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1.  Increased hypolipidemic benefits of cis-9, trans-11 conjugated linoleic acid in combination with trans-11 vaccenic acid in a rodent model of the metabolic syndrome, the JCR:LA-cp rat 
Conjugated linoleic acid (cis-9, trans-11 CLA) and trans-11 vaccenic acid (VA) are found naturally in ruminant-derived foods. CLA has been shown to have numerous potential health related effects and has been extensively investigated. More recently, we have shown that VA has lipid-lowering properties associated with reduced hepatic lipidogenesis and chylomicron secretion in the JCR:LA-cp rat. The aim of this study was to evaluate potential additional hypolipidemic effects of purified forms of CLA and VA in an animal model of the metabolic syndrome (the JCR:LA-cp rat).
Twenty four obese JCR:LA-cp rats were randomized and assigned to one of three nutritionally adequate iso-caloric diets containing 1% w/w cholesterol and 15% w/w fat for 16 wk: 1) control diet (CD), 2) 1.0% w/w cis-9, trans-11 CLA (CLA), 3) 1.0% w/w VA and 1% w/w cis-9, trans-11 CLA (VA+CLA). Lean rats were fed the CD to represent normolipidemic conditions.
Fasting plasma triglyceride (TG), total cholesterol and LDL-cholesterol concentrations were reduced in obese rats fed either the CLA diet or the VA+CLA diet as compared to the obese control group (p < 0.05, p < 0.001; p < 0.001, p < 0.01; p < 0.01, p < 0.001, respectively). The VA+CLA diet reduced plasma TG and LDL-cholesterol to the level of the normolipidemic lean rats and further decreased nonesterified fatty acids compared to the CLA diet alone. Interestingly, rats fed the VA+CLA diet had a higher food intake but lower body weight than the CLA fed group (P < 0.05). Liver weight and TG content were lower in rats fed either CLA (p < 0.05) or VA+CLA diets (p < 0.001) compared to obese control, consistent with a decreased relative protein abundance of hepatic acetyl-CoA carboxylase in both treatment groups (P < 0.01). The activity of citrate synthase was increased in liver and adipose tissue of rats fed, CLA and VA+CLA diets (p < 0.001) compared to obese control, suggesting increased mitochondrial fatty acid oxidative capacity.
We demonstrate that the hypolipidemic effects of chronic cis-9, trans-11 CLA supplementation on circulating dyslipidemia and hepatic steatosis are enhanced by the addition of VA in the JCR:LA-cp rat.
PMCID: PMC3161353  PMID: 20633302
2.  MR Molecular Imaging of Aortic Angiogenesis 
JACC. Cardiovascular imaging  2010;3(8):824-832.
The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression.
The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with ανβ3-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis.
Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with ανβ3-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16.
Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with ανβ3-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05).
Neovascular expansion is a prominent feature of the JCR:LA-cp model. MR imaging with ανβ3-targeted nanoparticles provided a noninvasive assessment of angiogenesis in untreated obese rats, which was suppressed by benfluorex.
PMCID: PMC3425389  PMID: 20705262
angiogenesis; atherosclerosis; metabolic syndrome; nanoparticle
3.  Differential Secretion of Satiety Hormones With Progression of Obesity in JCR: LA-corpulent Rats 
Obesity (Silver Spring, Md.)  2008;16(4):10.1038/oby.2007.128.
To characterize the gastrointestinal tract at the onset and in well-established obesity.
Methods and Procedures
Lean (+/?) and obese (cp/cp) male JCR:LA-cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified.
At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well-established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide-1 (GLP-1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats.
Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.
PMCID: PMC3827016  PMID: 18239578 CAMSID: cams3665
4.  Effect of prebiotic fibre supplementation on hepatic gene expression and serum lipids: a dose–response study in JCR:LA-cp rats 
The British journal of nutrition  2009;103(11):10.1017/S0007114509993539.
