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1.  Distinct metabolic effects following short-term exposure of different high-fat diets in male and female mice 
Endocrine journal  2014;61(5):457-470.
Obesity-associated hepatic lipid accumulation and chronic low-grade inflammation lead to metabolic defects. Saturated fatty acids (SFA) are a risk factor for, whereas unsaturated fatty acids (UFA) are thought to be protective against, developing metabolic diseases. Sex differences exist in the regulation of metabolism. We tested the hypothesis that diets high in SFA, mono-UFA (MUFA), or poly-UFA (PUFA) had early, sex-distinct effects that differentially contribute to long-term metabolic disturbance such as fatty liver and insulin resistance. Metabolic changes including body and fat mass, circulating leptin and glucose levels, plasma lipid profile, hepatic lipid accumulation, expression levels of genes related to lipid metabolism and low-grade inflammation, and tissue insulin sensitivity were compared between male and female mice fed with a low-fat chow, or high-fat SFA, MUFA, or PUFA for a short period of four days. SFA and MUFA males increased adiposity associated with increased liver lipid accumulation and rapid activation of inflammation in adipose and muscle tissues, whereas PUFA males did not show lipid accumulation or tissue inflammation compared to chow males. All SFA and UFA males displayed tissue insulin resistance. In contrast, female high-fat diet groups had normal liver lipid content and maintained tissue insulin sensitivity without showing tissue inflammation. Therefore, sex differences existed during early phase of development of metabolic dysfunction. The beneficial effects of PUFA, but not MUFA, were corroborated in protection of obesity, hyperlipidemia, fatty liver, and low-grade inflammation. The benefit of MUFA and PUFA in maintaining tissue insulin sensitivity in males, however, was questioned.
PMCID: PMC4045093  PMID: 24646677
sex difference; de novo lipogenesis; β-oxidation; insulin sensitivity; low-grade inflammation
2.  The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans 
The Journal of Clinical Investigation  2012;122(6):2176-2194.
Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element–binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.
PMCID: PMC3366390  PMID: 22546860
3.  Comparative Evaluation of Whole Body and Hepatic Insulin Resistance Using Indices from Oral Glucose Tolerance Test in Morbidly Obese Subjects with Nonalcoholic Fatty Liver Disease 
Journal of Obesity  2010;2010:741521.
Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a marker of Insulin Resistance (IR). Euglycemic-hyperinsulinemic clamp is the gold standard for measuring whole body IR (hepatic + peripheral IR). However, it is an invasive and expensive procedure. Homeostasis Model Assessment Index for Insulin Sensitivity (HOMA-IS), Quantitative Insulin Sensitivity Check Index (QUICKI) for hepatic IR and Insulin Sensitivity Index (ISI0,120), and Whole Body Insulin Sensitivity Index (WBISI) for whole body IR are the indices calculated after Oral Glucose Tolerance Test (OGTT). We used these indices as noninvasive methods of IR (inverse of insulin sensitivity) estimation and compared hepatic/peripheral components of whole body IR in NAFLD. Methods. 113 morbidly obese, nondiabetic subjects who underwent gastric bypass surgery and intraoperative liver biopsy were included in the study. OGTT was performed preoperatively and the indices were calculated. Subjects were divided into closely matched groups as normal, fatty liver (FL) and Non-Alcoholic Steatohepatitis (NASH) based on histology. Results. Whole body IR was significantly higher in both FL and NASH groups (NAFLD) as compared to Normal, while hepatic IR was higher only in NASH from Normal. Conclusions. FL is a manifestation of peripheral IR but not hepatic IR.
PMCID: PMC2925212  PMID: 20798875
4.  Regulation of fatty acid composition and lipid storage by thyroid hormone in mouse liver 
Cell & Bioscience  2014;4:38.
Thyroid hormones (THs) are potent hormones modulating liver lipid homeostasis. The perturbation of lipid homeostasis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a very common liver disorder. It was reported that NAFLD patients were associated with higher incidence of hypothyroidism. However, whether abnormal thyroid function contributes to the pathogenesis of NAFLD remains unclear.
We used in vivo models to investigate the influence of hypothyroidism and TH on hepatic lipid homeostasis. We did not observe hepatic triglyceride accumulation in the liver of hypothyroid mice, although the liver was enlarged. We then characterized the hepatic fatty acid composition with gas chromatography–mass spectrometry in mice under different thyroid states. We found that hypothyroidism decreased saturated fatty acid (SFA) content while TH treatment restored the level of SFA. In agreement with this finding, we observed that the expression of acetyl-CoA carboxylase 1 and fatty acid synthase, the rate-limit enzymes for de novo lipogenesis (DNL), decreased in hypothyroid mice while increased after TH treatment. We also found that the ratio of C18:1n-9/C18:0 and C16:1n-7/C16:0 was decreased by TH treatment, suggesting the activity of stearoyl-CoA desaturase-1 was suppressed. This finding indicated that TH is able to suppress triglyceride accumulation by reducing fatty acid desaturation. Additionally, we found that hepatic glycogen content was substantially influenced by TH status, which was associated with glycogen synthase expression. The increased glycogen storage might explain the enlarged liver we observed in hypothyroid mice.
