Liver Of Obese Rats Research Articles

Effects of high isoflavone soy diet vs casein or arginine‐supplemented casein diet on liver steatosis

Non‐alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function, is often associated with obesity. Arginine (Arg) plays a role in reducing body fat, but there is limited data as to the role that Arg may play in soy protein's ability to protect from fatty liver. The objective of this study was to find the role of native Arg in soy to protect from fatty liver in male obese Zucker rats (N=49; 6 weeks old). Rats had ad libitum access to water and were randomly assigned to one of 3 diets for 8 or 16 weeks: Casein (CAS) diet as control (0.6% Arg) or a casein diet supplemented to contain 1.3% Arg (ARG) or a soy protein isolate diet with high isoflavones (SPI) (1.3% Arg). SPI and ARG rats gained more weight (P<0.05) than CAS rats after 16 weeks only. The SPI rats had lower liver steatosis after 8 and 16 weeks (P<0.05 and P<0.001, respectively) compared to CAS & ARG rats. SPI rats had lower serum alanine amino transferase (ALT) & aminotransferase (AST) levels (P<0.05) compared to CAS after 16 weeks and AST was lower (P<0.05) compared to ARG rats. After 16 weeks the SPI rats had lower (P<0.05) serum ALT and AST levels than SPI rats at 8 weeks. Our results suggest that longer period of SPI feeding results in lower liver steatosis and serum ALT and AST levels while ARG diet had no effect on steatosis or ALT and AST levels. The protective effect of soy protein to reduce fatty liver does not appear to be due to its arginine content. Supported by ABI to RH

Carbenoxolone treatment ameliorated metabolic syndrome in WNIN/Ob obese rats, but induced severe fat loss and glucose intolerance in lean rats.

Background11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates local glucocorticoid action in tissues by catalysing conversion of inactive glucocorticoids to active glucocorticoids. 11β-HSD1 inhibition ameliorates obesity and associated co-morbidities. Here, we tested the effect of 11β-HSD inhibitor, carbenoxolone (CBX) on obesity and associated comorbidities in obese rats of WNIN/Ob strain, a new animal model for genetic obesity.Methodology/Principal FindingsSubcutaneous injection of CBX (50 mg/kg body weight) or volume-matched vehicle was given once daily for four weeks to three month-old WNIN/Ob lean and obese rats (n = 6 for each phenotype and for each treatment). Body composition, plasma lipids and hormones were assayed. Hepatic steatosis, adipose tissue morphology, inflammation and fibrosis were also studied. Insulin resistance and glucose intolerance were determined along with tissue glycogen content. Gene expressions were determined in liver and adipose tissue. CBX significantly inhibited 11β-HSD1 activity in liver and adipose tissue of WNIN/Ob lean and obese rats. CBX significantly decreased body fat percentage, hypertriglyceridemia, hypercholesterolemia, insulin resistance in obese rats. CBX ameliorated hepatic steatosis, adipocyte hypertrophy, adipose tissue inflammation and fibrosis in obese rats. Tissue glycogen content was significantly decreased by CBX in liver and adipose tissue of obese rats. Severe fat loss and glucose- intolerance were observed in lean rats after CBX treatment.Conclusions/SignificanceWe conclude that 11β-HSD1 inhibition by CBX decreases obesity and associated co-morbidities in WNIN/Ob obese rats. Our study supports the hypothesis that inhibition of 11β-HSD1 is a key strategy to treat metabolic syndrome. Severe fat loss and glucose -intolerance by CBX treatment in lean rats suggest that chronic 11β-HSD1 inhibition may lead to insulin resistance in normal conditions.

Dipeptidylpeptidase-­IV, a key enzyme for the degradation of incretins and neuropeptides: activity and expression in the liver of lean and obese rats

