scholarly journals Effects of Obesity and Short-Term Metformin Treatment on Liver Steatosis in Female Zucker Rats

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1640-1640
Author(s):  
Reza Hakkak ◽  
David Irby ◽  
Shannon Rose ◽  
Sirish Bennuri ◽  
Beverly Spray ◽  
...  
Keyword(s):  
Liver Disease ◽  
Rat Model ◽  
Liver Steatosis ◽  
Serum Markers ◽  
Zucker Rats ◽  
Metformin Treatment ◽  
Zucker Rat ◽  
Short Term ◽  
Obese Zucker Rat ◽  
Obese Rats

Abstract Objectives Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in adolescents in the US and World, and the risk has increased with the rise in obesity. We reported that obesity increases Fatty liver (steatosis) using an obese Zucker rat model. Metformin is an oral anti-hyperglycemic agent approved by the FDA to treat type 2 diabetes (T2D) in adults and children older than 10 years of age. There is insufficient evidence regarding the effects of metformin in pediatric liver steatosis. The objective of this study was to investigate the effects of short-term metformin treatment on liver steatosis and related serum markers for liver damage. Methods Five week old lean (n = 16) and obese (n = 16) female Zucker rats after one week of acclimation, received AIN-93 G diet for 8 weeks to induce NAFLD. After 8 weeks, lean and obese rats were randomly assigned to the following four groups (8 rats/group): 1) lean without metformin (LC), 2) lean with metformin (LMet), 3) obese without metformin (ObC), and 4) obese with metformin (ObMet). Metformin were mixed with AIN-93 G diet at 1000 mg/kg of diet. Rats were weighed twice per week. All rats were sacrificed 10 weeks post-metformin treatment and serum and livers were collected. Steatosis was semiquantitated as a score of 1 to 4 based upon the relative degree of steatosis within hepatocytes: 1) < 25%, 2) 25–50%, 3) 50–75%, and 4) >75%. Serums were collected to measure the levels of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) on a clinical analyzer. Results Obese rats gained significantly more weight (P < .001) than lean rats for both control and Metformin treatment groups and there was no significant difference between ObC vs. ObMet group (P = 0.20). The mean + SD liver steatosis scores for the LC, LMet, ObC and ObMet groups were 0.13 + o.3, 0.13 + o.3, 3.67 + 0.52 and 3.00 + 0.82. The ObMet treated rats had lower (P < 0.04) liver steatosis than ObC rats. There were no significant differences for the serum ALT and AST levels between groups. However, obesity increased significantly (P < 0.01) serum AST levels compared to LC but not in the metformin group. Conclusions In summary, in the obese zucker rat model, short-term metformin treatment decreased liver steatosis but did not impact serum markers of liver steatosis. Funding Sources Arkansas Children Research Institute/Arkansas Bioscience Institute.

scholarly journals Effects of Short-Term Metformin Treatment on Gut Microbiota Profile Using Female Obese Zucker Rat Model

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1213-1213
Author(s):  
Reza Hakkak ◽  
Chris Randolph ◽  
Sirish Bennuri ◽  
Michael Robeson
Keyword(s):  
Gut Microbiota ◽  
Rat Model ◽  
Zucker Rats ◽  
Metformin Treatment ◽  
Zucker Rat ◽  
Short Term ◽  
Fecal Samples ◽  
Obese Zucker Rat ◽  
Significant Difference ◽  
Obese Control

Abstract Objectives The correlation of short-term metformin treatment and specific alterations to the gut microbiota in obese models is less known. So, the objectives of this experiment was to investigate the effects of short-term metformin treatment on population of gut microbiota profile in obese rat model. Methods Five week old obese (n = 16) female Zucker rats after one week of acclimation, received AIN-93 G diet for 8 weeks and then rats were randomly assigned 8 rats/group): to 1) obese without metformin (ObC), or 2) obese with metformin (ObMet). Metformin were mixed with AIN-93G diet at 1000 mg/kg of diet. Rats were weighed twice per week. All rats were sacrificed 10 weeks post-metformin treatment and fecal samples were collected and kept at − 80c. Total microbial DNA were collected directly from the fecal samples using a PowerSoil® DNA isolation kit. Isolated DNA were used for shotgun-metagenomics data collection using Illumina NextSeq500 and analyzed using MetaPlAn and HUMAnN. DEICODE and Songbird used calculate log-ratios and differential ranks of taxa and functional pathways associated with metformin treatment respectively. The were then visualized using Qurro. Results There was no significant difference between ObC vs. ObMet group body weight (P = 0.20). Overall microbial beta-diversity (DEICODE), showed significant separation between the obese control and metformin samples (P = 0.0007). Differential ranking (Songbird) of Bacteroides dorei and B. massiliensis vs. all other Bacteroides spp., revealed that B. dorei and B. massiliensis were enriched in the obese metformin group, while the remaining Bacteroides spp. where enriched in the obese control group (P = 0.002). The differential ranking of pathway diversity contributed by the Bacteroides were also associated with treatment group (P = 0.008). Conclusions In summary, in the obese zucker rat model, short-term metformin treatment changes the gut microbiota profile. Funding Sources Arkansas Biosciences Institute.

