Hepatic Steatosis In Obese Mice Research Articles

Alpha Hydroxyl Acids from Mume Fructus and Schisandrae Chinensis Fructus Prevent Obesity by Inhibiting Intestinal Lipase in Diet-Induced Obese Mice.

Restriction of lipid uptake and absorption from the diet is regarded as an efficient strategy for the management of obesity, while lipase inhibition could successfully block the digestion of dietary lipids. Mume Fructus (MF) and Schisandrae Chinensis Fructus (SCF) were used as fruits, the biological effect of which on obesity desired more attention. Herein, the extracts of MF and SCF displayed significant efficacy in managing obesity in mice fed with a high-fat diet, via the inhibition of hydrolase activity of lipase in the digestive tract. Using the bioactivity guidance strategy, citric acid and malic acid were identified as the major lipase inhibitors from MF and SCF, respectively, which could prevent body weight gain, along with adipose tissue formation, and alleviate hyperlipidemia and hepatic steatosis in obese mice. Above all, MF and SCF could be used for the management of obesity via the lipase inhibition by citric acid and malic acid, displaying potential applications in healthy foods, nutritional supplements, and pharmaceutical materials.

Dietary Supplementation with Apis mellifera Wholemeal Flour Reduces Hepatic Steatosis in Obese Mice.

Dietary Supplementation with Apis mellifera Wholemeal Flour Reduces Hepatic Steatosis in Obese Mice.

NADPH oxidase 1 promotes hepatic steatosis in obese mice and is abrogated by augmented skeletal muscle mass.

Exercise as a lifestyle modification is a frontline therapy for nonalcoholic fatty liver disease (NAFLD), but how components of exercise attenuate steatosis is unclear. To uncouple the effect of increased muscle mass from weight loss in obesity, myostatin knockout mice were bred on a lean and obese db/db background. Myostatin deletion increases gastrocnemius (Gastrocn.) mass and reduces hepatic steatosis and hepatic sterol regulatory element binding protein 1 (Srebp1) expression in obese mice, with no impact on adiposity or body weight. Interestingly, hypermuscularity reduces hepatic NADPH oxidase 1 (Nox1) expression but not NADPH oxidase 4 (Nox4) in db/db mice. To evaluate a deterministic function of Nox1 on steatosis, Nox1 knockout mice were bred on a lean and db/db background. NOX1 deletion significantly attenuates hepatic oxidant stress, steatosis, and Srebp1 programming in obese mice to parallel hypermuscularity, with no improvement in adiposity, glucose control, or hypertriglyceridemia to suggest off-target effects. Directly assessing the role of NOX1 on SREBP1, insulin (Ins)-mediated SREBP1 expression was significantly increased in either NOX1, NADPH oxidase organizer 1 (NOXO1), and NADPH oxidase activator 1 (NOXA1) or NOX5-transfected HepG2 cells versus ?-galactosidase control virus, indicating superoxide is the key mechanistic agent for the actions of NOX1 on SREBP1. Metabolic Nox1 regulators were evaluated using physiological, genetic, and diet-induced animal models that modulated upstream glucose and insulin signaling, identifying hyperinsulinemia as the key metabolic derangement explaining Nox1-induced steatosis in obesity. GEO data revealed that hepatic NOX1 predicts steatosis in obese humans with biopsy-proven NAFLD. Taken together, these data suggest that hypermuscularity attenuates Srebp1 expression in db/db mice through a NOX1-dependent mechanism.NEW & NOTEWORTHY This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.

