Accretion of visceral fat and hepatic insulin resistance in pregnant rats

2008 ◽  
Vol 294 (2) ◽  
pp. E451-E455 ◽  
Author(s):  
Francine H. Einstein ◽  
Sigal Fishman ◽  
Radhika H. Muzumdar ◽  
Xiao Man Yang ◽  
Gil Atzmon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Visceral Fat ◽  
Hepatic Glucose Production ◽  
Late Gestation ◽  
Hepatic Insulin Resistance ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Hepatic Insulin Sensitivity ◽  
In Pregnancy

Insulin resistance (IR) is a hallmark of pregnancy. Because increased visceral fat (VF) is associated with IR in nonpregnant states, we reasoned that fat accretion might be important in the development of IR during pregnancy. To determine whether VF depots increase in pregnancy and whether VF contributes to IR, we studied three groups of 6-mo-old female Sprague-Dawley rats: 1) nonpregnant sham-operated rats (Nonpreg; n = 6), 2) pregnant sham-operated rats (Preg; n = 6), and 3) pregnant rats in which VF was surgically removed 1 mo before mating (PVF−; n = 6). VF doubled by day 19 of pregnancy (Nonpreg 5.1 ± 0.3, Preg 10.0 ± 1.0 g, P < 0.01), and PVF− had similar amounts of VF compared with Nonpreg (PVF− 4.6 ± 0.8 g). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp in late gestation in chronically catheterized unstressed rats. Glucose IR (mg·kg−1·min−1) was highest in Nonpreg (19.4 ± 2.0), lowest in Preg (11.1 ± 1.4), and intermediate in PVF− (14.7 ± 0.6; P < 0.001 between all groups). During the clamp, Nonpreg had greater hepatic insulin sensitivity than Preg [hepatic glucose production (HGP): Nonpreg 4.5 ± 1.3, Preg 9.3 ± 0.5 mg·kg−1·min−1; P < 0.001]. With decreased VF, hepatic insulin sensitivity was similar to nonpregnant levels in PVF− (HGP 4.9 ± 0.8 mg·kg−1·min−1). Both pregnant groups had lower peripheral glucose uptake compared with Nonpreg. In parallel with hepatic insulin sensitivity, hepatic triglyceride content was increased in pregnancy (Nonpreg 1.9 ± 0.4 vs. Preg 3.2 ± 0.3 mg/g) and decreased with removal of VF (PVF− 1.3 ± 0.4 mg/g; P < 0.05). Accretion of visceral fat is an important component in the development of hepatic IR in pregnancy, and accumulation of hepatic triglycerides is a mechanism by which visceral fat may modulate insulin action in pregnancy.

Effect of liver fat on insulin clearance

2007 ◽  
Vol 293 (6) ◽  
pp. E1709-E1715 ◽  
Author(s):  
Anna Kotronen ◽  
Satu Vehkavaara ◽  
Anneli Seppälä-Lindroos ◽  
Robert Bergholm ◽  
Hannele Yki-Järvinen
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Fat Content ◽  
Insulin Clearance ◽  
Liver Fat ◽  
Hepatic Insulin Resistance ◽  
Model Assessment ◽  
Liver Fat Content ◽  
Hepatic Insulin Sensitivity ◽  
Impaired Insulin

A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 ± 1 yr, body mass index (BMI) 26.3 ± 0.5 kg/m2]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU·kg−1·min−1for 240 min) clamp technique combined with the infusion of [3-3H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained ∼40% higher ( P < 0.0001) in the high (15.0 ± 1.5%) compared with the low (1.8 ± 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml·kg fat free mass−1·min−1) was inversely related to liver fat content ( r = −0.52, P < 0.0001), independent of age, sex, and BMI ( r = −0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0–41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance ( r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity ( r = −0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance.

scholarly journals Short-Term Strength Exercise Reduces Hepatic Insulin Resistance in Obese Mice by Reducing PTP1B Content, Regardless of Changes in Body Weight

2021 ◽  
Vol 22 (12) ◽  
pp. 6402
Author(s):  
Kellen Cristina da Cruz Rodrigues ◽  
Rodrigo Martins Pereira ◽  
Guilherme Francisco Peruca ◽  
Lucas Wesley Torres Barbosa ◽  
Marcella Ramos Sant’Ana ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Hepatic Insulin Resistance ◽  
Strength Exercise ◽  
Term Strength ◽  
Obese Mice ◽  
Short Term ◽  
Hepatic Insulin Sensitivity ◽  
Short Term Strength