Given the scarcity of donors, moderately fatty livers (FLs) are currently being considered as possible grafts for orthotopic liver transplantation (OLT), notwithstanding their poor tolerance to conventional cold preservation. The behaviour of parenchymal and sinusoidal liver cells during transplantation is being studied worldwide. Much less attention has been paid to the biliary tree, although this is considered the Achille's heel even of normal liver transplantation. To evaluate the response of the biliary compartment of FLs to the various phases of OLT reliable markers are necessary. Previously we demonstrated that Alkaline Phosphatase was scarcely active in bile canaliculi of FLs and thus ruled it out as a marker. As an alternative, dipeptidylpeptidase-IV (DPP-IV), was investigated. This ecto-peptidase plays an important role in glucose metabolism, rapidly inactivating insulin secreting hormones (incretins) that are important regulators of glucose metabolism. DPP-IV inhibitors are indeed used to treat Type II diabetes. Neuropeptides regulating bile transport and composition are further important substrates of DPP-IV in the enterohepatic axis. DPP-IV activity was investigated with an azo-coupling method in the liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. Protein expression was studied by immunofluorescence with the monoclonal antibody (clone 5E8). In Wistar rat liver, DPP-IV activity and expression were high in the whole biliary tree, and moderate in sinusoid endothelial cells, in agreement with the literature. Main substrates of DPP-IV in hepatocytes and cholangiocytes could be incretins GLP-1 and GIP, and neuropeptides such as vasoactive intestinal peptide (VIP) and substance P, suggesting that these substances are inactivated or modified through the biliary route. In lean Zucker rat liver the enzyme reaction and protein expression patterns were similar to those of Wistar rat. In obese rat liver the patterns of DPP-IV activity and expression in hepatocytes reflected the morphological alterations induced by steatosis as lipid-rich hepatocytes had scarce activity, located either in deformed bile canaliculi or in the sinusoidal and lateral domains of the plasma membrane. These findings suggest that bile canaliculi in steatotic cells have an impaired capacity to inactivate incretins and neuropeptides. Incretin and/or neuropeptide deregulation is indeed thought to play important roles in obesity and insulin-resistance. No alteration in enzyme activity and expression was found in the upper segments of the biliary tree of obese respect to lean Zucker and Wistar rats. In conclusion, this research demonstrates that DPP-IV is a promising in situ marker of biliary functionality not only of normal but also of fatty rats. The approach, initially devised to investigate the behaviour of the liver during the various phases of transplantation, appears to have a much higher potentiality as it could be further exploited to investigate any pathological or stressful conditions involving the biliary tract (i.e., metabolic syndrome and cholestasis) and the response of the biliary tract to therapy and/or to surgery.

More News About NUCB2/Nesfatin-1: A New Factor in the Hypothalamic Control of Glucose Homeostasis?

Insulin resistance and declining insulin production define a spectrum of metabolic diseases afflicting a growing portion of the population (1). Current estimates suggest that 26 million Americans have diabetes, with the incidence of type 2 diabetes involving insulin resistance and β-cell decompensation far exceeding that of type 1 diabetes. Treatment of type 2 diabetes involves secretagogues that increase insulin secretion and insulin sensitizers to improve insulin receptor (INSR) action (and likely include other effects on glucose production) (1). These drugs exhibit a short duration of efficacy in many patients and often require a multidrug approach as the disease progresses and insulin injections when other treatment options fail. A clear need exists for continued research aimed at developing more effective strategies for maintaining glycemic control. In this issue, Yang et al. (2) report that intracerebroventricular (ICV) infusion of nesfastin-1 improves glucose homeostasis in diet-induced obese rats by inhibiting hepatic glucose production. Improved insulin action is one mechanism for the reduction in hepatic glucose production. Increased phosphorylation of the INSR and insulin receptor substrate-1 was observed in lean and obese rats following ICV administration of nesfatin-1. Tyrosine phosphorylationof multiple residues in the insulin receptor substrate-1 coding sequence is an important early event following INSR activation. This leads to an intracellular signaling cascade that facilitates changes in energy metabolism by regulating gene transcription and enzymatic activity (3). The changes in phosphorylation of AKT, AMP-dependent protein kinase, mammalian target of rapamycin, and mammalian target of rapamycin complex 2 that were also observed were consistent with improved actions of these important downstream effectors in the INSR signaling cascade. Activity of phosphoenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, was also reduced in livers of lean and diet-induced obese rats administered nesfatin-1 ICV. Finally, a …

The influence of pioglitazone on the expression of adiponectin in the liver of high fat diet-induced obese rats