Pectin-derived oligogalacturonic acids ameliorate high-fat diet-induced obesity in mice by regulating gut microbiota and inflammation

Pectic oligosaccharides have been proposed as a novel prebiotic to prevent obesity and associated with metabolic disorders by regulating gut microbiota, but their various probiotic functions in the gut depended on their complex and heterogeneous sugar composition. This study aimed to obtain specific oligogalacturonic acids (POAS) from pectin and investigate the effects of POAS on high-fat diet-induced obesity in mice. The results showed that POAS improved body weight gain, serum lipids and hepatic steatosis in obese mice. POAS notably enhanced intestinal barrier function, reduced inflammatory response and regulated the expression of key genes in lipid synthesis and metabolism. Besides, POAS also promoted short-chain fatty acids (SCFAs) production. Furthermore, POAS alleviated the gut microbiota dysbiosis caused by HFD with significantly increasing beneficial gut microbiota such as Akkermansia and Lactobacillus. Spearman's correlation analysis indicated that these bacteria were strongly correlated with obesity-related parameters. We conclude that POAS is a potential prebiotic to treat obesity and related complications.

Diet Supplementation of Luteolin before Fatty Liver Formation Improves Hepatic Steatosis in Obese Mice by Inhibiting Visceral Adipose Tissue Lipolysis.

Serotonin (5-HT)-induced visceral adipocyte lipolysis is essential for the development of obesity-related complications. Diet supplementation of luteolin prevents high-fat diet (HFD)-fed mice against obesity and associated fatty liver. However, independent of the body weight loss, whether dietary luteolin can substantially reduce hepatic steatosis remains unclear. In differentiated 3T3-L1 cells, 5-HT treatment promotes adipocyte lipolysis, while luteolin significantly inhibits 5-HT-induced lipolysis, Ca2+ -PKG cascade, and SIRT1/FoxO1/AMPKα signaling through binding to 5-HT receptor HTR2B. Further, 5-week-old mice are fed with an HFD for 16 weeks. At the 6th, 8th, or 10th weeks of HFD feeding, some mice are switched to a luteolin-containing HFD, respectively. In all HFD-fed mice, body weight gain and body component are unaffected by dietary luteolin. However, diet supplementation of luteolin at the 6th or 8th, rather than at the 10th weeks, alleviates hepatic steatosis. Meanwhile, dietary luteolin reduces epididymal adipose tissue (EAT) lipolysis, and represses the level of lipolytic enzyme, the expression of Htr2b, and the activation of PKG and SIRT1/FoxO1/AMPKα signaling in EAT. Diet supplementation of luteolin before the formation of fatty liver protects HFD-fed mice against ectopic lipid deposition in liver by inhibiting visceral adipocyte lipolysis.

Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.

The aqueous extract of Phragmites rhizome improves hepatic steatosis in obese mice via the AMPK-mediated inhibition of ER stress

Phragmites rhizome has been documented to have antioxidative stress and anti-inflammation properties in several pathogenic models. We aimed to investigate the therapeutic effects and molecular mechanism of the aqueous extract of Phragmites rhizome (AP) in in vitro and in vivo hepatic steatosis models. We found that treatment with AP dose-dependently reduced lipid accumulation and endoplasmic reticulum (ER) stress in palmitate-treated human primary hepatocytes and attenuated hepatic steatosis and ER stress in high-fat diet (HFD)-fed mice. AMPK phosphorylation and autophagy markers in hepatocytes were augmented by AP. siRNA targeting AMPK or 3-methyladenine (3-MA) abolished the impacts of AP on palmitate-treated hepatocytes. These results suggest that AP treatment suppresses hepatic ER stress through AMPK/autophagy signaling, leading to attenuation of hepatic steatosis. The present study may provide a novel therapeutic approach for treating nonalcoholic fatty liver disease (NAFLD) and ER stress-mediated metabolic diseases using natural substances.

Driving arginine catabolism to activate systemic autophagy.