Obesity is closely related to insulin resistance and type 2 diabetes genesis. The liver is a key organ to glucose homeostasis since insulin resistance in this organ increases hepatic glucose production (HGP) and fasting hyperglycemia. The protein-tyrosine phosphatase 1B (PTP1B) may dephosphorylate the IR and IRS, contributing to insulin resistance in this organ. Aerobic exercise is a great strategy to increase insulin action in the liver by reducing the PTP1B content. In contrast, no study has shown the direct effects of strength training on the hepatic metabolism of PTP1B. Therefore, this study aims to investigate the effects of short-term strength exercise (STSE) on hepatic insulin sensitivity and PTP1B content in obese mice, regardless of body weight change. To achieve this goal, obese Swiss mice were submitted to a strength exercise protocol lasting 15 days. The results showed that STSE increased Akt phosphorylation in the liver and enhanced the control of HGP during the pyruvate tolerance test. Furthermore, sedentary obese animals increased PTP1B content and decreased IRS-1/2 tyrosine phosphorylation; however, STSE was able to reverse this scenario. Therefore, we conclude that STSE is an important strategy to improve the hepatic insulin sensitivity and HGP by reducing the PTP1B content in the liver of obese mice, regardless of changes in body weight.

Starch and β-glucan in a whole-grain-like structural form improve hepatic insulin sensitivity in diet-induced obese mice

2019 ◽  
Vol 10 (8) ◽  
pp. 5091-5101 ◽  
Author(s):  
Kaiyun Luo ◽  
Xufeng Wang ◽  
Genyi Zhang
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Homeostasis ◽  
Hepatic Insulin Resistance ◽  
Obese Mice ◽  
Structural Form ◽  
Whole Grain ◽  
Hepatic Insulin Sensitivity

WGLSF improves hepatic insulin resistance and glucose homeostasis in diet-induced obese mice.

scholarly journals PANDER transgenic mice display fasting hyperglycemia and hepatic insulin resistance

2014 ◽  
Vol 220 (3) ◽  
pp. 219-231 ◽  
Author(s):  
Claudia E Robert-Cooperman ◽  
Grace C Dougan ◽  
Shari L Moak ◽  
Mark G Athanason ◽  
Melanie N Kuehl ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Endocrine Pancreas ◽  
Isotope Labeling ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Fold Increase ◽  
Hepatic Insulin Resistance ◽  
Β Cell ◽  
Physiologic Function

PANcreatic-DERived factor (PANDER, FAM3B) is a novel protein that is highly expressed within the endocrine pancreas and to a lesser degree in other tissues. Under glucose stimulation, PANDER is co-secreted with insulin from the β-cell. Despite prior creation and characterization of acute hepatic PANDER animal models, the physiologic function remains to be elucidated from pancreas-secreted PANDER. To determine this, in this study, a transgenic mouse exclusively overexpressing PANDER from the endocrine pancreas was generated. PANDER was selectively expressed by the pancreatic-duodenal homeobox-1 (PDX1) promoter. The PANDER transgenic (PANTG) mice were metabolically and proteomically characterized to evaluate effects on glucose homeostasis, insulin sensitivity, and lipid metabolism. Fasting glucose, insulin and C-peptide levels were elevated in the PANTG compared with matched WT mice. Younger PANTG mice also displayed glucose intolerance in the absence of peripheral insulin sensitivity. Hyperinsulinemic–euglycemic clamp studies revealed that hepatic glucose production and insulin resistance were significantly increased in the PANTG with no difference in either glucose infusion rate or rate of disappearance. Fasting glucagon, corticosterones, resistin and leptin levels were also similar between PANTG and WT. Stable isotope labeling of amino acids in cell culture revealed increased gluconeogenic and lipogenic proteomic profiles within the liver of the PANTG with phosphoenol-pyruvate carboxykinase demonstrating a 3.5-fold increase in expression. This was matched with increased hepatic triglyceride content and decreased p-AMPK and p-acetyl coenzyme A carboxylase-1 signaling in the PANTG. Overall, our findings support a role of pancreatic β-cell-secreted PANDER in the regulation of hepatic insulin and lipogenenic signaling with subsequent impact on overall glycemia.

scholarly journals CB1 antagonism restores hepatic insulin sensitivity without normalization of adiposity in diet-induced obese dogs

2012 ◽  
Vol 302 (10) ◽  
pp. E1261-E1268 ◽  
Author(s):  
Stella P. Kim ◽  
Orison O. Woolcott ◽  
Isabel R. Hsu ◽  
Darko Stefanoski ◽  
L. Nicole Harrison ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Direct Effect ◽  
Fat Mass ◽  
Endocannabinoid System ◽  
Hepatic Insulin Resistance ◽  
Glucose Turnover ◽  
Peripheral Tissues ◽  
Hepatic Insulin Sensitivity ◽  
Subcutaneous Adiposity