Objective To observe the influence of pioglitazone on the expression of adiponectin in the liver of high fat diet-induced obese rats.Methods Forty male SD rats were randomly divided into control group which received regular diet ( n =10),high fat diet group ( n =15 ) and high fat diet goup administened pioglitazone ( n =15 ) on high fat diet.After twelve weeks,fasting blood glucose,fasting serum insulin,triglyceride,total cholesterol,and the histomorphologieal changes in liver were observed;insulin sensitivity test was performed;the fatty experimental group are treated with Pioglitazone(30mg · kg-1 · d-1,oral gavage),treatment was administered daily for 2 weeks.The control group and fatty control group all received an equal volume of vehicle (saline).The protein expression of adiponectin in the liver of rats was determined by immunohistochemistry.Results The insulin sensitive index was significantly decreased in the high-fat-diet rats compared with the control group[(0.021 ±0.010),(0.015 ±0.007),P ＜0.05] ;The protein level of adiponectin in the liver of fatty,control group was significantly decreased compared with the control group[(2929.73 ± 157.45 ),(3814.21 ±211.42),P ＜0.05],adiponectin in the liver of fatty experimental group was significantly increased compared with the fatty control group[(2929.73 ± 157.45),(3657.68 ±217.31 ),P ＜0.05].Conclusion Pioglitazone could improve the expression of adiponectin,and improve the resistance of insulin. Key words: Adiponectin; Insulin resistance; Liver; Pioglitazone

Soy Protein Isolate Mediated the Wnt/ β‐Catenin Signaling Pathway and Alleviated Fat Accumulation in the Liver of Obese Zucker Rats

Excessive fat accumulation in liver can lead to chronic liver diseases. Managing this situation in obese population is critical to the improvement of overall health. Dietary soy protein isolate (SPI) possess beneficial effects of anti‐obesity. Wnt/β‐Catenin pathway, a crucial mediator of adipogenesis, was repressed by obesity. However, the interaction between SPI and Wnt/β‐Catenin in the obese population is elusive. The current study aimed to investigate the dietary effects of SPI on Wnt/β‐Catenin in the liver of obese rats. Obese Zucker rats were fed with isocaloric diets containing SPI or casein for 17 weeks. Lean rats were included as the reference group. Histology analysis of the liver demonstrated structural change and difference in fat content by dietary treatments. Triglyceride (TAG) and non‐esterified fatty acid (NEFA) contents were significantly lower in the liver of SPI‐fed obese rats compared with casein‐fed obese rats. SREBP1‐c gene expression was also reduced by SPI treatment indicating reduced fat synthesis. β‐Catenin protein abundance in the liver was upregulated in obese rats by SPI comparing to casein. In vitro cell culture studies further confirmed the interaction between fat accumulation and Wnt/β‐Catenin signaling. Taken together, our results suggested that SPI restored the Wnt/β‐Catenin signaling pathway and alleviated the fat accumulation in the liver of obese rats.

Consumption of dehydrated Opuntia ficus Indica (nopal) prevents the development of fatty liver by modifying hepatic lipid metabolism in obese Zucker fa/fa rats

Opuntia ficus indica (nopal), a plant rich in bioactive compounds, has been widely used in the traditional Mexican medicine to treat diabetes. Therefore in the present study, we investigated the effect of nopal consumption in the prevention of fatty liver in obese Zucker rats.Six weeks old male Zucker (fa/fa) rats (n=12 per group) were fed with a control diet (AIN‐93G; C) or C+ Nopal for 7 weeks. After 7 weeks of dietary treatment, rats fed C+nopal decreased by 50% hepatic triglycerides with respect to control and reduced hepatomegaly and macrovesicular steatosis. In addition, increased serum levels of adiponectin, mRNA expression of genes involved in lipid oxidation (PPARα, CPT1 and ACOX) and lipid export (MTTP and PLTP), hepatic CPT1 and MTTP protein levels. Furthermore, rats fed C+nopal decreased postprandial serum insulin levels; increased liver pAkt/Akt ratio in the postprandial state and significantly decreased serum ALT and AST levels.This study shows that nopal consumption prevents the development of fatty liver in obese Zucker rats by increasing fatty acid oxidation and VLDL synthesis,, improving liver insulin signaling. Supported by Grupo Produce DF 2010 (to NT)Grant Funding Source: Produce

T-30 Preservation of obese rat livers by subnormothermic machine perfusion protects dipeptidylpeptidase–IV activity and expression in the biliary tree

T-30 Preservation of obese rat livers by subnormothermic machine perfusion protects dipeptidylpeptidase–IV activity and expression in the biliary tree

Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity

Ectopic deposition of lipids in liver and other extrahepatic tissues alters their function and occurs once adipose tissue fat storage capacity is exceeded. We investigated sexual dimorphism in the effects of dietary obesity on the liver insulin signaling pathway, as well as its connection to differences in hepatic fat accumulation. Ten-week-old Wistar rats of both sexes were fed a standard diet or a high-fat diet for 26 weeks. Insulin, adipokine levels, and glucose tolerance were measured. Lipid content, PPARα mRNA expression and protein levels of insulin receptor subunit β (IRβ), IR substrate 2 (IRS-2), Ser/Thr kinase A (Akt), and pyruvate dehydrogenase kinase isozyme 4 (PDK4) were measured in liver. In control rats, serum parameters and hepatic levels of IRβ, IRS-2, and Akt proteins pointed to a profile of better insulin sensitivity in females. In response to dietary treatment, female rats exhibited a greater increase in body mass and adiposity and lower liver fat accumulation than males, but maintained better glucose tolerance. The reduced insulin signaling capacity in the liver of obese female rats seems to prevent lipid accumulation and probably lipotoxicity-associated hepatic disorders.

Hepatoprotective and Hypolipidemic Effects of Red Ginseng Crude Extract in Obese Rats

The effect of red ginseng extract (RGE) on serum liver enzymes, lipids and some metabolic hormones was studied in obese rats. Sixty male rats were distributed into 6 equal groups. Group (1) was fed on basal diet (negative control), while the other groups were fed on high fat- diet for 8 weeks to induce obesity and hyperlipidemia. Thereafter, Group (2) was kept as positive (obese) control, while rats of groups (3), (4), (5) and (6) were orally given RGE at 50, 100, 150 and 200 mg/kg-1/day, respectively for 4 weeks. At the end of experiment (4 weeks), blood was collected from the rats for estimating serum biochemical constituents. Histological examination of the liver was carried out. The results showed that RGE significantly decreased serum levels of AST, ALT and ALP enzymes; TC, TG and LDL and insulin but decreased leptin hormone in obese-treated rats. The large dose (200 mg/kg-1) of RGE ameliorated the degenerative changes which seen in liver of obese rats. This study recommends that intake of red ginseng roots may be useful for obese patients who suffer from liver diseases associated with hyperlipidemia.

Comparative hepatic proteome analysis between lean and obese rats fed a high‐fat diet reveals the existence of gender differences

Gender differences in obesity stem from metabolic and hormonal differences between sexes and contribute to differences between women and men in health risks attributable to obesity. We hypothesized that liver may be an ideal target for the evaluation of gender differences in obesity development in response to a high-fat diet (HFD). Therefore, to test this hypothesis, we performed a global proteome analysis in the liver of lean and obese rats of both genders who were fed an HFD through 2-DE combined with MALDI-TOF-MS. When rats were exposed to HFD, male rats gained more body weight with increased values of plasma biochemical parameters than female rats. Image analysis and further statistical analysis of a 2-DE protein map allowed for the detection and identification of 34 proteins that were significantly modulated in a gender-dependent manner. We found 19 proteins showing identical gender-different regulation in both normal diet (ND) and HFD. Five proteins also showed clear gender differences in both ND and HFD; however, their regulation modes in HFD were opposite to those in ND. Of particular interest, 10 proteins showed gender differences only in either ND or HFD rats. Present proteomic insight into gender-dimorphic protein modulation in liver would aid in the improvement of gender awareness in the health-care system and in implementation of evidence-based gender-specific clinical recommendations.

Ciprofibrate, Clofibric Acid and Respective Glycinate Derivatives

Fibrates are widely prescribed in hyperlpidemic patients to prevent atherosclerosis. Their therapeutic use, however, can be associated with adverse effects like gastrointestinal disorders, myalgia, myositis and hepatotoxicity. In rodents large doses can even cause hepatocellular carcinoma. Additionally, interactions with the biotransformation of other compounds at the cytochrome P450 (CYP) system have been observed. Thus, the discovery of new substances or derivatives with less side effects is of great interest. In the present study the influence of a four-week daily oral administration of 2 mg/kg body weight ciprofibrate (CAS 52214-84-3) or of 100 mg/kg body weight clofibric acid (CAS 882-09-7) was compared to that of the respective doses of their newly synthesized glycine conjugates in adult male lean and obese Zucker rats. Although obese rats displayed distinctly higher serum lipid concentrations, after fibrate treatment values were significantly lowered in lean animals only. Livers of obese rats were significantly enlarged, histologically showing a fine-droplet like fatty degeneration and an increase in glycogen content, but no signs of inflammation. After fibrate administration histologically a hypertrophy, an eosinophilia, a reduced glycogen content and also hepatocyteapoptosis were observed. Livers of obese rats displayed higher CYP1A1 andCYP2E1 expression, but lower immunostaining for CYP2B1 and CYP3A2. No differences between the two groups of rats were seen with respect to CYP4A1 expression. Due to fibrate treatment especially CYP2E1 and CYP4A1, but also CYP1A1, 2B1 and 3A2 were induced. Resulting CYP mediated monooxygenase activities were also elevated in most cases. In general, effects of clofibric acid and clofibric acid glycinate (CAS 4896-55-3) were less distinct than those of ciprofibrate and its glycinate (CAS 640772-36-7). With no parameterinvestigated major differences were seen between the parent fibrates and their glycine conjugates. Thus, the present investigations revealed no noticeable advantages of the glycinates over ciprofibrate or clofibric acid.