Taken together, our study here suggested that hypothyroidism in mice might not lead to the development of NAFLD although the liver became enlarged. However, disturbed TH levels led to altered hepatic fatty acid composition and glycogen accumulation.
PMCID: PMC4124172  PMID: 25105012
Thyroid hormone; Liver; Fatty acid; Glycogen; NAFLD
5.  Serum retinol binding protein 4 is associated with visceral fat in human with nonalcoholic fatty liver disease without known diabetes: a cross-sectional study 
High serum Retinol Binding Protein 4 (RBP4) levels were associated with insulin-resistant states in humans. To determine which fat compartments are associated with elevated RBP4 levels in humans, we measured serum RBP4 and hepatic fat content (HFC), visceral (VFA) and subcutaneous abdominal fat area (SFA) in 106 subjects with non-alcoholic fatty liver disease (NAFLD) without known diabetes.
106 patients with NAFLD (M/F: 61/45, aged 47.44 ± 14.16 years) were enrolled. Subjects with known diabetes, chronic virus hepatitis, and those with alcohol consumption ≥30 g/d in man and ≥20 g/d in woman were excluded. Anthropometrics and laboratory tests, including lipid profile, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltransferase (γ-GT) were conducted. HFC, VFA and SFA were determined by CT scan. Serum RBP4 was detected by an enzyme immunoassay kit and validated by quantitative Western blotting.
Circulating RBP4 was negatively associated with high-density lipoprotein cholesterol (HDL-c) (r = −0.392, p < 0.001), but positively with waist-to-hip ratio (WHR) (r = 0.343, p = 0.001), triglyceride (r = 0.330, p = 0.002), VFA (r = 0.298, p = 0.027), systolic blood pressure (r = 0.247, p = 0.020), diastolic blood pressure (r = 0.241, p = 0.023), γ-GT (r = 0.239, p = 0.034), waist circumference (r = 0.218, p = 0.040). Differently, serum RBP4 levels were not associated with HFC (r = 0.199, p = 0.071), SFA, age, BMI, total cholesterol, low-density lipoprotein cholesterol (LDL-c), ALT or AST (all p > 0.05). Multiple linear regression analysis revealed that RBP4 correlated independently with VFA (Standard β = 0.357, p = 0.019) and HDL-c (Standard β = −0.345, p = 0.023) in all subjects, HDL-c (Standard β = −0.315, p = 0.040) in men, VFA/SFA in women (Standard β = 0.471, p = 0.049), not with HFC. However, serum RBP4 was positively correlated with HFC when HFC below 6.34% (r = 0.574, p = 0.001).
RBP4 could be a marker of abdominal obesity, however, the role of RBP4 in the pathogenesis of NAFLD is not sufficiently elucidated.
PMCID: PMC4419494  PMID: 25890223
Retinol binding protein 4; Visceral abdominal fat; Non-alcoholic fatty liver disease; Hepatic fat content
6.  Tree shrew (Tupaia belangeri chinensis), a novel non-obese animal model of non-alcoholic fatty liver disease 
Biology Open  2016;5(10):1545-1552.
Non-alcoholic fatty liver disease (NAFLD) is becoming a severe public health problem that is affecting a large proportion of the world population. Generally, NAFLD in patients is usually accompanied by obesity, hyperglycemia, insulin resistance (IR) and type 2 diabetes (T2D), for which numerous animal models have been generated in order to explore the pathogenesis and therapies of NAFLD. On the contrary, quite a number of NAFLD subjects, especially in Asian regions, are non-obese and non-diabetic; however, few animal models are available for the research of non-obese NAFLD. Here, four approaches (here called approach 1 to 4) corresponding to the variable compositions of diets were used to treat tree shrews (Tupaia belangeri chinensis), which have a closer evolutionary relationship to primates than rodents. Analysis of plasma biochemical parameters, hepatic histology, and the expression of hepatic lipid metabolic genes revealed that all four approaches led to hepatic lipid accumulation, liver injury and hypercholesterolemia, but had no effect on body weight and adipose tissue generation, or glycemia. Hepatic gene expression in tree shrews treated by approach 4 might suggest a different or non-canonical pathway leading to hepatic steatosis. In conclusion, the tree shrew displays hepatic steatosis and dyslipidemia, but remains non-obese and non-diabetic under high energy diets, which suggests that the tree shrew may be useful as a novel animal model for the research of human non-obese NAFLD.
Summary: This study suggests that the tree shrew (Tupaia belangeri chinensis) may be useful as a novel animal model for the research of human non-obese non-alcoholic fatty liver disease (NAFLD).
PMCID: PMC5087676  PMID: 27659689
Non-alcoholic fatty liver disease (NAFLD); Tree shrew (Tupaia belangeri chinensis); High energy diet; Animal model; Non-obese fatty liver
7.  Ameliorative effects of lutein on non-alcoholic fatty liver disease in rats 
AIM: To investigate the therapeutic effects of lutein against non-alcoholic fatty liver disease (NAFLD) and the related underlying mechanism.
