Obesity-related Non-alcoholic Fatty Liver Disease Research Articles

Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk.

Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.

Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.

A Novel Wistar Rat Model of Obesity-Related Nonalcoholic Fatty Liver Disease Induced by Sucrose-Rich Diet.

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is not fully understood, and experimental models are an alternative to study this issue. We investigated the effects of a simple carbohydrate-rich diet on the development of obesity-related NAFLD and the impact of physical training on the metabolic abnormalities associated with this disorder. Sixty Wistar rats were randomly separated into experimental and control groups, which were fed with sucrose-enriched (18% simple carbohydrates) and standard diet, respectively. At the end of each experimental period (5, 10, 20, and 30 weeks), 6 animals from each group were sacrificed for blood tests and liver histology and immunohistochemistry. From weeks 25 to 30, 6 animals from each group underwent physical training. The experimental group animals developed obesity and NAFLD, characterized histopathologically by steatosis and hepatocellular ballooning, clinically by increased thoracic circumference and body mass index associated with hyperleptinemia, and metabolically by hyperglycemia, hyperinsulinemia, hypertriglyceridemia, increased levels of very low-density lipoprotein- (VLDL-) cholesterol, depletion of the antioxidants liver enzymes superoxide dismutase and catalase, and increased hepatic levels of malondialdehyde, an oxidative stress marker. Rats that underwent physical training showed increased high-density lipoprotein- (HDL-) cholesterol levels. In conclusion, a sucrose-rich diet induced obesity, insulin resistance, oxidative stress, and NAFLD in rats.

Discovery of a Potent 9-Deazaxanthine-based Agent for the Treatment of Obesity-Related Non-alcoholic Fatty Liver Disease.

A series of deazaxanthine-based derivatives were rationally prepared and evaluated. 8g exhibited the most potent glucose-lowering effect on HepG2 cell line and modulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 8g at 25 mg/kg/day for 4 weeks manifested therapeutic effects on high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) by decreasing the weights of the body, liver, and fat. 8g also modulated the serum levels of fasting glucose and adiponectin, triglycerides, low-density lipoprotein-cholesterol, and alanine aminotransferase, as well as the hepatic concentrations of triglycerides, total cholesterol. Moreover, 8g significantly decreased steatosis and blocked the increase of adipocytes and the size of adipose tissues from NAFLD. In the DIO mice model, 8g ameliorated the obesity-related symptoms and normalized serum biomarkers.

Systematic review on intervention with prebiotics/probiotics in patients with obesity-related nonalcoholic fatty liver disease.

The gut microbiota is modulated by metabolic derangements, such as nutrition overload and obesity. The aim of this systematic review is to summarize the role of these gut modifiers in nonalcoholic fatty liver disease (NAFLD) and obesity. A systematic search of MEDLINE (from 1946), PubMed (from 1946) and EMBASE (from 1949) databases through May 2014 was carried out to identify relevant articles. The search terms were 'probiotic' AND 'NAFLD', 'prebiotic' AND 'NAFLD', 'antibiotic' AND 'NAFLD', 'probiotics' AND 'obesity', 'prebiotic' AND 'obesity' or 'antibiotic' AND 'obesity'; these terms were searched as text word in 'clinical trials' and as exploded medical subject headings where possible. The evidence in the literature is scant, due to the scarcity of appropriately powered, randomized, controlled clinical trials, involving various centers and population of different origin. Although probiotics and prebiotics have been proposed in the treatment and prevention of patients with obesity-related NAFLD, their therapeutic use is not supported by high-quality clinical studies.

The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity-Related Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apnea-hypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-related NAFLD has been associated with the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis, may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NFκB. Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecular mechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD.

High-fructose Intake in Obesity-related Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD involves a spectrum of conditions that include pure steatosis without inflammation, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Insulin resistance (IR) plays a main role in the pathophysiology of NAFLD by causing lipid accumulation in the hepatocytes, which may be followed by lipid peroxidation, production of reactive oxygen species and consequent inflammation. The consumption of carbohydrates, particularly sugars additives high in fructose increased dramatically in the past decades and appears to be at least one very important contributing factor in NAFDL pathogenesis. Recent studies suggest that the excessive consumption of fructose from sugar additives (mainly those found in sweetened beverages and processed foods) is linked to development and severity of NAFLD by induction of IR, postprandial hypertriglyceridemia and lipid accumulation in the liver, especially in individuals with overweight. We discuss the possible mechanisms involving fructose consumption, lipid accumulation and development of NASH. This review also presents the chief findings from all the studies that evaluated fructose consumption in human NAFLD.