Prebiotic fibres have been proposed to promote weight loss and lower serum cholesterol; however, the mechanisms are not fully understood. The aim of the present research was to identify possible mechanisms through which prebiotic fibres improve serum lipids. Lean and obese JCR:La-cp rats aged 8 weeks consumed one of three diets supplemented with 0, 10 or 20 % prebiotic fibre for 10 weeks. Rats were anaesthetised and a fasting blood sample was taken for lipid analysis. Real-time PCR was used to determine gene expression for cholesterol and fatty acid regulatory genes in liver tissue. Liver and caecal digesta cholesterol and TAG content were quantified. Both doses of prebiotic fibre lowered serum cholesterol levels by 24 % in the obese hyperlipidaemic rats (P<0·05). This change was associated with an increase in caecal digesta as well as an up-regulation of genes involved in cholesterol synthesis and bile production. Additionally, there was a 42 % reduction in TAG accumulation in the liver of the obese rats with 10 % prebiotic diet (P<0·05); however, no change in liver fatty acid synthase (FAS). Prebiotic fibres appear to lower cholesterol levels through increased cholesterol excretion in the form of bile and inhibit the accumulation of TAG in the liver through a mechanism unrelated to FAS. These effects appear to be limited to the obese model and particularly the 10 % dose. The present work is significant as it provides insight into the mechanisms of action for prebiotic fibres on lipid metabolism and furthers the development of dietary treatments for hypercholesterolaemia.
PMCID: PMC3827012  PMID: 20021705 CAMSID: cams3654
Inulin and oligofructose; Lipid metabolism; Liver TAG; Cholesterol content; Gene expression
5.  Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats 
The British journal of nutrition  2011;107(4):10.1017/S0007114511003163.
There is a growing interest in modulating gut microbiota with diet in the context of obesity. The purpose of the present study was to evaluate the dose-dependent effects of prebiotics (inulin and oligofructose) on gut satiety hormones, energy expenditure, gastric emptying and gut microbiota. Male lean and obese JCR:LA-cp rats were randomised to either of the following: lean 0 % fibre (LC), lean 10 % fibre (LF), lean 20 % fibre (LHF), obese 0 % fibre (OC), obese 10 % fibre (OF) or obese 20 % fibre (OHF). Body composition, gastric emptying, energy expenditure, plasma satiety hormone concentrations and gut microbiota (using quantitative PCR) were measured. Caecal proglucagon and peptide YY mRNA levels were up-regulated 2-fold in the LF, OF and OHF groups and 3-fold in the LHF group. Ghrelin O-acyltransferase mRNA levels were higher in obese v. lean rats and decreased in the OHF group. Plasma ghrelin response was attenuated in the LHF group. Microbial species measured in the Bacteroidetes division decreased, whereas those in the Firmicutes increased in obese v. lean rats and improved with prebiotic intake. Bifidobacterium and Lactobacillus increased in the OHF v. OC group. Bacteroides and total bacteria negatively correlated with percentage of body fat and body weight. Enterobacteriaceae increased in conjunction with glucose area under the curve (AUC) and glucagon-like peptide-1 AUC. Bacteroides and total bacteria correlated positively with ghrelin AUC yet negatively with insulin AUC and energy intake (P<0·05). Several of the mechanisms through which prebiotics act (food intake, satiety hormones and alterations in gut microbiota) are regulated in a dose-dependent manner. The combined effects of prebiotics may have therapeutic potential for obesity.
PMCID: PMC3827017  PMID: 21767445 CAMSID: cams3660
Inulin; Oligofructose; Satiety response; Gut microbiota
6.  Turnover of Phospholipids in an Unsaturated Fatty Acid Auxotroph of Escherichia coli 
Journal of Bacteriology  1972;112(3):1396-1407.
The membrane phospholipids of an unsaturated fatty acid auxotroph of Escherichia coli were found to undergo turnover. These phospholipids were excreted into the culture medium, and were replaced in the cell with newly synthesized phospholipids. Phospholipids of growing cells supplemented with elaidic acid underwent rapid turnover, while those of cells supplemented with oleate, or cis-vaccenate plus palmitoleate, underwent slow turnover. Starvation for required amino acids stimulated this turnover in the latter two cases. Protein was also lost from growing cells. However, after amino acid starvation this loss ceased while phospholipid turnover continued. Electron micrographs of growing cells indicated that large pieces of membrane-like material were separating from the cell surface.