scholarly journals Effects of Diet Containing Soy Protein Isolate on Liver Metabolic Methylation Status Using Obese Zucker Rat Model (P08-033-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Reza Hakkak ◽  
Soheila Korourian ◽  
Oleksandra Pavliv ◽  
Stepan Melnyk
Keyword(s):  
Rat Model ◽  
Soy Protein ◽  
Methylation Status ◽  
Liver Steatosis ◽  
Soy Protein Isolate ◽  
The United States ◽  
Protein Isolate ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Obese Zucker Rat

Abstract Objectives The obesity epidemic is continuing to grow in the United States and world for past two decades. There is a link between obesity and chronic diseases development such as diabetes, cardiovascular disease, certain types of cancer and liver diseases. Previously, we reported that obesity caused a significant increase liver steatosis and feeding soy protein isolate (SPI) reduced liver steatosis. The mechanism of SPI protection against liver steatosis is less known. We hypothesize that soy protein diet will reduce development of liver steatosis caused by obesity in part by changing methylation status. The objective of the present study was to investigate the effects of SPI feeding on liver metabolic methylation status using obese zucker rat model. Methods After one week of acclimation, five weeks old female lean and obese Zucker rats (n = 8/group) were randomly fed AIN-93-G diet with either casein (CAS as control) or SPI as source of protein for 22 weeks. Rats were weighted twice per week. Liver sample metabolites concentrations were measured using HPLC with Electrochemical Detection and LC-MS. Results Our results shows that; 1) obesity increased body weight significantly (P < 0.001) for both CAS and SPI diets; 2) Obese SPI-fed rats significantly (P < 0.001) reduced liver steatosis compared to obese CAS-fed rats. Also, our results show that liver metabolic profile in lean SPI-fed rats significantly (P < 0.025) increased SAM/SAH ratio (methylation ratio) compare to CAS-fed rats. Obese SPI-fed rats significantly (P < 0.001) decrease level of Homocysteine in liver and increase significantly (P < 0.001) Methionine/Homocysteine ratio. Conclusions In summary we showed that SPI diet can reduce liver steatosis by changing methylation status and improved metabolism of Homocysteine, toxic intracellular compound, through remethylation to Methionine. Funding Sources Arkansas Children's Research Institute's University Medical Group Fund grant program and Arkansas.

A diet containing a high- versus low-daidzein level does not protect against liver steatosis in the obese Zucker rat model

2017 ◽  
Vol 8 (3) ◽  
pp. 1293-1298 ◽  
Author(s):  
Andrea Bell ◽  
Soheila Korourian ◽  
Huawei Zeng ◽  
Joshua Phelps ◽  
Reza Hakkak
Keyword(s):  
Rat Model ◽  
Liver Steatosis ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Body Weights

Low daidzeinversushigh daidzein mean (±SD) body weights over 8 weeks.

scholarly journals Mechanism controlling sleep organization of the obese Zucker rats

1998 ◽  
Vol 84 (1) ◽  
pp. 253-256 ◽  
Author(s):  
David Megirian ◽  
Jacek Dmochowski ◽  
Gaspar A. Farkas
Keyword(s):  
Eye Movement ◽  
Rem Sleep ◽  
Nrem Sleep ◽  
Zucker Rats ◽  
Rapid Eye Movement ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Obese Zucker Rats ◽  
The Mean