The endocannabinoid system is highly implicated in the development of insulin resistance associated with obesity. It has been shown that antagonism of the CB1 receptor improves insulin sensitivity (SI). However, it is unknown whether this improvement is due to the direct effect of CB1 blockade on peripheral tissues or secondary to decreased fat mass. Here, we examine in the canine dog model the longitudinal changes in SI and fat deposition when obesity was induced with a high-fat diet (HFD) and animals were treated with the CB1 antagonist rimonabant. SI was assessed ( n = 20) in animals fed a HFD for 6 wk to establish obesity. Thereafter, while HFD was continued for 16 additional weeks, animals were divided into two groups: rimonabant (1.25 mg·kg−1·day−1 RIM; n = 11) and placebo ( n = 9). Euglycemic hyperinsulinemic clamps were performed to evaluate changes in insulin resistance and glucose turnover before HFD ( week −6) after HFD but before treatment ( week 0) and at weeks 2, 6, 12, and 16 of treatment (or placebo) + HFD. Magnetic resonance imaging was performed to determine adiposity- related changes in SI. Animals developed significant insulin resistance and increased visceral and subcutaneous adiposity after 6 wk of HFD. Treatment with RIM resulted in a modest decrease in total trunk fat with relatively little change in peripheral glucose uptake. However, there was significant improvement in hepatic insulin resistance after only 2 wk of RIM treatment with a concomitant increase in plasma adiponectin levels; both were maintained for the duration of the RIM treatment. CB1 receptor antagonism appears to have a direct effect on hepatic insulin sensitivity that may be mediated by adiponectin and independent of pronounced reductions in body fat. However, the relatively modest effect on peripheral insulin sensitivity suggests that significant improvements may be secondary to reduced fat mass.

Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

2013 ◽  
Vol 305 (3) ◽  
pp. E388-E395 ◽  
Author(s):  
Michael S. F. Wiedemann ◽  
Stephan Wueest ◽  
Flurin Item ◽  
Eugen J. Schoenle ◽  
Daniel Konrad
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Hepatic Insulin Sensitivity ◽  
Tissue Inflammation

High-fat feeding for 3–4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

Mediobasal hypothalamic PTEN modulates hepatic insulin resistance independently of food intake in rats

2014 ◽  
Vol 307 (1) ◽  
pp. E47-E60 ◽  
Author(s):  
Takashi Sumita ◽  
Hiraku Ono ◽  
Tokuko Suzuki ◽  
Gota Sakai ◽  
Kouichi Inukai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Metabolism ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Hepatic Insulin Sensitivity ◽  
Constitutive Activation ◽  
Tensin Homolog

Phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol (PI) 3,4,5-triphosphate and antagonizes PI 3-kinase. Insulin acts in the mediobasal hypothalamus (MBH) to not only suppress food intake and weight gain but also improve glucose metabolism via PI 3-kinase activation. Thus, the blocking of hypothalamic PTEN is a potential target for treating obesity as well as diabetes. However, genetic modification of PTEN in specific neuronal populations in the MBH yielded complex results, and no postnatal intervention for hypothalamic PTEN has been reported yet. To elucidate how postnatal modification of hypothalamic PTEN influences food intake as well as glucose metabolism, we bidirectionally altered PTEN activity in the MBH of rats by adenoviral gene delivery. Inhibition of MBH PTEN activity reduced food intake and weight gain, whereas constitutive activation of PTEN tended to induce the opposite effects. Interestingly, the effects of MBH PTEN intervention on food intake and body weight were blunted by high-fat feeding. However, MBH PTEN blockade improved hepatic insulin sensitivity even under high-fat-fed conditions. On the other hand, constitutive activation of MBH PTEN induced hepatic insulin resistance. Hepatic Akt phosphorylation and the G6Pase expression level were modulated bidirectionally by MBH PTEN intervention. These results demonstrate that PTEN in the MBH regulates hepatic insulin sensitivity independently of the effects on food intake and weight gain. Therefore, hypothalamic PTEN is a promising target for treating insulin resistance even in states of overnutrition.

