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

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.

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1640-1640
Author(s):  
Reza Hakkak ◽  
David Irby ◽  
Shannon Rose ◽  
Sirish Bennuri ◽  
Beverly Spray ◽  
...  

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.


2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Reza Hakkak ◽  
Soheila Korourian ◽  
Oleksandra Pavliv ◽  
Stepan Melnyk

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.


2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Reza Hakkak ◽  
Soheila Korourian ◽  
Steven Foley ◽  
Bruce Erickson

2017 ◽  
Vol 8 (3) ◽  
pp. 1293-1298 ◽  
Author(s):  
Andrea Bell ◽  
Soheila Korourian ◽  
Huawei Zeng ◽  
Joshua Phelps ◽  
Reza Hakkak

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


2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Song ◽  
Li-Ying Sun ◽  
Zhi-Jun Zhu ◽  
Lin Wei ◽  
Wei Qu ◽  
...  

Background and AimsBiliary atresia (BA) is an idiopathic neonatal cholestasis and is the most common indication in pediatric liver transplantation (LT). Previous studies have suggested that the gut microbiota (GM) in BA is disordered. However, the effect of LT on gut dysbiosis in patients with BA has not yet been elucidated.MethodsPatients with BA (n = 16) and healthy controls (n = 10) were recruited. In the early life of children with BA, Kasai surgery is a typical procedure for restoring bile flow. According to whether BA patients had previously undergone Kasai surgery, we divided the post-LT patients into the with-Kasai group (n = 8) and non-Kasai group (n = 8). Fecal samples were collected in both the BA and the control group; among BA patients, samples were obtained again 6 months after LT. A total of 40 fecal samples were collected, of which 16 were pre-LT, 14 were post-LT (8 were with-Kasai, 6 were non-Kasai), and 10 were from the control group. Metagenomic sequencing was performed to evaluate the GM.ResultsThe Kruskal-Wallis test showed a statistically significant difference in the number of genes between the pre-LT and the control group, the pre-LT and the post-LT group (P &lt; 0.05), but no statistical difference between the post-LT and the control group. Principal coordinate analysis also showed that the microbiome structure was similar between the post-LT and control group (P &gt; 0.05). Analysis of the GM composition showed a significant decrease in Serratia, Enterobacter, Morganella, Skunalikevirus, and Phifllikevirus while short chain fatty acid (SCFA)-producing bacteria such as Roseburia, Blautia, Clostridium, Akkermansia, and Ruminococcus were increased after LT (linear discriminant analysis &gt; 2, P &lt; 0.05). However, they still did not reach the normal control level. Concerning functional profiles, lipopolysaccharide metabolism, multidrug resistance, polyamine biosynthesis, GABA biosynthesis, and EHEC/EPEC pathogenicity signature were more enriched in the post-LT group compared with the control group. Prior Kasai surgery had a specific influence on the postoperative GM.ConclusionLT partly improved the GM in patients with BA, which provided new insight into understanding the role of LT in BA.


1998 ◽  
Vol 9 (1) ◽  
pp. 38-45 ◽  
Author(s):  
N J Laping ◽  
B A Olson ◽  
J R Day ◽  
B M Brickson ◽  
L C Contino ◽  
...  

Clusterin is a multifunctional glycoprotein associated with development and tissue injury. Because renal function decreases with advancing age in the obese Zucker rat, clusterin mRNA expression was examined in the kidney of young adult Zucker rats and compared with age-related changes in renal clusterin mRNA expression in Fischer 344 (F344) rats. Renal clusterin mRNA levels in the obese Zucker rat were 2.5-fold higher by 3 mo of age and fourfold higher at 5 mo of age compared with the lean strain. In comparison, renal clusterin mRNA in 12-mo-old F344 rats was twofold higher than in 3-mo-old animals and was tenfold higher at 24 mo of age. Clusterin mRNA was positively correlated with urinary protein excretion and negatively correlated with creatinine clearance in Zucker rats. Clusterin was increased in select nephrons of the obese Zucker rat kidney and in 24-mo-old F344 rat kidney as assessed by in situ hybridization. Increased expression of clusterin mRNA occurred mostly in the tubular epithelium of dilated, convoluted proximal tubules. These data indicate that renal clusterin mRNA levels increase as a function of age and that age-related increases in renal clusterin and the associated tubular abnormalities are accelerated in obese Zucker rats.


1998 ◽  
Vol 84 (1) ◽  
pp. 253-256 ◽  
Author(s):  
David Megirian ◽  
Jacek Dmochowski ◽  
Gaspar A. Farkas

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.


1992 ◽  
Vol 281 (3) ◽  
pp. 607-611 ◽  
Author(s):  
I Dugail ◽  
A Quignard-Boulangé ◽  
X Le Liepvre ◽  
B Ardouin ◽  
M Lavau

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.


1978 ◽  
Vol 77 (3) ◽  
pp. 417-418 ◽  
Author(s):  
W. R. CROWLEY ◽  
J. M. GEORGE ◽  
D. M. JACOBOWITZ

Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20014, U.S.A. and *Department of Medicine, Ohio State University, College of Medicine, Columbus, Ohio, U.S.A. (Received 20 September 1977) The genetically obese Zucker rat exhibits several endocrine disorders, including defects of the female reproductive system such as delayed puberty, irregular oestrous cycles, failure to mate and refractoriness to pseudopregnancy-inducing stimuli (Saiduddin, Bray, York & Swerdloff, 1973). Zucker rats show hyperdipsia, increased plasma osmolality and excrete a large volume of urine with a decreased osmolality and an increased protein content, suggesting a deficiency in the regulation of body fluids (York & Bray, 1971, 1973; Bray, York & Swerdloff, 1973). These considerations, plus the recent findings that in Zucker rats the concentration of noradrenaline is reduced in the hypothalamic paraventricular nucleus and increased in the median eminence (Cruce, Thoa & Jacobowitz, 1976), prompted us to measure levels of arginine-vasopressin (AVP) and


1989 ◽  
Vol 257 (3) ◽  
pp. 917-919 ◽  
Author(s):  
I Dugail ◽  
X Le Liepvre ◽  
A Quignard-Boulangé ◽  
J Pairault ◽  
M Lavau

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.


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