Megirian, David, Jacek Dmochowski, and Gaspar A. Farkas. Mechanism controlling sleep organization of the obese Zucker rat. J. Appl. Physiol. 84(1): 253–256, 1998.—We tested the hypothesis that the obese ( fa/fa) Zucker rat has a sleep organization that differs from that of lean Zucker rats. We used the polygraphic technique to identify and to quantify the distribution of the three main states of the rat: wakefulness (W), non-rapid-eye-movement (NREM), and rapid-eye-movement (REM) sleep states. Assessment of states was made with light present (1000–1600), at the rats thermoneutral temperature of 29°C. Obese rats, compared with lean ones, did not show significant differences in the total time spent in the three main states. Whereas the mean durations of W and REM states did not differ statistically, that of NREM did ( P = 0.046). However, in the obese rats, the frequencies of switching from NREM sleep to W, which increased, and from NREM to REM sleep, which decreased, were statistically significantly different ( P = 0.019). Frequency of switching from either REM or W state was not significantly different. We conclude that sleep organization differs between lean and obese Zucker rats and that it is due to a disparity in switching from NREM sleep to either W or REM sleep and the mean duration of NREM sleep.

scholarly journals Gene expression of lipid storage-related enzymes in adipose tissue of the genetically obese Zucker rat. Co-ordinated increase in transcriptional activity and potentiation by hyperinsulinaemia

1992 ◽  
Vol 281 (3) ◽  
pp. 607-611 ◽  
Author(s):  
I Dugail ◽  
A Quignard-Boulangé ◽  
X Le Liepvre ◽  
B Ardouin ◽  
M Lavau
Keyword(s):  
Adipose Tissue ◽  
Mrna Level ◽  
Lipid Storage ◽  
Zucker Rats ◽  
Transcriptional Level ◽  
Transcription Rate ◽  
Mrna Levels ◽  
Zucker Rat ◽  
Obese Zucker Rat ◽  
Obese Rats

The genetically obese Zucker rat displays excessive fat storage capacity which is due to a tissue-specific increase in the activities of a number of lipid storage-related enzymes in adipose tissue. The aim of this study was to investigate the molecular mechanism responsible for this phenomenon. Lean (Fa/fa) and obese (fa/fa) Zucker rats were studied during the early stages of adipose tissue overdevelopment, both before (at 16 days of age) and after (at 30 days of age) the emergence of hyperinsulinaemia, in order to delineate the effects of the fatty genotype independently of those of hyperinsulinaemia. Lipoprotein lipase (LPL), glycerophosphate dehydrogenase (GPDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and malic enzyme (ME) mRNA levels in the adipose tissue of lean and obese rats were assessed by Northern blot analysis, and the relative transcription rates of the corresponding genes were compared in the two genotypes by a nuclear run-on assay. In normoinsulinaemic 16-day-old pre-obese rats, mRNA levels were increased over control values (LPL, 5-fold; ME, 2-fold; GAPDH, 3-fold), in close correlation with genotype-mediated differences in enzyme activities. Stimulation of the transcription rates of the ME and GAPDH genes was observed in obese rats, which could fully account for differences in steady-state mRNA levels. At this age, GPDH activity, mRNA level and transcription rate were similar in the two genotypes. In hyperinsulinaemic 30-day-old obese rats, a 6-7-fold increase in both mRNA and the transcription rate of GPDH emerged, together with an amplification of the genotype-mediated differences observed in younger animals (GAPDH, 6-fold; ME, 7.9-fold; LPL, 10-fold). These results demonstrate that the obese genotype exerts a co-ordinated control on the expression of these genes in adipose tissue, mainly at the transcriptional level. This genotype effect is greatly amplified by the development of hyperinsulinaemia.

scholarly journals Adipsin mRNA amounts are not decreased in the genetically obese Zucker rat

1989 ◽  
Vol 257 (3) ◽  
pp. 917-919 ◽  
Author(s):  
I Dugail ◽  
X Le Liepvre ◽  
A Quignard-Boulangé ◽  
J Pairault ◽  
M Lavau
Keyword(s):  
Gene Expression ◽  
High Fat Diet ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Obese Mice ◽  
High Fat ◽  
Adult Rats ◽  
Obese Zucker Rat ◽  
Obese Rats ◽  
Obese Zucker Rats

Adipsin gene expression as assessed by mRNA amounts was examined in adipose tissue of genetically obese rats at the onset (16 days of age) or at later stages (30 and 60 days of age) of obesity. Amounts of mRNA were equivalent in obese and lean rats at 16 days of age. In adult rats, we observed a 2-fold decrease in adipsin mRNA in the obese rats compared with control lean rats, which was abolished by weaning the animals on a high-fat diet. Our data show that, in sharp contrast with genetically obese mice, adipsin mRNA is not suppressed in genetically obese Zucker rats.