The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. It is a progressive disorder involving a spectrum of conditions that include pure steatosis without inflammation, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. The key factor in the pathophysiology of NAFLD is insulin resistance that determines lipid accumulation in the hepatocytes, which may be followed by lipid peroxidation, production of reactive oxygen species and consequent inflammation. Recent studies suggest that the characteristics of the gut microbiota are altered in NAFLD, and also, that small intestinal bacterial overgrowth (SIBO) contributes to the pathogenesis of this condition. This review presents the chief findings from all the controlled studies that evaluated SIBO, gut permeability and endotoxemia in human NAFLD. We also discuss the possible mechanisms involving SIBO, lipid accumulation and development of NASH. The understanding of these mechanisms may allow the development of new targets for NASH treatment in the future.

Nutrition: a promising route for prevention and management of obesity-related nonalcoholic fatty liver disease

When dealing with the treatment of obesity-linked illnesses - in particular nonalcoholic fatty liver disease - beyond diet, various nutritional ingredients are reported to be useful as silymarin, spirulina, choline, folic acid, methionine and vitamin E, all of them showing promising but not definite results. An emerging field of study is represented by prebiotics/probiotics and restoration of normal gut flora, which could play a fundamental role diet and various its components. It is noteworthy to point out that both improving or reducing the severity of nonalcoholic fatty liver disease bear a positive consequence on evolution of atherosclerosis and its cardiovascular-associated disease, such as coronary artery disease, even though the involved immunologic mechanisms are gaining greater credit in the most recent literature, without excluding the role of nutrition in modulating the acquired immunity in this condition.

Clinical outcomes and resource utilisation in Medicare patients with chronic liver disease: a historical cohort study

ObjectiveThe aim of this study is to assess recent trends in health resource utilisation and patient outcomes of Medicare beneficiaries with chronic liver disease (CLD).SettingLiver-related mortality is the 10th leading...

ITCH Deficiency Protects From Diet-Induced Obesity

Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesity-related inflammation and insulin resistance, we compared wild-type and Itch(-/-) mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch(-/-) mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from Itch(-/-) mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity.

Investigation of adropin and leptin levels in pediatric obesity-related nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is the accumulation of excess fat in the liver in the absence of alcohol consumption, which is commonly associated with obesity and increased risk of atherosclerosis as well as insulin resistance. Adropin is a recently identified protein encoded by the gene related with energy homeostasis, which is expressed in the liver and the brain and has a role in preventing insulin resistance and obesity. The aim of this study was to investigate the serum adropin and leptin levels in obese adolescents and compare the patients with, and without, NAFLD and with healthy controls. Sixty-four obese adolescents (30 with NAFLD, 34 without NAFLD) and 36 healthy controls were enrolled in the study. Serum adropin and leptin levels were evaluated by sandwich enzyme-linked immunosorbent assay. Serum adropin levels were significantly lower in obese children than healthy controls (3.2±1.0 and 9.2±1.2 ng/mL, respectively, p=0.001). Serum leptin levels were significantly higher in patients than in controls (12.4±1.1 and 4.1±3.1 pg/mL, respectively; p=0.000). Serum adropin levels of patients with NAFLD were significantly lower than in patients without NAFLD (2.9±0.5 and 3.5±1.2 ng/mL, respectively; p=0.023) and healthy controls (p=0.000). Logistic regression analysis showed that a decrease in adropin levels was the only independent factor for fatty liver disease in obese adolescents (odds ratio: 3.07, 95% confidence interval 1.14-8.2, p=0.026). Leptin, relative weight and HOMA-IR of the patients were not independent risk factors for NAFLD. In this study, serum adropin levels were significantly lower in obese adolescents with fatty liver disease compared to patients without fatty liver disease and healthy controls. Lower adropin level was an independent risk factor for NAFLD in obese adolescents in logistic regression analysis. Assessment of serum adropin concentrations may provide a reliable indicator of fatty liver disease in obese adolescents.

