Sodium glucose cotransporter 2 inhibitor dapagliflozin depressed adiposity and ameliorated hepatic steatosis in high-fat diet induced obese mice

Abstract

With the increasing obesity prevalence, the rates of obesity-related diseases, including type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases, have increased dramatically. Dapagliflozin, one of the sodium glucose cotransporter inhibitors, not only exerts hypoglycaemic effects through increasing urinary glucose excretion but alsoreprograms the metabolic system, leading to benefits in metabolic and cardiovascular diseases. In this study, pre-established obese mice on a high-fat diet were given dapagliflozin by gavage for fourweeks. It showed that dapagliflozin can enhance fat utilization and browning of adipose tissue and improve local oxidative stress, thus inhibiting fat accumulation and hepatic steatosis without disturbance in body weight or plasma glycolipid level. Overall, our study highlights the potential clinical application of SGLT2 inhibition in the prevention of obesity and related metabolic diseases, such as insulin resistance, NAFLD, and diabetes.

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

“…Administration of SGLT-2i leads to net loss of calories and consequent attenuation of body weight gain, while reducing the accumulated white adipose tissue [ 99 , 105 , 106 , 107 ]. In fact, it has been found that SGLT-2i promote weight loss through improvement of systemic IR, increased body temperature and basal metabolism via regulation of the AMP/ATP ratio [ 19 ].…”

“…However, it should be noted that not all studies point towards a beneficial effect of SGLT-2i on body weight. Several studies have shown that administration of SGLT-2i does not exert any significant effect on body weight gain, epididymal fat weight or food intake [ 30 , 105 , 110 , 111 ]. In addition, although several studies reported strong effects of low dose ipragliflozin ( Table 4 ) on weight loss [ 100 , 112 , 113 ], supplementation of an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks did not significantly alter the body weight of AMLN diet fed mice, while it improved liver function, hepatic fibrosis and NA score [ 114 ].…”

“…SGLT-2i have been also shown to reverse the HFD-induced down regulation of genes involved in FA β-oxidation and lipolysis in the liver of various mouse models of NAFLD [ 30 , 84 , 107 , 108 ]. Indeed, it has been shown that expression of PPARα is induced by SGLT-2i [ 84 , 105 , 107 , 114 ]. PPARα activation is predominant for regulation of genes related to the FA β-oxidation process in mitochondria, such as peroxisomal acyl-CoA oxidase1 (ACOX1) and enoyl-CoA hydratase, CPT1, and cytochrome-mediated (CYP4A1 and CYP4A3) [ 44 ].…”

“…Meng et al, demonstrated that induction of AMPK/mTOR activity is dominant pathway in empagliflozin-induced beneficial effects on liver inflammation and ALT levels [ 117 ]. Dapagliflozin treatment also induced AMPK/mTOR pathway activation through phosphorylation of liver kinase B1 (LKB1; a ubiquitously expressed master serine/threonine kinase that activates downstream kinases of the AMPK pathway) [ 105 , 138 ]. Previous studies have demonstrated that AMPK activation is required for SGLT-2i induced autophagy-dependent lipid catabolism [ 30 , 117 ].…”

Dapagliflozin promotes browning of white adipose tissue through the FGFR1-LKB1-AMPK signaling pathway

“…Specifically, following DAPA treatment, obese mice fed a high-fat diet experienced weight loss, primarily through reduction in subcutaneous and visceral fat pools. Additionally, DAPA treatment promotes mitochondrial biogenesis and increases cellular energy expenditure [ 15 , 16 ]. Notably, the expression of UCP1 in both WAT and BAT was significantly elevated, indicating DAPA’s ability to promote the activation of BAT and the “browning” of WAT [ 14 ].…”