METHODS: After 9 d of acclimation to a constant temperature-controlled room (20 °C-22 °C) under 12 h light/dark cycles, male Sprague-Darley rats were randomly divided into two groups and fed a standard commercial diet (n = 8) or a high-fat diet (HFD) (n = 32) for 10 d. Animals receiving HFD were then randomly divided into 4 groups and administered with 0, 12.5, 25, or 50 mg/kg (body weight) per day of lutein for the next 45 d. At the end of the experiment, the perinephric and abdominal adipose tissues of the rats were isolated and weighed. Additionally, serum and liver lipid metabolic condition parameters were measured, and liver function and insulin resistance state indexes were assessed. Liver samples were collected and stained with hematoxylin eosin and Oil Red O, and the expression of the key factors related to insulin signaling and lipid metabolism in the liver were detected using Western blot and real-time polymerase chain reaction analyses.
RESULTS: Our data showed that after being fed a high-fat diet for 10 d, the rats showed a significant gain in body weight, energy efficiency, and serum total cholesterol (TC) and triglyceride (TG) levels. Lutein supplementation induced fat loss in rats fed a high-fat diet, without influencing body weight or energy efficiency, and decreased serum TC and hepatic TC and TG levels. Moreover, lutein supplementation decreased hepatic levels of lipid accumulation and glutamic pyruvic transaminase content, and also improved insulin sensitivity. Lutein administration also increased the expression of key factors in hepatic insulin signaling, such as insulin receptor substrate-2, phosphatidylinositol 3-kinase, and glucose transporter-2 at the gene and protein levels. Furthermore, high-dose lutein increased the expression of peroxisome proliferators activated receptor-α and sirtuin 1, which are associated with lipid metabolism and insulin signaling.
CONCLUSION: These results demonstrate that lutein has positive effects on NAFLD via the modulation of hepatic lipid accumulation and insulin resistance.
PMCID: PMC4499348  PMID: 26185377
Lutein; Non-alcoholic fatty liver disease; Insulin resistance; Sirtuin 1; Peroxisome proliferators activated receptor-α
8.  Enhancement of Muscle Mitochondrial Oxidative Capacity and Alterations in Insulin Action Are Lipid Species Dependent 
Diabetes  2009;58(11):2547-2554.
Medium-chain fatty acids (MCFAs) have been reported to be less obesogenic than long-chain fatty acids (LCFAs); however, relatively little is known regarding their effect on insulin action. Here, we examined the tissue-specific effects of MCFAs on lipid metabolism and insulin action.
C57BL6/J mice and Wistar rats were fed either a low-fat control diet or high-fat diets rich in MCFAs or LCFAs for 4–5 weeks, and markers of mitochondrial oxidative capacity, lipid levels, and insulin action were measured.
Mice fed the MCFA diet displayed reduced adiposity and better glucose tolerance than LCFA-fed animals. In skeletal muscle, triglyceride levels were increased by the LCFA diet (77%, P < 0.01) but remained at low-fat diet control levels in the MCFA-fed animals. The LCFA diet increased (20–50%, P < 0.05) markers of mitochondrial metabolism in muscle compared with low-fat diet–fed controls; however; the increase in oxidative capacity was substantially greater in MCFA-fed animals (50–140% versus low-fat–fed controls, P < 0.01). The MCFA diet induced a greater accumulation of liver triglycerides than the LCFA diet, likely due to an upregulation of several lipogenic enzymes. In rats, isocaloric feeding of MCFA or LCFA high-fat diets induced hepatic insulin resistance to a similar degree; however, insulin action was preserved at the level of low-fat diet–fed controls in muscle and adipose from MCFA-fed animals.
MCFAs reduce adiposity and preserve insulin action in muscle and adipose, despite inducing steatosis and insulin resistance in the liver. Dietary supplementation with MCFAs may therefore be beneficial for preventing obesity and peripheral insulin resistance.
PMCID: PMC2768163  PMID: 19720794
9.  Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease 
Non-alcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome, which is known to be associated with insulin resistance (IR). NAFLD occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and excretion as very low-density lipoprotein (VLDL). To estimate the effects of IR on hepatic lipid excretion, mRNA expression levels of genes involved in VLDL assembly were analyzed in NAFLD liver. Twenty-two histologically proven NAFLD patients and 10 healthy control subjects were enrolled in this study. mRNA was extracted from liver biopsy samples and real-time PCR was performed to quantify the expression levels of apolipoprotein B (apoB), microsomal triglyceride transfer protein (MTP) and liver fatty-acid binding protein (L-FABP). Hepatic expression levels of the genes were compared between NAFLD patients and control subjects. In NAFLD patients, we also examined correlations between expression levels of the genes and metabolic factors, including IR, and the extent of obesity and hepatic lipid accumulation. Hepatic expression levels of apoB, MTP and L-FABP were significantly up-regulated in NAFLD patients compared to control subjects. The expression levels of MTP were correlated with those of apoB, but not with those of L-FABP. In the NAFLD liver, the expression levels of MTP were significantly reduced in patients with HOMA-IR >2.5. In addition, a significant reduction in MTP expression was observed in livers with advanced steatosis. Enhanced expression of genes involved in VLDL assembly may be promoted to release excess lipid from NAFLD livers. However, the progression of IR and hepatic steatosis may attenuate this compensatory process.