Non‐alcoholic fatty liver disease and hepatocellular carcinoma in a 7‐year‐old obese boy: coincidence or comorbidity?

Hepatocellular carcinoma (HCC) may develop from non-alcoholic fatty liver disease (NAFLD) either in the presence or in the absence of established cirrhosis. Non-cirrhotic patients with NAFLD-related HCC are usually adult, male and obese. However, this association has not been reported yet in younger age groups. Objectives In the present study, the clinical case of a 7-yaer-old obese boy with steatosis and HCC is presented. A 7-year-old boy, with no evidence of chronic liver disease, was admitted for assessment of a liver mass. Preliminary assessment was suggestive of a combined and severe liver steatosis together with a malignant disease. A biopsy confirmed the suspected diagnosis of HCC; interestingly, the non-neoplastic liver was surrounded and characterized by the presence of steatosis and ballooning, and being absent of lobular inflammation and fibrosis. Chemotherapy and diet changes were conducted successfully with ultrasound characteristics suggesting improvements on both aspects: conventional liver mass resection could take place. This case report suggests that HCC might develop in paediatric age patients with obesity-related NAFLD, even in the absence of fibrosis.

Exploration of a symptoms experience in people with obesity-related nonalcoholic fatty liver disease

BackgroundNonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition strongly associated with obesity that can result in premature death. Little is known about the symptoms experience in this progressive disease, preventing health care providers from intervening in the early stages. PurposeThis study explicated symptoms in persons with NAFLD at higher risk of disease progression defined as the presence of one or two copies of the PNPLA3 (rs738409)-G allele. MethodGuided by the Symptoms Experience Model, 42 persons older than 21 years of age with diagnosed NAFLD were recruited from Western Michigan specialty offices in this cross-sectional descriptive study design. The Memorial Symptom Assessment Scale was used to measure the symptoms experience. DiscussionParticipants (97%) experienced 1 or more symptoms (average number of symptoms 12.02, standard deviation = 8.817). There was no statistically significant relationship between symptoms and the PNPLA3 (rs738409) variants. Significant predictors of mean frequency, severity, and distress of symptoms (the Total Memorial Symptom Scale) (F[15, 25] = 2.609, p = .016) were identified. ConclusionPeople with NAFLD experience an average of 12 symptoms.

Taraxacum official (dandelion) leaf extract alleviates high-fat diet-induced nonalcoholic fatty liver

The purpose of this study is to determine the protective effect of Taraxacum official (dandelion) leaf extract (DLE) on high-fat-diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. To determine the hepatoprotective effect of DLE, we fed C57BL/6 mice with normal chow diet (NCD), high-fat diet (HFD), HFD supplemented with 2g/kg DLE DLE (DL), and HFD supplemented with 5 g/kg DLE (DH). We found that the HFD supplemented by DLE dramatically reduced hepatic lipid accumulation compared to HFD alone. Body and liver weights of the DL and DH groups were significantly lesser than those of the HFD group, and DLE supplementation dramatically suppressed triglyceride (TG), total cholesterol (TC), insulin, fasting glucose level in serum, and Homeostatic Model Assessment Insulin Resistance (HOMA-IR) induced by HFD. In addition, DLE treatment significantly increased activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in liver and muscle protein. DLE significantly suppressed lipid accumulation in the liver, reduced insulin resistance, and lipid in HFD-fed C57BL/6 mice via the AMPK pathway. These results indicate that the DLE may represent a promising approach for the prevention and treatment of obesity-related nonalcoholic fatty liver disease.