Macroautophagy/autophagy is a conserved cellular self-digestive mechanism to catabolize superfluous or damaged cellular components to maintain cell homeostasis. Impaired autophagy underlies multiple pathophysiological states, including aging, neurodegenerative, inflammatory, and metabolic diseases. Intermittent fasting and caloric restriction are effective means by which to activate autophagy, yet relatively few people can sustain such intensive interventions in real-world settings. Moreover, current pharmacotherapies do not yet fully exploit autophagic flux as a target mechanism. Here, we discuss recent work, which demonstrates that arginine catabolism is a tractable process to activate autophagy with utility to treat obesity and its complications. Hepatocyte-specific transgenic activation of arginine catabolism, or systemic administration of an anti-tumor pharmacotherapy, pegylated arginine deiminase, each promote energy expenditure and insulin sensitivity, and reduce dyslipidemia and hepatic steatosis in obese mice. These effects depend upon hepatocyte Fgf21, and whole-body Becn1 expression. The data suggest that hepatocyte and systemic arginine catabolism drive autophagy, and identify an index pharmacological agent to leverage this process.

3-N-butylphthalide protects against high-fat-diet-induced obesity in C57BL/6 mice and increases metabolism in lipid-accumulating cells

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.

Activation of N-methyl-D-aspartate receptor regulates insulin sensitivity and lipid metabolism.

Rationale: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity.Methods: We examined the glutamate level in the obese mouse induced by a high-fat diet (HFD) for 12 weeks. To assess the role of NMDAR in insulin sensitivity and lipid metabolism, we tested the effects of Memantine (an NMDAR antagonist) and NMDA (an NMDAR agonist) on mice fed with HFD or standard chow diet. The in vitros NMDAR roles were analyzed in hepatocytes and potential mechanisms involved in regulating lipid metabolism were investigated.Results: Glutamate was increased in the serum of HFD-treated mice. The NMDAR blockade by Memantine decreased the susceptibility to insulin resistance and hepatic steatosis in obese mice. NMDA treatment for 6 months induced obesity in mice, characterized by hyperglycemia, hyperlipidemia, insulin resistance, and pathological changes in the liver. We provided in vitro evidence demonstrating that NMDAR activation facilitated metabolic syndrome in obesity through promoting lipid accumulation. NMDAR inhibition attenuated lipid accumulation induced by palmitic acid. Mechanistically, NMDAR activation impaired fatty acid oxidation by reducing PPARα phosphorylation and activity. The PPARα activity reduction induced by NMDAR activation was reversibly mediated by ERK1/2 signaling.Conclusion: These findings revealed that targeting NMDAR might be a promising therapeutic strategy for metabolic syndrome in obesity.

Allicin Regulates Energy Homeostasis through Brown Adipose Tissue.

SummaryBrown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a natural product in garlic, has multiple biological and pharmacological functions. However, the role of allicin in the regulation of metabolic organs, particularly BAT activation, has not been well studied. Here, we show that allicin imparts a significant effect by inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in obese mice. These observations strongly correlate with the activation of BAT. Notably, allicin plays a role in BAT activation, which may partly contribute to the Sirt1-PGC1α-Tfam pathway. In addition, allicin can significantly increase the succinylation levels of UCP1 in BAT by inhibiting sirt5, whereas excess allicin induces autophagy/mitophagy and mitochondrial dysfunction. Thus, our findings point to allicin as a promising therapeutic approach for the treatment of obesity and metabolic disorders.

Iridoids of Valeriana fauriei contribute to alleviating hepatic steatosis in obese mice by lipophagy

Nonalcoholic fatty liver disease (NAFLD) is a common risk factor for metabolic syndrome that increases the risk of future cardiovascular disease, stroke, and diabetes. Recently, autophagy has been proposed as a means to prevent NAFLD. We investigated whether substances with autophagy-inducing activity alleviate NAFLD. The Valeriana fauriei (V. fauriei) was selected as a potential autophagy inducer among various natural materials using a Cyto-ID autophagy detection kit. V. fauriei 70 % ethanol extract (VFE) increased LC3II levels in the presence of the lysosomal inhibitor and reduced the GFP/mCherry puncta ratio, suggesting that VFE enhanced autophagy. VFE reduced oleic acid (OA)-induced lipid accumulation and increased the number of autophagosome in hepatocytes. Autophagy induction by VFE is due to inhibition of mTORC1 activity. VFE supplementation reduced fatty liver by downregulating lipogenesis-related genes and increased the autophagy, as revealed by TEM and IHC analysis in the fatty liver. We identified iridoids as main compounds of VFE; didrovaltrate (DI), valeriotriate B (VAL B), valeriotetrate C (VAL C), valtrate (VAL), and valechlorine (VC) were shown to enhance autophagy. These compounds also reduced OA-induced lipid accumulation in an Atg5-dependent manner. Taken together, VFE and its iridoids might be effective in alleviating fatty liver by acting as autophagy enhancers to break down LDs.

Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance.

Obesity is an increasing pathophysiological problem in developed societies. Despite all major progress in understanding molecular mechanisms of obesity, currently available anti-obesity drugs have shown limited efficacy with severe side effects. CRISPR interference (CRISPRi) mechanism based on catalytically dead Cas9 (dCas9) and single guide RNA (sgRNA) was combined with a targeted nonviral gene delivery system to treat obesity and obesity-induced type 2 diabetes. A fusion peptide targeting a vascular and cellular marker of adipose tissue, prohibitin, was developed by conjugation of adipocyte targeting sequence (CKGGRAKDC) to 9-mer arginine (ATS-9R). (dCas9/sgFabp4) + ATS-9R oligoplexes showed effective condensation and selective delivery into mature adipocytes. Targeted delivery of the CRISPRi system against Fabp4 to white adipocytes by ATS-9R induced effective silencing of Fabp4, resulting in reduction of body weight and inflammation and restoration of hepatic steatosis in obese mice. This RNA-guided DNA recognition platform provides a simple and safe approach to regress and treat obesity and obesity-induced metabolic syndromes.

“Living High-training Low” Improves Hepatic Steatosis In Obese Mice

“Living High-training Low” Improves Hepatic Steatosis In Obese Mice

Pear Extract and Malaxinic Acid Reverse Obesity, Adipose Tissue Inflammation, and Hepatosteatosis in Mice.

Obesity and diabetes are major public health problems and are emerging as pandemics. Considerable evidence suggests that pear fruit consumption is associated with a lower risk of obesity-related complications. Thus, the present study is conducted to investigate the therapeutic potential of pear extract (PE) for reversing obesity and associated metabolic complications in high-fat diet-induced obese mice. Obesity is induced in male C57BL/6 mice fed a high-fat diet for 11 weeks. After the first 6 weeks on the diet, obese mice are administered vehicle or PE for 5 weeks. PE treatment decreases body weight gain, expands white adipose tissue (WAT), and causes hepatic steatosis in obese mice, as well as inhibits adipogenesis and lipogenesis. Impaired glucose tolerance and insulin resistance are improved by PE. In addition, PE reduces macrophage infiltration and expression of pro-inflammatory genes and deactivates mitogen-activated protein kinases in WAT. Finally, malaxinic acid is identified as an active component responsible for the anti-obesity effects of PE in mice. The results demonstrate that PE supplementation ameliorates diet-induced obesity and associated metabolic complications and suggest the health-beneficial effects of both pear fruits and malaxinic acid in counteracting these diseases.

Hepatic Sympathetic Denervation Reduces Hepatic Steatosis and Blunts Liver Lipid Acquisition Pathways in Diet‐Induced Obese Mice

