Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading to blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. It is associated with clinical states such as obesity, insulin resistance, and type 2 diabetes, and covers a wide range of liver changes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. Metabolic disorders, such as lipid accumulation, insulin resistance, and inflammation, have been implicated in the pathogenesis of NAFLD, but the underlying mechanisms, including those that drive disease progression, are not fully understood. Both innate and recruited immune cells mediate the development of insulin resistance and NASH. Therefore, modifying the polarization of resident and recruited macrophage/Kupffer cells is expected to lead to new therapeutic strategies in NAFLD. Oxidative stress is also pivotal for the progression of NASH, which has generated interest in carotenoids as potent micronutrient antioxidants in the treatment of NAFLD. In addition to their antioxidative function, carotenoids regulate macrophage/Kupffer cell polarization and thereby prevent NASH progression. In this review, we summarize the molecular mechanisms involved in the pathogenesis of NAFLD, including macrophage/Kupffer cell polarization, and disturbed hepatic function in NAFLD. We also discuss dietary antioxidants, such as β-cryptoxanthin and astaxanthin, that may be effective in the prevention or treatment of NAFLD.

Objective We reported previously that empagliflozin—a sodium-glucose cotransporter (SGLT) 2 inhibitor—exhibited preventive effects against obesity. However, it was difficult to extrapolate these results to human subjects. Here, we performed a therapeutic study, which is more relevant to clinical situations in humans, to investigate antiobesity effects of empagliflozin and illustrate the mechanism underlying empagliflozin-mediated enhanced fat browning in obese mice. Research design and methods After 8 weeks on a high-fat diet (HFD), C57BL/6J mice exhibited obesity, accompanied by insulin resistance and low-grade chronic inflammation. Cohorts of obese mice were continued on the HFD for an additional 8-week treatment period with or without empagliflozin. Results Treatment with empagliflozin for 8 weeks markedly increased glucose excretion in urine, and suppressed HFD-induced weight gain, insulin resistance and hepatic steatosis. Notably, empagliflozin enhanced oxygen consumption and carbon dioxide production, leading to increased energy expenditure. Consistently, the level of uncoupling protein 1 expression was increased in both brown and white (WAT) adipose tissues of empagliflozin-treated mice. Furthermore, empagliflozin decreased plasma levels of interleukin (IL)-6 and monocyte chemoattractant protein-1, but increased plasma levels of IL-33 and adiponectin in obese mice. Finally, we found that empagliflozin reduced M1-polarized macrophage accumulation, while inducing the anti-inflammatory M2 phenotype of macrophages in the WAT and liver, thereby attenuating obesity-related chronic inflammation. Conclusions Treatment with empagliflozin attenuated weight gain by increasing energy expenditure and adipose tissue browning, and alleviated obesity-associated inflammation and insulin resistance by alternative macrophage activation in the WAT and liver of obese mice.

Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.