PMCID: PMC251577  PMID: 4629658
7.  Lipid composition of Zymomonas mobilis: effects of ethanol and glucose. 
Journal of Bacteriology  1983;154(3):1291-1300.
Zymomonas mobilis is an alcohol-tolerant microorganism which is potentially useful for the commercial production of ethanol. This organism was found to contain cardiolipin, phosphatidylethanolamine, phosphatidylglycerol, and phosphatidylcholine as major phospholipids. Vaccenic acid was the most abundant fatty acid, with lesser amounts of myristic, palmitic, and palmitoleic acids. No branched-chain or cyclopropane fatty acids were found. Previous studies in our laboratory have shown that ethanol induces the synthesis of phospholipids enriched in vaccenic acid in Escherichia coli (L. O. Ingram, J. Bacteriol. 125:670-678, 1976). The fatty acid composition of Z. mobilis, an obligately ethanol-producing microorganism, represents an extreme of the trend observed in E. coli. In Z. mobilis, vaccenic acid represents over 75% of the acyl chains in the polar membrane lipids. Glucose and ethanol had no major effect on the fatty acid composition of Z. mobilis. However, both glucose and ethanol caused a decrease in phosphatidylethanolamine and phosphatidylglycerol and an increase in cardiolipin and phosphatidylcholine. Ethanol also caused a dose-dependent reduction in the lipid-to-protein ratios of crude membranes. The lipid composition of Z. mobilis may represent an evolutionary adaptation for survival in the presence of ethanol.
PMCID: PMC217603  PMID: 6853446
8.  Leptin Deficiency and Its Effects on Tibial and Vertebral Bone Mechanical Properties in Mature Genetically Lean and Obese JCR:LA-Corpulent Rats 
Journal of Obesity  2012;2012:650193.
Leptin signaling deficient rodents have emerged as models of obesity/insulin resistance syndrome. Altered leptin signaling, however, can affect axial and appendicular bone geometrical properties differently, and, thus, we hypothesized that leptin-deficiency would differentially influence mechanical properties of vertebrae and tibiae compared to lean rats. Mature (9 mo) leptin receptor deficient obese (cp/cp; n = 8) and lean (+/?; n = 7) male JCR:LA-corpulent rats were used to test that hypothesis. Tibiae and the sixth lumbar vertebrae (L6) were scanned with micro-CT and were broken in three point-bending (tibiae) or axial loading (L6). Supporting the hypothesis, vertebrae and tibiae were differentially affected by leptin signaling deficiency. Tibiae, but not vertebrae, were significantly shorter in obese rats and achieved a significantly greater load (>18%), displacement (>15%), and stress (>18%) at the proportional limit, relative to the lean rats. Conversely, L6 in obese rats had significantly reduced displacement (>25%) and strain (>32%) at proportional limit, relative to the lean rats. Those combined results suggest that the etiology and duration of obesity may be important determinants of bone mechanical properties, and axial and appendicular bones may be affected differently.
PMCID: PMC3409537  PMID: 22888408
9.  Arterial Retention of Remnant Lipoproteins Ex Vivo Is Increased in Insulin Resistance Because of Increased Arterial Biglycan and Production of Cholesterol-Rich Atherogenic Particles That Can Be Improved by Ezetimibe in the JCR:LA-cp Rat 
Literature supports the “response-to-retention” hypothesis—that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA-cp rat model of metabolic syndrome (MetS) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance.
Methods and Results
Arteries from control and MetS (insulin-resistant) JCR:LA-cp rats were perfused ex vivo with Cy5-labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and MetS rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in MetS rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls.
Increased progression of atherosclerotic cardiovascular disease in MetS and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and MetS.
PMCID: PMC3541624  PMID: 23316299
arterial remodeling; biglycan; metabolic syndrome; triglyceride-rich remnant lipoproteins
10.  Glucose Tolerance, Lipids, and GLP-1 Secretion in JCR:LA-cp Rats Fed a High Protein Fiber Diet 
Obesity (Silver Spring, Md.)  2008;16(1):10.1038/oby.2007.16.