PMCID: PMC3440820  PMID: 22977624
apolipoprotein B; fatty-acid binding protein; homeostasis model assessment of insulin resistance; microsomal triglyceride transfer protein; non-alcoholic fatty liver disease; very low-density lipoprotein
10.  Extracts from Aralia elata (Miq) Seem alleviate hepatosteatosis via improving hepatic insulin sensitivity 
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease that is strongly associated with obesity and dysregulation of insulin in the liver. However, currently no pharmacological agents have been established for the treatment of NAFLD. In this regard, we sought to evaluate the anti-NAFLD effects of Aralia elata (Miq) Seem (AE) extract and its ability to inhibit hepatic lipid accumulation and modulate cellular signaling in a high fat diet (HFD)-induced obese mouse model.
A model of hepatic steatosis in the HepG2 cells was induced by oleic acid. Intracellular lipid droplets were detected by Oil-Red-O staining, and the expression of sterol regulatory element-binding protein 1(SREBP-1), Fatty acid synthase (FAS), Acetyl-CoA carboxylase (ACC) 1 and 2, Peroxisome proliferator activated receptor-α (PPARα), and carnitine palmitoyl transferase 1(CPT-1) was analyzed by real time reverse transcription–Polymerase chain reaction (qRT–PCR). And glucose consumption was measured with commercial kit. Furthermore, Male C57BL/6 J mice were fed with HFD to induce NAFLD. Groups of mice were given plant extracts orally at 100 and 300 mg/kg at daily for 4 weeks. After 3 weeks of AE extract treatment, we performed oral glucose tolerance test (OGTT). Liver tissue was procured for histological examination, Phosphoinositide 3-kinase (PI3K) and Protein kinase B (PKB/Akt) activity.
In the present study, AE extract was shown to reduce hepatic lipid accumulation and significantly downregulate the level of lipogenic genes and upregulate the expression of lipolysis genes in HepG2 cells. And also, AE extract significantly increased the glucose consumption, indicating that AE extract improved insulin resistance. Subsequently, we confirmed the inhibitory activity of AE extract on NAFLD, in vivo. Treatment with AE extract significantly decreased body weight and the fasting glucose level, alleviated hyperinsulinism and hyperlipidemia, and reduced glucose levels, as determined by OGTT. Additionally, AE extract decreased PI3K and Akt activity.
Our results suggest that treatment with AE extract ameliorated NAFLD by inhibiting insulin resistance through activation of the Akt/GLUT4 pathway.
Electronic supplementary material
The online version of this article (doi:10.1186/s12906-015-0871-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4595215  PMID: 26438035
Aralia elata (Miq) Seem; Non-Alcoholic Fatty Liver Disease; Insulin Resistance
11.  Liver, Muscle and Adipose Tissue Insulin Action is Directly Related to Intrahepatic Triglyceride Content in Obese Subjects 
Gastroenterology  2008;134(5):1369-1375.
Background & Aims
Nonalcoholic fatty liver disease is associated with insulin resistance and diabetes. The purpose of this study was to determine the relationship between intrahepatic triglyceride (IHTG) content and insulin action in liver (suppression of glucose dioduction), skeletal muscle (stimulation of glucose uptake) and adipose tissue (suppression of lipolysis) in non-diabetic, obese subjects.
A euglycemic-hyperinsulinemic clamp procedure and stable isotopically labeled tracer infusions were used to assess insulin action, and magnetic resonance spectroscopy was used to determine IHTG content, in 42 non-diabetic, obese subjects (BMI 36±4 kg/m2) who had a wide range of IHTG content (1%−46%).
Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration, was inversely correlated with IHTG content (r=−0.599; P<0.001). The ability of insulin to suppress the release of fatty acids from adipose tissue and to stimulate glucose uptake by skeletal muscle were also inversely correlated with IHTG content (adipose tissue: r=−0.590; P<0.001; skeletal muscle: r=−0.656; P<0.001). Multivariate linear regression analyses found that IHTG content was the best predictor of insulin action in liver, skeletal muscle and adipose tissue, independent of BMI and percent body fat, and accounted for 34%, 42%, and 44% of the variability in these tissues, respectively (P< 0.001 for each model).
These results demonstrate that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle and adipose tissue in non-diabetic, obese subjects. Therefore, NAFLD should be considered part of a multi-organ system derangement in insulin sensitivity.
PMCID: PMC2629391  PMID: 18355813
12.  Membrane Synthesis, Specific Lipid Requirements, and Localized Lipid Composition Changes Associated with a Positive-Strand RNA Virus RNA Replication Protein 
Journal of Virology  2003;77(23):12819-12828.
