Given the impact of SGLT2 inhibitors to reduce overall mortality and CV risk in T2D, improved understanding of cellular and transcriptional mechanisms responsible for metabolic effects is required. We fed C57BL/6J mice a 60% high fat diet (HFD) for 4 weeks prior to assignment to one of 3 groups: (1) 60% HFD, (2) HFD with canagliflozin (CANA, 25 mg/kg/day), and (3) HFD weight-matched (WM) to CANA via caloric restriction. Mice were analyzed after 4-8 weeks. CANA reduced fasting glucose by 47% (P<0.0001), improved glucose tolerance, and 25% lower body weight vs. HFD (p<0.0001). CANA promoted shift toward lipid utilization, with respiratory quotient <0.7 even during feeding, and a 3.7 and 2.0-fold increase in plasma and liver β-hydroxybutyrate (both p<0.01 vs. HFD). In parallel, liver glycogen and cholesterol were reduced by 55% and 28%, and triglycerides were shifted toward polyunsaturated species.
To identify potential mechanisms responsible for these fasting-like phenotypes, we analyzed the molecular impact of CANA. Liver transcriptomic analysis revealed marked downregulation of lipogenesis, glycolysis, and steroid synthesis pathways (p<0.01), while the lipid oxidative regulatory genes PPARα and PGC1α were increased by 2.8 and 4-fold, respectively. CANA significantly increased hepatic FAD+ (2.4-fold) and AMP (1.3-fold), in parallel with a 12-fold increase in AMPK phosphorylation and 50% reduction in Tor-dependent phosphorylation of S6. Hepatic gene expression of FGF-21, a hormonal regulator of fatty acid oxidation and ketogenesis, was increased by 4.5-fold, with parallel 2.2-fold increase in plasma FGF-21 in CANA-treated mice (p<0.vs. HFD for both). These effects were independent of insulin sensitivity or glucagon signaling. Collectively, these data demonstrate CANA induction of a fasting-like state by coordinated transcriptional-metabolic reprogramming, and identify FGF-21 as a potential molecular metabolic switch.
S. Osataphan: None. C. Macchi: None. V. Sales: None. C. Kozuka: None. J.I. Chimene-Weiss: None. Y. Tangjaroenpaisan: None. J. Morningstar: None. R. Gerszten: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.