ALDH2 rs671 is associated with elevated FPG, reduced glucose clearance and hepatic insulin resistance in Japanese men

2021 ◽  
Author(s):  
Kageumi Takeno ◽  
Yoshifumi Tamura ◽  
Saori Kakehi ◽  
Hideyoshi Kaga ◽  
Ryuzo Kawamori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Alcohol Consumption ◽  
Alcohol Intake ◽  
Fasting Glucose ◽  
Fat Distribution ◽  
Hepatic Insulin Resistance ◽  
Japanese Men ◽  
Hepatic Insulin Sensitivity ◽  
Glucose Clearance

Abstract Background A recent meta-analysis of genome-wide association studies data from East Asians identified acetaldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males. Methods We studied 94 non-obese, non-diabetic, Japanese men. Using a two-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided the subjects into risk carrying group with ALDH2 rs671 G/G (n=53) and non-risk carrying group with ALDH2 rs671 G/A or A/A (n=41). Results The risk carrying group had significantly higher levels of alcohol consumption (18.4 (IQR, 10.4–48.9) vs. 12.1(IQR, 1.3–29.0) g/day; P=0.003), elevated fasting plasma glucose (FPG) (97.5±7.9 vs. 93.5±6.2 mg/dL; P=0.010), lower hepatic insulin sensitivity (61.7±20.5% vs.73.1±15.9%; P=0.003) and lower fasting glucose clearance (0.84±0.8 dL·m -2·min -1 vs. 0.87±0.09 dL·m -2·min -1; P=0.047) than the non-risk carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r=-0.262, P=0.011), fasting glucose clearance (r=-0.370, P&lt;0.001) or FPG (r=0.489, P&lt;0.001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, while only alcohol consumption was a significant independent correlate for fasting glucose clearance. Conclusion Our data suggested that high-alcohol-intake dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.

scholarly journals Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice

2020 ◽  
Vol 61 (12) ◽  
pp. 1565-1576 ◽  
Author(s):  
Abudukadier Abulizi ◽  
Daniel F. Vatner ◽  
Zhang Ye ◽  
Yongliang Wang ◽  
Joao-Paulo Camporez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Plasma Membrane ◽  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Lipid Droplet ◽  
Microsomal Triglyceride Transfer Protein ◽  
Hepatic Insulin Resistance ◽  
Hepatic Insulin Sensitivity ◽  
Hepatic Insulin Signaling ◽  
Ceramide Content

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp−/−) mice and age-weight matched wild-type control mice. Young (10–12-week-old) L-Mttp−/− mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp−/− mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKCε activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp−/− mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKCε activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp−/− mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKCε activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp−/− mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp−/− mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp−/− mice.

Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production

2005 ◽  
Vol 289 (3) ◽  
pp. G592-G598 ◽  
Author(s):  
Aldo Grefhorst ◽  
Jildou Hoekstra ◽  
Terry G. J. Derks ◽  
D. Margriet Ouwens ◽  
Julius F. W. Baller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Production Rate ◽  
Hepatic Steatosis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pi3 Kinase ◽  
Hepatic Insulin Resistance ◽  
Nonesterified Fatty Acid ◽  
Hepatic Insulin Sensitivity

Accumulation of triglycerides (TG) in the liver is generally associated with hepatic insulin resistance. We questioned whether acute hepatic steatosis induced by pharmacological blockade of β-oxidation affects hepatic insulin sensitivity, i.e., insulin-mediated suppression of VLDL production and insulin-induced activation of phosphatidylinositol 3-kinase (PI3-kinase) and PKB. Tetradecylglycidic acid (TDGA), an inhibitor of carnitine palmitoyl transferase-1 (CPT1), was used for this purpose. Male C57BL/6J mice received 30 mg/kg TDGA or its solvent intraperitoneally and were subsequently fasted for 12 h. CPT1 inhibition resulted in severe microvesicular hepatic steatosis (19.9 ± 8.3 vs. 112.4 ± 25.2 nmol TG/mg liver, control vs. treated, P < 0.05) with elevated plasma nonesterified fatty acid (0.68 ± 0.25 vs. 1.21 ± 0.41 mM, P < 0.05) and plasma TG (0.39 ± 0.16 vs. 0.60 ± 0.10 mM, P < 0.05) concentrations. VLDL-TG production rate was not affected on CPT1 inhibition (74.9 ± 15.2 vs. 79.1 ± 12.8 μmol TG·kg−1·min−1, control vs. treated) although treated mice secreted larger VLDL particles (59.3 ± 3.6 vs. 66.6 ± 4.5 nm diameter, P < 0.05). Infusion of insulin under euglycemic conditions suppressed VLDL production rate in control and treated mice by 43 and 54%, respectively, with formation of smaller VLDL particles (51.2 ± 2.5 and 53.2 ± 2.8 nm diameter). Insulin-induced insulin receptor substrate (IRS)1- and IRS2-associated PI3-kinase activity and PKB-phosphorylation were not affected on TDGA treatment. In conclusion, acute hepatic steatosis caused by pharmacological inhibition of β-oxidation is not associated with reduced hepatic insulin sensitivity, indicating that hepatocellular fat content per se is not causally related to insulin resistance.

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