Dietary CLA Combined with Palm Oil or Ovine Fat Differentially Influences Fatty Acid Deposition in Tissues of Obese Zucker Rats

The effect of dietary conjugated linoleic acid (CLA) supplementation in combination with fat from vegetable versus animal origin on the fatty acid deposition, including that of individual 18:1 and 18:2 (conjugated and non-conjugated) isomers, in the liver and muscle of obese rats was investigated. For this purpose, 32 male Zucker rats were randomly assigned to one of four diets containing palm oil or ovine fat, supplemented or not with 1% of 1:1 cis(c)9,trans(t)11 and t10,c12 CLA isomers mixture. Total fatty acid content decreased in the liver and muscle of CLA-fed rats. In the liver, CLA increased saturated fatty acids (SFA) in 11.9% and decreased monounsaturated fatty acids (MUFA) in 6.5%. n-3 Polyunsaturated fatty acids (PUFA) relative proportions were increased in 30.6% by CLA when supplemented to the ovine fat diet. In the muscle, CLA did not affect SFA but decreased MUFA and PUFA percentages. The estimation of Δ9-indices 16 and 18 suggested that CLA inhibited the stearoyl-CoA desaturase activity in the liver (a decrease of 13-38%), in particular when supplemented to the ovine fat diet. Concerning CLA supplementation, the t10,c12 isomer percentage was 60-80% higher in the muscle than in the liver. It is of relevance that rats fed ovine fat, containing bio-formed CLA, had more c9,t11 CLA isomer deposited in both tissues than rats fed palm oil plus synthetic CLA. These results highlight the importance to further clarify the biological effects of consuming foods naturally enriched in CLA, alternatively to CLA dietary supplementation.

Roux-en-Y gastric bypass improves hepatic mitochondrial function in obese rats

BackgroundObesity-related fatty liver disease is linked to mitochondrial dysfunction and oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates mitochondrial function and is a transcriptor of multiple genes that produce antioxidants. Because Roux-en-Y gastric bypass (RYGB) improves fatty liver and decreases the oxidative stress in the liver, we hypothesized that RYGB activates Nrf2 and increases cytochrome C oxidase subunit II (COX-II) in the liver of obese rats. MethodsSprague-Dawley rats were fed a high-fat diet for 16 weeks. The obese rats underwent either RYGB (n = 20) or a sham operation (n = 20). The tissues were harvested 13 weeks postoperatively. The nuclear fraction and mitochondrial extracts were used for protein analysis with immunoblotting. Immunostaining was done on liver sections for COX-II, Nrf2, and the macrophage marker ED2 and F4/80. The gels were quantified using densitometry; P ≤ .05 was considered significant. ResultsRYGB increased COX-II expression in the liver sections (3330 ± 56 versus 2056 ± 37 for RYGB versus sham, P < .001). The total (nuclear and cytoplasmic) Nrf2 expression was high in the obese sham-operated control (2456 ± 45 versus 4352 ± 76, RYGB versus sham, P < .001). However, the nuclear fraction of Nrf2 was significantly increased in the RYGB liver (2341 ± 46 versus 1352 ± 35, RYGB versus sham, P < .001). Furthermore, Nrf2 protein co-localized with the molecular markers of Kupffer cells. ConclusionsDiet-induced fatty liver is associated with mitochondrial dysfunction. RYGB increases COX-II, which is involved in mitochondrial respiration, and increases the nuclear translocation of the Nrf2 transcriptional factor, which is involved in mitochondrial biogenesis and function. Taken together, these data suggest that surgically induced weight loss is associated with improved mitochondrial function in obese rats.

Akt Stimulates Hepatic SREBP1c and Lipogenesis through Parallel mTORC1-Dependent and Independent Pathways

Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.