Multifunctional RNA replication protein 1a of brome mosaic virus (BMV), a positive-strand RNA virus, localizes to the cytoplasmic face of endoplasmic reticulum (ER) membranes and induces ER lumenal spherules in which viral RNA synthesis occurs. We previously showed that BMV RNA replication in yeast is severely inhibited prior to negative-strand RNA synthesis by a single-amino-acid substitution in the ole1w allele of yeast Δ9 fatty acid (FA) desaturase, which converts saturated FAs (SFAs) to unsaturated FAs (UFAs). Here we further define the relationships between 1a, membrane lipid composition, and RNA synthesis. We show that 1a expression increases total membrane lipids in wild-type (wt) yeast by 25 to 33%, consistent with recent results indicating that the numerous 1a-induced spherules are enveloped by invaginations of the outer ER membrane. 1a did not alter total membrane lipid composition in wt or ole1w yeast, but the ole1w mutation selectively depleted 18-carbon, monounsaturated (18:1) FA chains and increased 16:0 SFA chains, reducing the UFA-to-SFA ratio from ∼2.5 to ∼1.5. Thus, ole1w inhibition of RNA replication was correlated with decreased levels of UFA, membrane fluidity, and plasticity. The ole1w mutation did not alter 1a-induced membrane synthesis, 1a localization to the perinuclear ER, or colocalization of BMV 2a polymerase, nor did it block spherule formation. Moreover, BMV RNA replication templates were still recovered from cell lysates in a 1a-induced, 1a- and membrane-associated, and nuclease-resistant but detergent-susceptible state consistent with spherules. However, unlike nearby ER membranes, the membranes surrounding spherules in ole1w cells were not distinctively stained with osmium tetroxide, which interacts specifically with UFA double bonds. Thus, in ole1w cells, spherule-associated membranes were locally depleted in UFAs. This localized UFA depletion helps to explain why BMV RNA replication is more sensitive than cell growth to reduced UFA levels. The results imply that 1a preferentially interacts with one or more types of membrane lipids.
PMCID: PMC262592  PMID: 14610203
13.  Metabolic inflexibility and insulin resistance in obese adolescents with nonalcoholic fatty liver disease 
Pediatric diabetes  2014;16(3):211-218.
Non-alcoholic fatty liver disease (NAFLD) is a comorbidity of childhood obesity.
We examined whole-body substrate metabolism and metabolic characteristics in obese adolescents with versus without NAFLD.
Twelve obese (BMI≥95th) adolescents with and without NAFLD [intrahepatic triglyceride (IHTG) ≥5.0 % versus <5.0 %] were pair-matched for race, gender, age and % body fat.
Insulin sensitivity (IS) was assessed by a 3-hour hyperinsulinemic-euglycemic clamp and whole-body substrate oxidation by indirect calorimetry during fasting and insulin-stimulated conditions.
Adolescents with NAFLD had increased (P<0.05) abdominal fat, lipids and liver enzymes compared with those without NAFLD. Fasting glucose concentration was not different between groups, but fasting insulin concentration was higher (P<0.05) in the NAFLD group compared with those without. Fasting hepatic glucose production and hepatic IS did not differ (P>0.1) between groups. Adolescents with NAFLD had higher (P<0.05) fasting glucose oxidation and a tendency for lower fat oxidation. Adolescents with NAFLD had lower (P<0.05) insulin-stimulated glucose disposal and lower peripheral IS compared with those without NAFLD. Although RQ increased significantly from fasting to insulin-stimulated conditions in both groups (main effect, P<0.001), the increase in RQ was lower in adolescents with NAFLD versus those without (interaction, P=0.037).
NAFLD in obese adolescents is associated with adverse cardiometabolic profile, peripheral insulin resistance and metabolic inflexibility.
PMCID: PMC4339626  PMID: 24754380
nonalcoholic fatty liver disease; visceral fat; insulin sensitivity; childhood obesity
14.  Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model 
Journal of hepatology  2010;52(5):727-736.
Background & Aims
In this study, we sought to determine the temporal relationship between hepatic mitochondrial dysfunction, hepatic steatosis and insulin resistance, and to examine their potential role in the natural progression of non-alcoholic fatty liver disease (NAFLD) utilising a sedentary, hyperphagic, obese, Otsuka Long–Evans Tokushima Fatty (OLETF) rat model.
OLETF rats and their non-hyperphagic control Long–Evans Tokushima Otsuka (LETO) rats were sacrificed at 5, 8, 13, 20, and 40 weeks of age (n = 6–8 per group).
At 5 weeks of age, serum insulin and glucose and hepatic triglyceride (TG) concentrations did not differ between animal groups; however, OLETF animals displayed significant (p < 0.01) hepatic mitochondrial dysfunction as measured by reduced hepatic carnitine palmitoyl-CoA transferase-1 activity, fatty acid oxidation, and cytochrome c protein content compared with LETO rats. Hepatic TG levels were significantly elevated by 8 weeks of age, and insulin resistance developed by 13 weeks in the OLETF rats. NAFLD progressively worsened to include hepatocyte ballooning, perivenular fibrosis, 2.5-fold increase in serum ALT, hepatic mitochondrial ultrastructural abnormalities, and increased hepatic oxidative stress in the OLETF animals at later ages. Measures of hepatic mitochondrial content and function including β-hydroxyacyl-CoA dehydrogenase activity, citrate synthase activity, and immunofluorescence staining for mitochondrial carbamoyl phosphate synthetase-1, progressively worsened and were significantly reduced at 40 weeks in OLETF rats compared to LETO animals.
