7 research outputs found
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\u2032 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
SGLT2 Inhibitor Canagliflozin Triggers Hepatic Transcriptional Reprogramming and Impacts Systemic Metabolism in Mice with Diet-Induced Obesity
To determine the impact of SGLT2 inhibition and reduction in plasma glucose on transcriptional and metabolic responses, we fed normoglycemic C57BL/6J mice a 60% HFD for 4 weeks prior to assignment to one of 3 groups (n=12/group): (1) HFD ad libitum (HFD), (2) HFD ad libitum with canagliflozin (CANA, 30mg/kg/day), and (3) HFD weight-matched to CANA-treated mice via caloric restriction (CR). Fasting plasma glucose was reduced by 68 mg/dl (p66% of parenchyma, X2 p=0.056) but no change in triglyceride content (4.3 \ub1 1.7 vs. 3.7 \ub1 1.2 mg/g tissue, p=0.85).
To evaluate transcriptional responses to resolution of glucotoxicity, RNA was extracted from liver and processed for microarray analysis (Mouse Gene 2.0 ST). 2048 genes were differentially expressed between CANA and HFD (p<0.05). Pathway analysis revealed downregulation of de novo lipogenesis, glycolysis and steroid biosynthesis, and upregulation of TCA cycle and electron transport chain (p<0.05). Parallel targeted metabolite profiling (LC/MS) revealed significant changes in 31 metabolites and 59 lipid species (p<0.05). Among these, deoxycholic acid, C3 malonyl-canitine, malonic acid, and the ketones acetoacetate and \u3b2-hydroxybutyrate were significantly higher in CANA. Moreover there were significant increases in polyunsaturated fatty acids within triglyceride fractions.
Collectively, these data indicate that SGLT2 inhibition and sustained reduction in plasma glucose trigger altered hepatic transcriptional programs, inducing not only ketogenesis and oxidative catabolism but also reduced de novo lipogenesis, potentially via reduced activation of key lipid and carbohydrate regulatory transcription factors SREBP2 and ChREBP