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    • Although the present study revealed that increased

    2018-10-23

    Although the present study revealed that increased UGE drove reductions in adiposity and ectopic fat, these findings may be limited because the effects of empagliflozin were evaluated using preventative treatments rather than a therapeutic study design. Additional therapeutic studies will aid in the translation of experimental results regarding the anti-obesity effects of SGLT2 inhibitors to clinical settings. The differences among the clinical doses of empagliflozin used for humans (10 and 25mg/d) and the experimental doses used for rats (3mg/kg/d) (Thomas et al., 2012) and mice (3 and 10mg/kg/d) in the present study may reflect differences in the pharmacokinetic parameters between humans and rodents. The linear pharmacokinetics of empagliflozin indicate that the maximum plasma concentration (Cmax) after 3mg/kg of this drug is administered can be estimated as approximately 500nM; even if a 10-fold higher concentration is assumed to be present in the kidney, this would still be below the apparent Ki (inhibition constant; 8500nM) of empagliflozin for SGLT-1 (Grempler et al., 2012). Therefore, the relevant inhibition of human, mouse, or rat SGLT-1 by pharmacological doses of empagliflozin would not be expected. Pharmacologically induced glucosuria leads to adaptive responses in glucose homeostasis and hormone release, and the genetic or pharmacological inhibition of SGLT2 has beneficial effects on hyperinsulinemia and hyperglycaemia (Tahara et al., 2013; Vallon et al., 2013). Conversely, SGLT2 inhibition induces EGP in mice (Bonner et al., 2015; Neschen et al., 2015). In patients with type 2 diabetes, SGLT2 inhibitors also increase EGP and plasma abscisic acid levels, as well as decrease plasma glucose and insulin levels (Ferrannini et al., 2014; Merovci et al., 2014). The empagliflozin-induced hormonal change in relative hyperglucagonemia can be explained by reductions in glycaemia and insulin release, as insulin normally restrains glucagon secretion via paracrine action (Maruyama et al., 1984). Moreover, a recent study suggested that the inhibition of SGLT2 with dapagliflozin directly triggered glucagon secretion in pancreatic alpha-cells (Bonner et al., 2015). Our study confirmed that empagliflozin induced the expression of genes involved in hepatic glucose production and glucagon release and reduced the ratio of insulin to glucagon. Moreover, empagliflozin decreased the number and size of pancreatic islets, although it did not alter alpha-cell mass. These results suggest that the suppression of hyperinsulinemia by empagliflozin causes relative hyperglucagonemia and increases EGP. This relative hyperglucagonemia may promote lipolysis, contributing to fat utilization and the release of ketone bodies in DIO mice. Consistent with previous reports demonstrating the anti-obesity effects of SGLT2 inhibitors (Devenny et al., 2012; Nakano et al., 2015; Yokono et al., 2014), we found that the administration of empagliflozin mitigated HFD-induced weight gain and fatty liver changes. Our findings suggest an underlying mechanism for the weight reduction that depends partially on increased energy expenditure and enhanced fatty acid oxidation. In our study, empagliflozin enhances the phosphorylation of AMPKα and ACC in skeletal muscle. A recent study found that canagliflozin activates AMPK in vitro and lowers liver lipid content (Hawley et al., 2016). Once activated, AMPK acts to restore energy homeostasis by promoting catabolic pathways, including fatty acid oxidation, while inhibiting anabolic pathways, including fatty acid synthesis (Hardie, 2014; Hardie et al., 2016). Adiponectin activates AMPK via adiponectin receptor 1 in skeletal muscle (Yamauchi and Kadowaki, 2008). Moreover, the inhibition of SGLT2 increases energy expenditure, leading to the increase of AMP/ATP (Gowans et al., 2013). Therefore, the potential mechanisms of activation of AMPK by empagliflozin are, at least in part, via increased adiponectin expression in WAT and elevation of AMP/ATP. Because the phosphorylation of ACC by AMPK is known to lower muscle lipid content, our results suggest a potential benefit of empagliflozin and other SGLT2 inhibitors in protecting against obesity or ectopic fat accumulation. In the present study, the low dose of empagliflozin tended to increase the phosphorylation levels of ACC and AMPK, which contributed to the decreases in ectopic fat in the liver and muscle in the absence of weight reduction.