We have shown that individually, dietary fiber and protein increase secretion of the anorexigenic and insulinotropic hormone, glucagon-like peptide-1 (GLP-1).
Our objective was to combine, in one diet, high levels of fiber and protein to maximize GLP-1 secretion, improve glucose tolerance, and reduce weight gain.
Methods and Procedures
Lean (+/?) and obese (cp/cp) male James C Russell corpulent (JCR:LA-cp) rats lacking a functional leptin receptor were fed one of four experimental diets (control, high protein (HP), high fiber (HF, prebiotic fiber inulin), or combination (CB)) for 3 weeks. An oral glucose tolerance test (OGTT) was performed to evaluate plasma GLP-1, insulin and glucose. Plasma lipids and intestinal proglucagon mRNA expression were determined.
Energy intake was lower with the HF diet in lean and obese rats. Weight gain did not differ between diets. Higher colonic proglucagon mRNA in lean rats fed a CB diet was associated with higher GLP-1 secretion during OGTT. The HP diet significantly reduced plasma glucose area under the curve (AUC) during OGTT in obese rats, which reflected both an increased GLP-1 AUC and higher fasting insulin. Diets containing inulin resulted in the lowest plasma triglyceride and total cholesterol levels.
Overall, combining HP with HF in the diet increased GLP-1 secretion in response to oral glucose, but did not improve glucose tolerance or lipid profiles more than the HF diet alone did. We also suggest that glycemic and insulinemic response to prebiotics differ among rat models and future research work should examine their role in improving glucose tolerance in diet-induced vs. genetic obesity with overt hyperleptinemia.
PMCID: PMC3827014  PMID: 18223610 CAMSID: cams3664
11.  Relationship between bactericidal action of complement and fluidity of cellular membranes. 
Infection and Immunity  1978;19(1):12-17.
The mode of complement-mediated killing of Escherichia coli B cells grown at 25 and 42 degrees C and of E. coli K-12 UFAts cells grown in the presence of oleic and elaidic aicds was examined in relation to their membrane lipid compositions and the thermodynamic properties of membrane phospholipids. Phospholipids isolated from 25 degrees C-grown cells of strain B and from oleic acid-incorporated cells of strain K-12 UFAts had lower phase transition temperatures than did phospholipids from E. coli strain B grown at 42 degrees C or those from strain K-12 UFAts grown on elaidic acid. The rate of cellular susceptibility to complement action closely correlated with the liquid crystalline phase of phospholipids of cell membranes. These findings suggest that membrane fluidity is obligatory for the final expression of complement action.
PMCID: PMC414040  PMID: 342407
12.  Chronic Active Hepatitis Induced by Helicobacter hepaticus in the A/JCr Mouse Is Associated with a Th1 Cell-Mediated Immune Response 
Infection and Immunity  1998;66(7):3142-3148.
Helicobacter hepaticus infection in A/JCr mice results in chronic active hepatitis characterized by perivascular, periportal, and parenchymal infiltrates of mononuclear and polymorphonuclear cells. This study examined the development of hepatitis and the immune response of A/JCr mice to H. hepaticus infection. The humoral and cell-mediated T helper immune response was profiled by measuring the postinfection (p.i.) antibody response in serum, feces, and bile and by the production of cytokines and proliferative responses by splenic mononuclear cells to H. hepaticus antigens. Secretory immunoglobulin A (IgA) and systemic IgG2a antibody developed by 4 weeks p.i. and persisted through 12 months. Splenocytes from infected mice proliferated and produced more gamma interferon (IFN-γ) than interleukin-4 (IL-4) or IL-5 when cultured with H. hepaticus outer membrane proteins. The predominantly IgG2a antibody response in serum and the in vitro production of IFN-γ in excess of IL-4 or IL-5 are consistent with a Th1 immune response reported in humans and mice infected with Helicobacter pylori and Helicobacter felis, respectively. Mice infected with H. hepaticus developed progressively severe perivascular, periportal, and hepatic parenchymal lesions consisting of lymphohistiocytic and plasmacytic cellular infiltrates. In addition, transmural typhlitis was observed at 12 months p.i. The characterization of a cell-mediated Th1 immune response to H. hepaticus infection in the A/JCr mouse should prove valuable as a model for experimental regimens which manipulate the host response to Helicobacter.