Our study documents that hepatic mitochondrial dysfunction precedes the development of NAFLD and insulin resistance in the OLETF rats. This evidence suggests that progressive mitochondrial dysfunction contributes to the natural history of obesity-associated NAFLD.
PMCID: PMC3070177  PMID: 20347174
Non-alcoholic fatty liver disease; Fatty acid oxidation; Mitochondrial dysfunction; OLETF rat
15.  Severity of Nonalcoholic Fatty Liver Disease and Progression to Cirrhosis Associate With Atherogenic Lipoprotein Profile 
Background & Aims
Nonalcoholic fatty liver disease (NAFLD) is independently associated with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in non-diabetic patients with histologically proven NAFLD.
We performed a case–control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 non-diabetic subjects with histologically confirmed NAFLD vs lean (N=81) and obese (N=81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or a tissue repository.
Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B (APOB); increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein particles (LDL-Ps) and small-dense LDL (sdLDL) cholesterol, and increased percent sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, levels of triglyceride and APOB, concentrations of LDL-P and LDL-C, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased development of cirrhosis.
Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.
PMCID: PMC4395517  PMID: 25311381
NASH; metabolic syndrome; obesity; steatosis; heart disease
16.  Toll-like receptor 7 affects the pathogenesis of non-alcoholic fatty liver disease 
Scientific Reports  2016;6:27849.
Recently, a possible link between toll-like receptor 7 (TLR7) and liver disease was suggested, although it was limited to fibrosis. Based on this report, we investigated whether TLR7 has a pivotal role in non-alcoholic fatty liver disease (NAFLD). The TLR7 signaling pathway, which is activated by imiquimod (TLR7 ligand) naturally, induced autophagy and released insulin-like growth factor 1 (IGF-1) into medium from hepatocytes. Lipid accumulation induced by unsaturated fatty acid (UFA; arachidonic acid:oleic acid = 1:1) in hepatocytes, was attenuated in TLR7 and autophagy activation. Interestingly, TLR7 activation attenuated UFA-induced lipid peroxidation products, such as malondialdehyde (MDA) and 4-Hydroxy-2-Nonenal (4-HNE). To clarify a possible pathway between TLR7 and lipid peroxidation, we treated hepatocytes with MDA and 4-HNE. MDA and 4-HNE induced 2-folds lipid accumulation in UFA-treated hepatocytes via blockade of the TLR7 signaling pathway’s IGF-1 release compared to only UFA-treated hepatocytes. In vivo experiments carried out with TLR7 knockout mice produced results consistent with in vitro experiments. In conclusion, TLR7 prevents progression of NAFLD via induced autophagy and released IGF-1 from liver. These findings suggest a new therapeutic strategy for the treatment of NAFLD.
PMCID: PMC4899790  PMID: 27279075
17.  Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity 
PLoS ONE  2014;9(3):e91111.
Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages.
PMCID: PMC3956460  PMID: 24638078
18.  Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance 
Nutrients  2015;7(11):9127-9138.
Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL) cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD). Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA) as compared to monounsaturated (MUFA) or polyunsaturated (PUFA) fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.
PMCID: PMC4663582  PMID: 26556368
saturated fat; carbohydrate; fructose; liver fat; steatosis
19.  Mechanisms of intrahepatic triglyceride accumulation 
World Journal of Gastroenterology  2016;22(4):1664-1673.
Hepatic steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents in the Western World. Etiologically, obesity and associated insulin resistance or excess alcohol intake are the most frequent causes of hepatic steatosis. However, steatosis also often occurs with chronic hepatitis C virus (HCV) infection and is also found in rare but potentially life-threatening liver diseases of pregnancy. Clinical significance and outcome of hepatic triglyceride accumulation are highly dependent on etiology and histological pattern of steatosis. This review summarizes current concepts of pathophysiology of common causes of hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, chronic HCV infections, drug-induced forms of hepatic steatosis, and acute fatty liver of pregnancy. Regarding the pathophysiology of NAFLD, this work focuses on the close correlation between insulin resistance and hepatic triglyceride accumulation, highlighting the potential harmful effects of systemic insulin resistance on hepatic metabolism of fatty acids on the one side and the role of lipid intermediates on insulin signalling on the other side. Current studies on lipid droplet morphogenesis have identified novel candidate proteins and enzymes in NAFLD.
PMCID: PMC4721997  PMID: 26819531
Steatosis; Lipid accumulation; Fatty acids; Insulin resistance; Triglycerides
20.  Postprandial triglyceride-rich lipoproteins induce hepatic insulin resistance in HepG2 cells independently of their receptor-mediated cellular uptake 
► The pathophysiological link between NAFLD and hepatic insulin resistance is unknown. ► We studied the effect of postprandial lipoproteins on hepatic insulin sensitivity. ► Postprandial lipoproteins cause liver steatosis and hepatic insulin resistance. ► We characterize the underlying molecular mechanisms. ► Postprandial lipoproteins are a link between NAFLD and hepatic insulin resistance.
Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance with the molecular basis of this association being not well understood. Here we studied the effect of hepatic triglyceride accumulation induced by postprandial triglyceride-rich lipoproteins (TGRL) on hepatic insulin sensitivity in HepG2 cells. Incubation of HepG2 cells with purified TGRL particles induced hepatocellular triglyceride accumulation paralleled by diminished insulin-stimulated glycogen content and glycogen synthase activity. Accordingly, insulin-induced inhibition of glycogen synthase phosphorylation as well as insulin-induced GSK-3 and AKT phosphorylation were reduced by TGRL. The effects of TGRL were dependent on the presence of apolipoproteins and more pronounced for denser TGRL. Moreover, TGRL effects required the presence of heparan sulfate-proteoglycans on the cell membrane and lipase activity but were independent of the cellular uptake of TGRL particles by receptors of the LDL receptor family. We suggest postprandial lipemia to be an important factor in the pathogenesis of NAFLD.
PMCID: PMC3167371  PMID: 21704120
BMI, body mass index; DAPI, 4′,6-diamidino-2-phenylindole; DMEM, dulbeccos minimal essential media; FCS, fetal calf serum; GS, glycogen synthase; GSK-3, glycogen synthase kinase 3; HL, hepatic lipase; HOMA-IR, homeostasis model assessment of insulin resistance; HSPG, heparan sulfate proteoglycans; LPL, lipoprotein lipase; LRP, LDL-receptor-related protein; NAFLD, non-alcoholic fatty liver disease; PBS, phosphate buffered saline; RAP, receptor-associated protein; ROS, reactive oxygen species; Sf, Svedberg flotation rate; TGRL, triglyceride-rich lipoproteins; THL, tetrahydrolipstatin; Glucose metabolism; Hepatic insulin resistance; Insulin signaling; Liver steatosis; Postprandial lipemia
21.  Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 
Journal of Clinical Investigation  2006;116(3):817-824.
Hepatic steatosis is a core feature of the metabolic syndrome and type 2 diabetes and leads to hepatic insulin resistance. Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis. We used a diet-induced rat model of nonalcoholic fatty liver disease (NAFLD) and hepatic insulin resistance to explore the impact of suppressing Acc1, Acc2, or both Acc1 and Acc2 on hepatic lipid levels and insulin sensitivity. While suppression of Acc1 or Acc2 expression with antisense oligonucleotides (ASOs) increased fat oxidation in rat hepatocytes, suppression of both enzymes with a single ASO was significantly more effective in promoting fat oxidation. Suppression of Acc1 also inhibited lipogenesis whereas Acc2 reduction had no effect on lipogenesis. In rats with NAFLD, suppression of both enzymes with a single ASO was required to significantly reduce hepatic malonyl-CoA levels in vivo, lower hepatic lipids (long-chain acyl-CoAs, diacylglycerol, and triglycerides), and improve hepatic insulin sensitivity. Plasma ketones were significantly elevated compared with controls in the fed state but not in the fasting state, indicating that lowering Acc1 and -2 expression increases hepatic fat oxidation specifically in the fed state. These studies suggest that pharmacological inhibition of Acc1 and -2 may be a novel approach in the treatment of NAFLD and hepatic insulin resistance.
PMCID: PMC1366503  PMID: 16485039
22.  Crocetin improves the insulin resistance induced by high-fat diet in rats 
Sheng, L | Qian, Z | Shi, Y | Yang, L | Xi, L | Zhao, B | Xu, X | Ji, H
British Journal of Pharmacology  2008;154(5):1016-1024.
Background and purpose:
The amelioration of insulin resistance by treatment with crocetin is closely related to the hypolipidaemic effect. The present study is designed to clarify the insulin-sensitizing mechanism of crocetin by elucidating the mechanism of regulation of lipid metabolism by crocetin.
Experimental approach:
Rats given a high-fat diet were treated with crocetin for 6 weeks before hyperinsulinaemic–euglycaemic clamp. 14C-palmitate was used as tracer to track the fate of non-esterified fatty acids or as substrate to measure β-oxidation rate. Triglyceride clearance in plasma and lipoprotein lipase activity in tissues were tested. Content of lipids in plasma and tissues was determined. Real-time PCR was used to assay the level of mRNA from genes involved in non-esterified fatty acid and triglyceride uptake and oxidation.
Key results:
Crocetin prevented high-fat-diet induced insulin resistance (increased clamp glucose infusion rate), raised hepatic non-esterified fatty acid uptake and oxidation, accelerated triglyceride clearance in plasma, enhanced lipoprotein lipase activity in liver, and reduced the accumulation of detrimental lipids (DAG and long-chain acyl CoA) in liver and muscle. Genes involved in hepatic lipid metabolism which are regulated by peroxisome proliferator-activated receptor-α, were modulated to accelerate lipid uptake and oxidation.