Correction to Synthesis and Biological Evaluation of 5-Benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione Derivatives for the Treatment of Obesity-Related Nonalcoholic Fatty Liver Disease

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionCorrection to Synthesis and Biological Evaluation of 5-Benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione Derivatives for the Treatment of Obesity-Related Nonalcoholic Fatty Liver DiseaseLiang Ma, Caifeng Xie, Yan Ran, Xiaolin Liang, Li Huang, Heying Pei, Jinying Chen, Juan Liu, Yun Sang, Huijun Lai, Aihua Peng, Mingli Xiang, Yuquan Wei, and Lijuan Chen*Cite this: J. Med. Chem. 2013, 56, 2, 591Publication Date (Web):January 14, 2013Publication History Published online14 January 2013Published inissue 24 January 2013https://doi.org/10.1021/jm3019047Copyright © 2013 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views677Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (111 KB) Get e-Alerts Get e-Alerts

Evaluation of serum neopterin levels and its relationship with adipokines in pediatric obesity-related nonalcoholic fatty liver disease and healthy adolescents

Nonalcoholic fatty liver disease (NAFLD) is associated with inflammation and increased risk of atherosclerosis. Neopterin is regarded as a biochemical marker of cell-mediated immunity, which is secreted by monocytes and macrophages, mainly in response to interferon-gamma. The aim of the present study was to investigate the serum neopterin levels in obese adolescents and compare the neopterin levels in patients with and without NAFLD and also with healthy controls. The second aim of the study was to research the possible relationship between neopterin levels and adipokines (leptin, adiponectin, resistin, and ghrelin). Ninety-three obese adolescents (39 with NAFLD, 54 without NAFLD) and 55 healthy controls were enrolled in the study. Serum levels of neopterin and adipokines were measured with high-performance liquid chromatography and sandwich enzyme-linked immunosorbent assay, respectively. Serum neopterin levels were significantly higher in patients with NAFLD (3.20 ± 0.09 nmol/L) than in their healthy peers (2.91 ± 0.08 nmol/L) (p=0.020). Neopterin levels were positively correlated with leptin levels in obese patients (r=0.380, p<0.001) and in the group comprising all individuals (r=0.206, p<0.05). There was no correlation between neopterin concentrations and relative weight, alanin aminotransferase, adiponectin, resistin, and ghrelin levels. The serum neopterin levels were significantly higher in obese adolescents with fatty liver disease compared to controls, and this may be related to increased cell-mediated immunity in fatty liver disease.

Exposure to ambient air particulate matter and non-alcoholic fatty liver disease

The present study was designed to alert the public opinion and policy makers on the supposed enhancing effects of exposure to ambient air particulate matter with aerodynamic diameters < 2.5 mm (PM2.5) on non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in Western countries. For far too long literature data have been fixated on pulmonary diseases and/or cardiovascular disease, as consequence of particulate exposure, ignoring the link between the explosion of obesity with related syndromes such as NAFLD and air pollution, the worst characteristics of nowadays civilization. In order to delineate a clear picture of this major health problem, further studies should investigate whether and at what extent cigarette smoking and exposure to ambient air PM2.5 impact the natural history of patients with obesity-related NAFLD, i.e., development of non alcoholic steatohepatitis, disease characterized by a worse prognosis due its progression towards fibrosis and hepatocarcinoma.

Expression of Inflammation-Related Genes Is Altered in Gastric Tissue of Patients with Advanced Stages of NAFLD

Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD.

Synthesis and Biological Evaluation of 5-Benzylidenepyrimidine-2,4,6(1H,3H,5H)-trione Derivatives for the Treatment of Obesity-Related Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD), one of chronic liver diseases, seems to be rising as the obesity epidemic continues. In this study, 54 novel (thio)barbituric acid derivatives have been synthesized and evaluated for pharmacological activity. 7h exhibited potent glucose-lowering effects on insulin-resistant HepG2 cells and regulated adiponectin and leptin expression in 3T3-L1 adipocytes. Oral administration of 7h at 25 mg kg(-1) day(-1) for 4 weeks improved the progression of high fat diet-induced NAFLD by reducing the weight of body, liver, and fat, as well as modulating serum levels of fasting glucose, insulin, triglycerides, LDL-c, ALT, adiponectin and hepatic contents of triglycerides, total cholesterol. H&E stainings revealed that 7h blocked fat deposition in liver and the increase of adipocyte number and size in adipose tissues from NAFLD. Furthermore, treatment with 7h alleviated the obese clinical symptoms, recovered serum biomarkers to appropriate ranges, and improved glucose tolerance by OGTT and IGTT in DIO mice.