PMCID: PMC108325  PMID: 9632578
13.  Thermal Tolerance of Zymomonas mobilis: Temperature-Induced Changes in Membrane Composition † 
The membrane composition of Zymomonas mobilis changed dramatically in response to growth temperature. With increasing temperature, the proportion of vaccenic acid declined with an increase in myristic acid, the proportion of phosphatidylcholine and cardiolipin increased with decreases in phosphatidylethanolamine and phosphatidylglycerol, and the phospholipid/protein ratio of the membrane declined. These changes in membrane composition were correlated with changes in thermal tolerance and with changes in membrane fluidity. Cells grown at 20°C were more sensitive to inactivation at 45°C than were cells grown at 30°C, as expected. However, cells grown at 41°C (near the maximal growth temperature for Z. mobilis) were hypersensitive to thermal inactivation, suggesting that cells may be damaged during growth at this temperature. When cells were held at 45°C, soluble proteins from cells grown at 41°C were rapidly lost into the surrounding buffer in contrast to cells grown at lower temperatures. The synthesis of phospholipid-deficient membranes during growth at 41°C was proposed as being responsible for this increased thermal sensitivity.
PMCID: PMC239058  PMID: 16347087
14.  Age- and Sex-Associated Plasma Proteomic Changes in Growth Hormone Receptor Gene–Disrupted Mice 
Growth hormone receptor gene–disrupted (GHR−/−) mice are dwarf, insulin sensitive, and long lived despite being obese. In order to identify characteristics associated with their increased longevity, we studied age-related plasma proteomic changes in these mice. Male and female GHR−/− mice and their littermate controls were followed longitudinally at 8, 16, and 24 months of ages for plasma proteomic analysis. Relative to control littermates, GHR−/− mice had increased levels of apolipoprotein A-4 and retinol-binding protein-4 and decreased levels of apolipoprotein E, haptoglobin, and mannose-binding protein-C. Female GHR−/− mice showed decreased inflammatory cytokines including interleukin-1β and monocyte chemotactic protein-1. Additionally, sex differences were found in specific isoforms of apolipoprotein E, RBP-4, haptoglobin, albumin, and hemoglobin subunit beta. In conclusion, we find plasma proteomic changes in GHR−/− mice that favor a longer life span as well as sex differences indicative of an improved health span in female mice.
PMCID: PMC3403865  PMID: 22156438
Growth hormone receptor; Plasma; Proteomics; Sex; Aging
15.  Effects of Elaidic Acid on Lipid Metabolism in HepG2 Cells, Investigated by an Integrated Approach of Lipidomics, Transcriptomics and Proteomics 
PLoS ONE  2013;8(9):e74283.
Trans fatty acid consumption in the human diet can cause adverse health effects, such as cardiovascular disease, which is associated with higher total cholesterol, a higher low density lipoprotein-cholesterol level and a decreased high density lipoprotein-cholesterol level. The aim of the study was to elucidate the hepatic response to the most abundant trans fatty acid in the human diet, elaidic acid, to help explain clinical findings on the relationship between trans fatty acids and cardiovascular disease. The human HepG2 cell line was used as a model to investigate the hepatic response to elaidic acid in a combined proteomic, transcriptomic and lipidomic approach. We found many of the proteins responsible for cholesterol synthesis up-regulated together with several proteins involved in the esterification and hepatic import/export of cholesterol. Furthermore, a profound remodeling of the cellular membrane occurred at the phospholipid level. Our findings contribute to the explanation on how trans fatty acids from the diet can cause modifications in plasma cholesterol levels by inducing abundance changes in several hepatic proteins and the hepatic membrane composition.