Conclusions and implications:
Through regulating genes involved in lipid metabolism, crocetin accelerated hepatic uptake and oxidation of non-esterified fatty acid and triglyceride, and reduced lipid availability to muscle, thus decreasing lipid accumulation in muscle and liver, and consequently improving sensitivity to insulin.
PMCID: PMC2451043  PMID: 18469847
crocetin; fatty-acid clearance; insulin resistance; lipoprotein lipase; peroxisome proliferator-activated receptor-α
23.  Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Disease: Is the Liver Another Target? 
Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.
PMCID: PMC3473309  PMID: 23087670
sleep apnea; intermittent hypoxia; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis
24.  The Role of Patatin-Like Phospholipase Domain-Containing 3 on Lipid-induced Hepatic Steatosis and Insulin Resistance in Rats 
Hepatology (Baltimore, Md.)  2013;57(5):1763-1772.
Genome wide array studies have associated the Patatin-like Phospholipase Domain-containing 3 (PNPLA3) gene polymorphisms with hepatic steatosis. However, it is unclear whether PNPLA3 functions as a lipase or a lipogenic enzyme and whether PNPLA3 is involved in the pathogenesis of hepatic insulin resistance. To address these questions we treated high-fat-fed rats with specific antisense oligonucleotides to decrease hepatic and adipose pnpla3 expression. Reducing pnpla3 expression prevented hepatic steatosis, which could be attributed to decreased fatty acid esterification measured by the incorporation of [U-13C]-palmitate into hepatic triglyceride. While the precursors for phosphatidic acid (PA) [long-chain fatty acyl-CoAs and lysophosphatidic acid (LPA)] were not decreased, we did observe an ~20% reduction in the hepatic PA content, ~35% reduction in PA / LPA ratio, and ~60–70% reduction in transacylation activity at the level of acyl-CoA:1-acylglycerol-sn-3-phosphate acyltransferase. These changes were associated with an ~50% reduction in hepatic diacylglycerol (DAG) content, an ~80% reduction in hepatic protein kinase Cε activation, and increased hepatic insulin sensitivity, as reflected by a twofold greater suppression of endogenous glucose production during the hyperinsulinemic-euglycemic clamp. Finally, in humans, hepatic PNPLA3 mRNA expression was strongly correlated with hepatic triglyceride and DAG content, supporting a potential lipogenic role of PNPLA3 in humans. Taken together these data suggest that PNPLA3 may function primarily in a lipogenic capacity and inhibition of PNPLA3 may be a novel therapeutic approach for treatment of NAFLD associated hepatic insulin resistance.
PMCID: PMC3597437  PMID: 23175050
Esterification; Diacylglycerol; High Fat Diet; Nonalcoholic Fatty Liver Disease; Antisense Oligonucleotide
25.  Palmitoleic acid prevents palmitic acid-induced macrophage activation and consequent p38 MAPK-mediated skeletal muscle insulin resistance 
Molecular and Cellular Endocrinology  2014;393(1-2):129-142.
•Palmitate-treated macrophage-conditioned medium causes myotube insulin resistance.•This involves activation of myotube p38 mitogen activated protein kinase.•Conditioned medium effects are mediated by tumour necrosis factor-α.•These effects are prevented by addition of palmitoleate.•Palmitoleate treatment of macrophages is insulin sensitising for myotubes.
Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation.
PMCID: PMC4148479  PMID: 24973767
ABAF, anti-bacterial, anti-fungal; ANOVA, analysis of variance; AS160, Akt substrate of 160 kDa; BSA, bovine serum albumin; CM, conditioned medium; CXCL2, Chemokine (C-X-C motif) ligand 2; DMEM, Dulbecco’s modified Eagle's medium; DMSO, dimethylsulphoxide; ERK, extracellular signal-related kinase; FA, fatty acid; FBS, foetal bovine serum; GLUT, glucose transporter; GSK, glycogen synthase kinase; IKK, inhibitor κ kinase; IκBα, inhibitor κBα; IL, interleukin; iNOS, inducible nitric oxide synthase; IR, insulin resistance; IRS1, insulin receptor substrate-1; JNK, C-jun n-terminal kinase; LPS, lipopolysaccharide; mac, macrophage; MAPK, mitogen-activated protein kinase; MCP1, monocyte chemoattractant protein; NFκB, nuclear factor-κB; PI3K, phosphoinositol 3-kinase; palm, palmitate; PBS, phosphate-buffered saline; PKC, protein kinase C; PMA, phorbol myristate acetate; RIPA, radioimmunoprecipitation; SDS-PAGE, sodium dodecyl sulphate, polyacrylamide gel electrophoresis; SFA, saturated fatty acid; siRNA, small interfering RNA; T2D, type 2 diabetes; TLR, Toll-like Receptor; TNFα, tumour necrosis factor-α; UFA, unsaturated fatty acid; Fatty acid; Tumour necrosis factor-α; p38 Mitogen-activated protein kinase; Insulin resistance; Skeletal muscle; Macrophage

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