Contrasting apoptotic responses of conjugated linoleic acid in the liver of obese Zucker rats fed palm oil or ovine fat

We hypothesized that reducing weight properties of conjugated linoleic acid (CLA) are due to adipocyte apoptosis and that CLA differentially modulates the apoptotic responses in hepatic lipotoxicity from rats fed saturated fat diets. Obese Zucker rats were fed atherogenic diets (2% w/w of cholesterol) formulated with high (15% w/w) saturated fat, from vegetable or animal origin, supplemented or not with 1% of a mixture (1:1) of cis-9, trans-11 and trans-10, cis-12 CLA isomers for 14 weeks. CLA induced no changes on retroperitoneal fat depot weight, which was in line with similar levels of apoptosis. Interestingly, CLA had a contrasting effect on cell death in the liver according to the dietary fat. CLA increased hepatocyte apoptosis, associated with upregulation of Fas protein in rats fed palm oil, compared to rats receiving palm oil alone. However, rats fed ovine fat alone displayed the highest levels of hepatic cell death, which were decreased in rats fed ovine fat plus CLA. This reducing effect of CLA was related to positively restoring endoplasmic reticulum (ER) ATF-6α, BiP and CHOP protein levels and increasing phosphorylated c-Jun NH 2-terminal kinase (JNK) and c-Jun, thus suggesting an adaptive response of cell survival. These findings reinforce the role of CLA as regulator of apoptosis in the liver. Moreover, the dietary fat composition is a key factor in activation of apoptosis.

PL-130 Roux-en-Y gastric bypass (RYGB) improves mitochondrial function in the liver of obese rats via Nrf2

Obesity-related fatty liver disease is linked to mitochondrial dysfunction and oxidative stress. RYGB decreases both steatosis and oxidative stress in the liver. Nuclear erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates mitochondrial function and protects cells by activating antioxidants and detoxifying enzymes. Cytochrome C oxidase subunit II (COXII) is central to electron transfer in the mitochondrial respiratory chain. Objective: We hypothesized that RYGB activates Nrf2 and COXII in livers of obese rats.

A novel genetically-obese rat model with elevated 11beta-hydroxysteroid dehydrogenase type 1 activity in subcutaneous adipose tissue

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and plays an important role in the development of obesity and metabolic syndrome. 11β-HSD1 activity is lower in liver and higher in omental adipose tissue of obese rodent models like obese zucker rats, Ob/Ob and db/db mice. Here, we report the 11β-HSD1 activity in liver and adipose tissue of lean and obese rats of WNIN/Ob strain, a new genetic rat model of obesity. 11β-HSD1 activity in liver, omental and subcutaneous adipose tissues of 3 month-old male WNIN/Ob lean and obese rats was assayed. As observed in other rodent models, 11β-HSD1 activity was lower in liver and higher in omental adipose tissue. In contrast to other rodent obese models, WNIN/Ob obese rats had elevated 11β-HSD1 activity in subcutaneous adipose tissue, which is in line with the observation in human obesity. Here, we conclude that dysregulation of 11β-HSD1 in WNIN/Ob obese rat model is identical to human obesity, which makes it an excellent model for studying the effect of 11β-HSD1 inhibitors in ameliorating obesity and metabolic syndrome.

Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats.

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARγ ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARγ ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.

Effects of Citrus Auraptene (7-Geranyloxycoumarin) on Hepatic Lipid Metabolism in Vitro and in Vivo

Recent reports have shown that citrus auraptene (7-geranyloxycoumarin) possesses valuable pharmacological properties, including anticarcinogenic, anti-inflammatory, antihelicobacter, antigenotoxic, and neuroprotective effects. In the present study, we investigated the effect of dietary auraptene on hepatic lipid metabolism both in vitro and in vivo. Results suggested that auraptene has the ability to normalize lipid abnormalities in HepG2 hepatocytes. After 4 weeks of auraptene feeding, abdominal white adipose tissue weight and hepatic triglyceride (TG) levels were dose-dependently lowered in Otsuka Long-Evans Tokushima fatty (OLETF) rats. The activities of carnitine palmitoyltransferase, a key enzyme in mitochondrial fatty acid β-oxidation, and peroxisomal β-oxidation were markedly and dose-dependently enhanced in OLETF rat livers by auraptene feeding. Additionally, hepatic expression of acyl-CoA oxidase, the initial enzyme of the peroxisomal β-oxidation system, was significantly and dose-dependently enhanced by auraptene administration. These results suggest that auraptene administration alleviates obesity and hepatic TG accumulation in part through lipolysis enhancement in the livers of obese OLETF rats.