PMCID: PMC3772929  PMID: 24058537
16.  Perinatal Bisphenol A Exposure in C57B6/129svj Male Mice: Potential Altered Cytokine/Chemokine Production in Adulthood 
Pregnant mice (n = 3) were exposed to BPA by intraperitoneal injection, from gestation day 9.5 until end of lactation. Male offspring were evaluated for cytokine production at 20 wk-of-age. One pregnant control mouse produced no males, precluding statistical analysis. However, recurring shifts in cytokines were suggested in the adult BPA offspring. Serum showed a numeric increase in 16 of 21 basal cytokine levels. ConA-stimulated splenocytes showed a numeric increase in 17 of 21 cytokines, and LPS-stimulated splenocytes an increase in 18 of 21 cytokines. The cytokine profile was one of TH1 up-regulation more than TH2, and with skewing toward TH17 responses.
PMCID: PMC2922731  PMID: 20717544
bisphenol; developmental; cytokines; immune
17.  Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation. 
Journal of Clinical Investigation  1992;90(4):1568-1575.
The genetically obese Zucker rat (fa/fa) is characterized by a severe resistance to the action of insulin to stimulate skeletal muscle glucose transport. The goal of the present study was to identify whether the defect associated with this insulin resistance involves an alteration of transporter translocation and/or transporter activity. Various components of the muscle glucose transport system were investigated in plasma membranes isolated from basal or maximally insulin-treated skeletal muscle of lean and obese Zucker rats. Measurements of D- and L-glucose uptake by membrane vesicles under equilibrium exchange conditions indicated that insulin treatment resulted in a four-fold increase in the Vmax for carrier-mediated transport for lean animals [from 4.5 to 17.5 nmol/(mg.s)] but only a 2.5-fold increase for obese rats [from 3.6 to 9.1 nmol/(mg.s)]. In the lean animals, this increase in glucose transport function was associated with a 1.8-fold increase in the transporter number as indicated by cytochalasin B binding, a 1.4-fold increase in plasma membrane GLUT4 protein, and a doubling of the average carrier turnover number (intrinsic activity). In the obese animals, there was no change in plasma membrane transporter number measured by cytochalasin B binding, or in GLUT4 or GLUT1 protein. However, there was an increase in carrier turnover number similar to that seen in the lean litter mates. Measurements of GLUT4 mRNA in red gastrocnemius muscle showed no difference between lean and obese rats. We conclude that the insulin resistance of the obese rats involves the failure of translocation of transporters, while the action of insulin to increase the average carrier turnover number is normal.
PMCID: PMC443204  PMID: 1401086
18.  Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats 
Hypertension  2009;53(3):508-515.
Obesity-associated inflammation causes insulin resistance. Obese adipose tissue displays hypertrophied adipocytes and increased expression of the cannabinoid-1 receptor. Cobalt protoporphyrin (CoPP) increases heme oxygenase-1 (HO-1) activity, increasing adiponectin and reducing inflammatory cytokines. We hypothesize that CoPP administration to Zucker diabetic fat (ZDF) rats would improve insulin sensitivity and remodel adipose tissue. Twelve-week-old Zucker lean and ZDF rats were divided into 4 groups: Zucker lean, Zucker lean–CoPP, ZDF, and ZDF–CoPP. Control groups received vehicle and treatment groups received CoPP (2 mg/kg body weight) once weekly for 6 weeks. Serum insulin levels and glucose response to insulin injection were measured. At 18 weeks of age, rats were euthanized, and aorta, kidney, and subcutaneous and visceral adipose tissues were harvested. HO-1 expression was measured by Western blot analysis and HO-1 activity by serum carbon monoxide content. Adipocyte size and cannabinoid-1 expression were measured. Adipose tissue volumes were determined using MRI. CoPP significantly increased HO-1 activity, phosphorylated AKT and phosphorylated AMP kinase, and serum adiponectin in ZDF rats. HO-1 induction improved hyperinsulinemia and insulin sensitivity in ZDF rats. Subcutaneous and visceral adipose tissue volumes were significantly decreased in ZDF rats. Adipocyte size and cannabinoid-1 expression were both significantly reduced in ZDF–CoPP rats in subcutaneous and visceral adipose tissues. This study demonstrates that HO-1 induction improves insulin sensitivity, downregulates the peripheral endocannabinoid system, reduces adipose tissue volume, and causes adipose tissue remodeling in a model of obesity-induced insulin resistance. These findings suggest HO-1 as a potential therapeutic target for obesity and its associated health risks.
