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The effects of SGLT-2 inhibitors canagliflozin on hepatic transcription

ABSTRACT: We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE114614 | GEO | 2021/05/13

REPOSITORIES: GEO

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The effects of SGLT-2 inhibitors canagliflozin on hepatic transcription

Project description:We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity. Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and CV risk in T2D, 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. We utilized an integrated transcriptomic-metabolomics approach to demonstrate that CANA modulates key nutrient-sensing pathways, with activation of AMPK and inhibition of 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. Taken together, these data demonstrate that SGLT-2 inhibition triggers a fasting-like transcriptional and metabolic paradigm.

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