Supplementary MaterialsSupplemental data jciinsight-4-123130-s183. induces transcriptional reprogramming to activate catabolic pathways, boost 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 AMG 837 excess 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. 0.0001). While fasting glucose was also decreased in WM mice, the reduction was greater in magnitude in CANA-treated mice ( 0.05). CANA also attenuated HFD-induced putting on weight (Amount 1C); weights of WM mice had been comparable to those of CANA-treated mice, according to study style. CANA-treated mice possess improved oral blood sugar tolerance, with better magnitude in comparison with WM group (Amount 1D). Insulin amounts had been very similar in the fasting condition in every 3 groupings but had been lower at a quarter-hour after blood sugar gavage in CANA-treated mice in comparison with both control and WM mice (Amount 1E). Oddly enough, glucose-stimulated GLP-1 amounts had been low in WM mice but had been preserved in CANA-treated mice at amounts comparable to those of HFD-fed mice (Amount 1F). In comparison, fasting glucagon amounts didn’t differ between groupings (Amount 1G). Insulin awareness, evaluated by insulin tolerance examining, didn’t differ between groupings (Amount 1H). Likewise, despite lower fasting blood sugar with CANA, there is no transformation in glycemic response to glucagon or pyruvate (Supplemental Amount 1, A and B; supplemental materials available on the web with this post; https://doi.org/10.1172/jci.understanding.123130DS1). Needlessly to say, water consumption was significantly elevated in CANA-treated mice AMG 837 (Amount 1I), likely because of elevated urine result through osmotic diuresis. Open up in another window Amount 1 Canagliflozin decreases blood glucose, increases blood sugar tolerance, and causes a change toward lipid usage.(A) Urinary glucose in HFD, fat matched (WM), and HFD + CANA (CANA) following an right away fast, after eight weeks of treatment (= 8C11/group). (B) Blood sugar after a 16-hour fast (= 8/group). (C) Bodyweight (= 12/group). (D) Mouth blood sugar tolerance (2 g/kg, = 12/group). (E) Plasma insulin, fasting and a quarter-hour after blood sugar gavage (= 8/group). (F) Plasma glucagon-like peptide-1 (GLP-1), fasting and a quarter-hour after blood sugar gavage (= 8/group). (G) Fasting plasma glucagon (= 6/group). (H) Insulin tolerance (0.75 U/kg, = 8/group). (I) Drinking water consumption (= 6C12/group). (J) Respiratory exchange proportion (= 6C12/group). (K) Serum-free essential fatty acids (4-hour fast, = 11C12/group). (L) Serum ketones (LC/MS, = 7C8/group). beliefs (1- or 2-method Mouse monoclonal to EphA4 ANOVA). * 0.05, ** 0.01, *** 0.001, **** 0.0001 in HFD vs. CANA. # 0.05, ## 0.01, ### 0.001, #### 0.0001 in WM vs. CANA; and $ 0.05, $$ 0.01, $$$ 0.001, $$$$ 0.0001 in WM vs. HFD. We hypothesized which the reduction in blood sugar carbon resources through glycosuria would cause utilization AMG 837 of choice fuel sources, such as for example essential fatty acids and proteins. Indeed, metabolic cage analysis confirmed low respiratory system exchange ratio ( 0 persistently.7) in CANA-treated mice, even through AMG 837 the given state (Amount 1J), implying increased lipid or ketone usage, in comparison with both WM and HFD mice. O2 consumption, high temperature production, exercise, and food intake were unchanged (Supplemental Number 1, CCG). Raises in whole-body fatty acid mobilization and utilization in CANA-treated mice were also supported by a pattern to improved free fatty acids (Number 1K) and a significant increase in the serum ketones acetoacetate and 3-hydroxybutyrate (as measured by LC/MS) (Number 1L and Supplemental Number 1H). Serum valine, leucine, isoleucine, and total branched chain amino acids (BCAA) tended to decrease in CANA-treated mice (Supplemental Number 1, H and I). To further assess weight-dependent versus weight-independent effects of CANA treatment, we also analyzed in vivo rate of metabolism in slim mice fed a low-fat diet (LFD) (Supplemental Number 2). Much like HFD-fed mice, CANA induced glycosuria, reduced fasting glucose, improved glucose tolerance, improved whole body lipid oxidation, and improved serum -hydroxybutyrate levels. By contrast, CANA did not change body weight or adipose cells mass in LFD-fed mice. Therefore, metabolic reactions to CANA happen actually in the absence of excess weight loss. CANA reduced hepatic steatosis and shifts gas utilization from carbohydrates toward catabolic lipid rate of metabolism and ketogenesis. To better understand the effect of CANA at a cells level, we analyzed liver lipid rate of metabolism. H&E staining exposed a significant reduction in hepatic steatosis in CANA-treated mice (Number 2A);.