PMCID: PMC2745551  PMID: 19171794
insulin resistance; heme oxygenase-1; adiponectin; adiposity; endocannabinoid; pAMPK
19.  Effect of Cerulenin on Growth and Lipid Metabolism of Mycoplasmas 
Cerulenin markedly inhibited the growth of Acholeplasma laidlawii. A. axanthum and A. granularum were less susceptible, whereas the sterol-requiring Mycoplasma species examined showed very little susceptibility. The inhibition was not reversed by the addition of long-chain fatty acids to the medium. At a concentration of 20 μg/ml, cerulenin inhibited the incorporation of [14C]acetate into A. laidlawii membrane lipids, but it had no effect on either protein or nucleic acid biosynthesis. Cerulenin inhibited both the de novo synthesis of long-chain fatty acids and the elongation of medium-chain fatty acids. As a result, carotenoid biosynthesis was stimulated, and increased amounts of oleic and elaidic acids were incorporated into membrane polar lipids. Our studies support the concept that cerulenin can serve as a useful tool for obtaining better control of fatty acid composition of A. laidlawii membranes.
PMCID: PMC429518  PMID: 1267428
20.  Effects of Intake of Maternal Dietary Elaidic Acids during Pregnancy and Lactation on the Fatty Acid Composition of Plasma, Erythrocyte Membrane, and Brain in Rat Pups 
To investigate the effects of a dam's dietary elaidic acid (EA) intake during pregnancy and lactation on the fatty acid composition of plasma, erythrocyte membrane, and brain in rat pups, we fed two groups of dams either a soybean oil diet (SOD) or a shortening diet (SHD) containing soybean oil (10%) or shortening (10%), respectively. Although EA was not detected in the SOD, EA accounted for 25.3% of all fatty acid content in the SHD. On day 8 after birth, the EA levels in the stomach, plasma, and erythrocyte membrane of pups nursed by the dams fed the SHD were 11.6 ± 1.03%, 7.18 ± 1.20%, and 5.82 ± 1.00%, respectively. Although on day 8 after birth the EA level of the brains of pups nursed by SHD-fed dams was 0.56 ± 0.24%, EA was not detected on day 21 or day 82 after birth. These results suggest that EA intake during pregnancy and lactation supplies EA to plasma, remains in the erythrocyte membrane of pups, and moves into the brain in early infancy.
PMCID: PMC3806163  PMID: 24194980
21.  Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice 
The Journal of Clinical Investigation  2007;117(10):2877-2888.
Obesity is associated with a state of chronic, low-grade inflammation characterized by abnormal cytokine production and macrophage infiltration into adipose tissue, which may contribute to the development of insulin resistance. During immune responses, tissue infiltration by macrophages is dependent on the expression of osteopontin, an extracellular matrix protein and proinflammatory cytokine that promotes monocyte chemotaxis and cell motility. In the present study, we used a murine model of diet-induced obesity to examine the role of osteopontin in the accumulation of adipose tissue macrophages and the development of insulin resistance during obesity. Mice exposed to a high-fat diet exhibited increased plasma osteopontin levels, with elevated expression in macrophages recruited into adipose tissue. Obese mice lacking osteopontin displayed improved insulin sensitivity in the absence of an effect on diet-induced obesity, body composition, or energy expenditure. These mice further demonstrated decreased macrophage infiltration into adipose tissue, which may reflect both impaired macrophage motility and attenuated monocyte recruitment by stromal vascular cells. Finally, obese osteopontin-deficient mice exhibited decreased markers of inflammation, both in adipose tissue and systemically. Taken together, these results suggest that osteopontin may play a key role in linking obesity to the development of insulin resistance by promoting inflammation and the accumulation of macrophages in adipose tissue.
