mellitus, Type 2
 Diglycerides
 Energy Metabolism
 Fasting
 Fatty Liver
 Fibroblast Growth Factors
 Insulin
 Ketones
 Lipid Metabolism
 Lipids
 Liver
 Male
 Mice
 Mice, Inbred C57BL
 Mice, Knockout
 Obesity
 Signal Transduction
 Sirolimus
 Sodium-Glucose Transporter 2
 Sodium-Glucose Transporter 2 Inhibitors

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URI

https://hdl.handle.net/20.500.14740/5411

Collections

Scopus: Year 1983-2021

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