Non‐alcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, is directly associated with obesity and a significant contributor to chronic metabolic and cardiovascular diseases. We recently demonstrated that diet‐induced NAFLD is accompanied by robust elevations in hepatic sympathetic nerve activity (SNA), and that pharmacological or surgical reductions in hepatic SNA reduces hepatic steatosis in obese mice. However, the underlying molecular mechanisms through which liver SNA contributes to NAFLD remain unknown. We hypothesized that liver SNA contributes to hepatic steatosis via influences on both liver acquisition and disposal pathways. Starting at 6 wks of age, male C57B1/6 mice were fed a high fat diet (HFD, 60% fat) or remained on normal chow (NC, 5% fat) for 10 wks. Liver selective sympathetic denervation was then performed by applying 10% phenol to the hepatic nerve bundle, whereas saline served as a sham surgery. Seven days after surgery, histological examination (Oil Red O) confirmed widespread and severe lipid accumulation in the liver of HFD mice relative to NC counterparts (0.6±0.4% vs 38±7% stained area, NC Sham vs HFD Sham, p<0.05), which was reduced following liver denervation (16±5% stained area, HFD Denervation, p<0.05 vs HFD sham). Western blot analysis revealed that hepatic carnitine palmitoyltransferase 1a (CPT1a), as an indicator of mitochondria b‐oxidation, and acyl‐coenzyme A oxidase 1 (ACOX1), as a marker of peroxisomal b‐oxidation, were elevated following HFD feeding (CPT1a: 1.0±0.0 vs 1.5±0.1; ACOX1: 1.0±0.1 vs 1.2±0.1 fold NC, NC Sham vs HFD Sham, p<0.05 for both). Liver denervation did not affect hepatic CPT1a and ACOX1 expression in either diet group (e.g. CPT1a fold NC: NC Denervation 0.9±0.1; HFD Denervation 1.4±0.2, p>0.05 vs respective Sham). In addition, liver denervation did not alter microsomal triglyceride transfer protein, an endoplasmic reticulum protein involved in the processing of VLDL in either diet group. Real time PCR analysis showed robust obesity‐associated elevations in liver fatty acid transport protein 5, suggestive of increased liver FFA uptake, which was reduced by 30% following removal of liver SNA (2.9±1.1 vs 9.7±1.0 fold NC, NC Sham vs HFD Sham, p<0.05; 6.9±0.8 fold NC, HFD Denervation, p=0.2). Liver immunohistochemistry also indicated that the FFA transport protein cluster of differentiation 36 (CD36) was upregulated following HFD feeding and reduced in obese mice following removal of hepatic SNA (Figure). Lastly, HFD feeding resulted in an upregulation of mRNA indicators of triglyceride synthesis, (e.g. acyl‐CoA diacylglycerol acyltransferase 2: 1.0±0.2 vs 2.6±0.2 fold NC, NC Sham vs HFD Sham, p<0.05), which were reduced by liver denervation in HFD animals (1.4±0.2 fold NC, HFD Denervation, p<0.05 vs HFD sham). Collectively, these findings indicate that removal of the liver sympathetic nerves appears to beneficially alter hepatic triglyceride storage during HFD feeding by influencing lipid acquisition pathways, with less of an effect on triglyceride disposal mechanisms. These data also reinforce the idea that targeting hepatic sympathetic overactivity may be a novel therapeutic strategy to treat NAFLD.Support or Funding InformationHL116776This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

α7-Nicotinic Acetylcholine Receptor Agonist Ameliorates Nicotine Plus High-Fat Diet-Induced Hepatic Steatosis in Male Mice by Inhibiting Oxidative Stress and Stimulating AMPK Signaling.

α7-Nicotinic acetylcholine receptor (α7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether PNU-282987 (PNU), a specific α7nAChR agonist, is effective in preventing nicotine plus HFD-induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily intraperitoneal injections of 0.75 mg/kg body weight (BW) of nicotine, PNU (0.26 mg/kg BW), PNU plus nicotine, or saline for 10 weeks. PNU treatment was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis, and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress and activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) together with inhibition of its downstream target sterol regulatory element binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl-coenzyme A-carboxylase (ACC). We conclude that the α7nAChR agonist PNU protects against nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. α7nAChR agonists may be an effective therapeutic strategy for ameliorating fatty liver disease, especially in obese smokers.

Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ERα/HGF/Met Pathway.

Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, how macrophages affect hepatocytes remains elusive. Mineralocorticoid receptor (MR) has been implicated to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1 [encoding ERα]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ERα/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance and provide potential new therapeutic strategies for NAFLD and T2DM.

New Medications for the Treatment of Diabetes.

New Medications for the Treatment of Diabetes.

Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction.

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.