scholarly journals Effects of Short- and Long-Term Soy Protein Feeding on Hepatic Cytochrome P450 Expression in Obese Nonalcoholic Fatty Liver Disease Rat Model

2021 ◽  
Vol 8 ◽  
Author(s):  
Melisa Kozaczek ◽  
Walter Bottje ◽  
Diyana Albataineh ◽  
Reza Hakkak
Keyword(s):  
Cytochrome P450 ◽  
Liver Disease ◽  
Fatty Liver ◽  
Rat Model ◽  
Soy Protein ◽  
Fatty Liver Disease ◽  
Liver Steatosis ◽  
Short Term ◽  
Nonalcoholic Fatty Liver

Obesity can lead to chronic health complications such as nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by lipid aggregation in the hepatocytes and inflammation of the liver tissue as a consequence that can contribute to the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we reported that feeding obese Zucker rats with soy protein isolate (SPI) can reduce liver steatosis when compared with a casein (CAS) diet as a control. However, the effects of SPI on cytochrome P450 (CYP) in an obese rat model are less known. In addition, there is a lack of information concerning the consumption of soy protein in adolescents and its effect in reducing the early onset of NAFLD in this group. Our main goal was to understand if the SPI diet had any impact on the hepatic CYP gene expression when compared with the CAS diet. For this purpose, we used the transcriptomic data obtained in a previous study in which liver samples were collected from obese rats after short-term (eight-week) and long-term (16-week) feeding of SPI (n = 8 per group). To analyze this RNAseq data, we used Ingenuity Pathway Analysis (IPA) software. Comparing short- vs long-term feeding revealed an increase in the number of downregulated CYP genes from three at 8 weeks of SPI diet to five at 16 weeks of the same diet (P ≤ 0.05). On the other hand, upregulated CYP gene numbers showed a small increase in the long-term SPI diet compared to the short-term SPI diet, from 14 genes at 8 weeks to 17 genes at 16 weeks (P ≤ 0.05). The observed changes may have an important role in the attenuation of liver steatosis.

Glucose uptake and GLUT-4 protein distribution in skeletal muscle of the obese Zucker rat

1994 ◽  
Vol 267 (1) ◽  
pp. R236-R243 ◽  
Author(s):  
J. T. Brozinick ◽  
G. J. Etgen ◽  
B. B. Yaspelkis ◽  
J. L. Ivy
Keyword(s):  
Plasma Membrane ◽  
Glucose Uptake ◽  
Protein Concentration ◽  
Protein Translocation ◽  
Zucker Rats ◽  
Zucker Rat ◽  
Protein Distribution ◽  
Glut 4 ◽  
Obese Zucker Rat ◽  
Obese Rats

The rates of muscle glucose uptake of lean and obese Zucker rats were assessed by hindlimb perfusion under basal conditions (no insulin), in the presence of a maximally stimulating concentration of insulin (10 mU/ml), and after muscle contraction elicited by electrical stimulation of the sciatic nerve. After perfusion, plasma and microsomal membranes were isolated from selected hindlimb muscles for determination of GLUT-4 protein distribution. Under basal conditions, rates of glucose uptake were similar for lean and obese rats despite plasma membranes from lean rats containing 82% more GLUT-4 protein than obese rats. Insulin stimulation resulted in significant increases in plasma membrane GLUT-4 protein concentration in lean but not obese rats. Glucose uptake of lean rats (35.3 +/- 4.7 mumol.h-1.g-1) in the presence of insulin was approximately fourfold greater than that of obese rats (8.8 +/- 1.3 mumol.h-1.g-1), but this difference in glucose uptake could not be completely accounted for by the difference in plasma membrane GLUT-4 protein concentration. Stimulation by contraction resulted in significant increases in plasma membrane GLUT-4 protein concentration in both lean and obese rats and similar rates of glucose uptake. These results suggest that the muscle insulin resistance of the obese Zucker rat is due to 1) a reduced plasma membrane GLUT-4 protein concentration, which results in part from an impairment in the insulin-stimulated GLUT-4 protein translocation process, and 2) a defect in the insulin-stimulated activation of this protein. However, contraction-stimulated glucose uptake, GLUT-4 protein translocation, and activation are normal in the obese Zucker rat.

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