PMCID: PMC1964510  PMID: 17823662
22.  Adipose Tissue Lipolysis Is Upregulated in Lean and Obese Men During Acute Resistance Exercise  
Diabetes Care  2008;31(7):1397-1399.
OBJECTIVE—To investigate the effect of acute resistance exercise on adipose tissue triacylglycerol lipase activity (TGLA) in lean and obese men.
RESEARCH DESIGN AND METHODS—Nine lean and eight obese men performed 30 min of circuit resistance exercise. Adipose tissue and blood were sampled during exercise for TGLA, metabolite, and hormone determinations. Respiratory exchange ratio (RER) was measured throughout exercise.
RESULTS—Energy expenditure of exercise relative to body mass was higher in the lean and RER was higher in the obese men, suggesting lower fat oxidation. TGLA increased 18-fold at 5 min of exercise in the lean men and 16-fold at 10 min of exercise in the obese men. The delayed lipolytic activation in the obese men was reflected in serum nonesterified fatty acid and glycerol concentrations. Plasma insulin increased in the obese but did not change in the lean men.
CONCLUSIONS—Resistance exercise upregulated adipose tissue lipolysis and enhanced energy expenditure in lean and obese men, with a delayed lipolytic activation in the obese men.
PMCID: PMC2453678  PMID: 18375413
23.  Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide 
Diabetologia  2012;55(10):2741-2746.
Plasma ceramide concentrations correlate with insulin sensitivity, inflammation and atherosclerotic risk. We hypothesised that plasma ceramide concentrations are increased in the presence of elevated fatty acid levels and are regulated by increased liver serine C-palmitoyltransferase (SPT) activity.
Lean humans and rats underwent an acute lipid infusion and plasma ceramide levels were determined. One group of lipid-infused rats was administered myriocin to inhibit SPT activity. Liver SPT activity was determined in lipid-infused rats, and obese, insulin resistant mice. The time and palmitate dose-dependent synthesis of intracellular and secreted ceramide was determined in HepG2 liver cells.
Plasma ceramide levels were increased during lipid infusion in humans and rats, and in obese, insulin-resistant mice. The increase in plasma ceramide was not associated with changes in liver SPT activity, and inhibiting SPT activity by ~50% did not alter plasma ceramide levels in lipid-infused rats. In HepG2 liver cells, palmitate incorporation into extracellular ceramide was both dose- and time-dependent, suggesting the liver cells rapidly secreted the newly synthesised ceramide.
Elevated systemic fatty acid availability increased plasma ceramide but this was not associated with changes in hepatic SPT activity, suggesting that liver ceramide synthesis is driven by substrate availability rather than increased SPT activity. This report also provides evidence that the liver is sensitive to the intracellular ceramide concentration, and an increase in liver ceramide secretion may help protect the liver from the deleterious effects of intracellular ceramide accumulation.
PMCID: PMC3576922  PMID: 22854889
De novo ceramide synthesis; Ex vivo SPT activity; HepG2 liver cells; Lipid infusion; Liver; Myriocin
24.  Distinct regulation of stearoyl-CoA desaturase 1 gene expression by cis and trans C18:1 fatty acids in human aortic smooth muscle cells 
Genes & Nutrition  2011;7(2):209-216.
Consumption of trans fatty acids is positively correlated with cardiovascular diseases and with atherogenic risk factors. Trans fatty acids might play their atherogenic effects through lipid metabolism alteration of vascular cells. Accumulation of lipids in vascular smooth muscle cells is a feature of atherosclerosis and a consequence of lipid metabolism alteration. Stearoyl-CoA desaturase 1 (scd1) catalyses the production of monounsaturated fatty acids (e.g. oleic acid) and its expression is associated with lipogenesis induction and with atherosclerosis development. We were interested in analysing the regulation of delta-9 desaturation rate and scd1 expression in human aortic smooth muscle cells (HASMC) exposed to cis and trans C18:1 fatty acid isomers (cis-9 oleic acid, trans-11 vaccenic acid or trans-9 elaidic acid) for 48 h at 100 μM. Treatment of HASMC with these C18:1 fatty acid isomers led to differential effects on delta-9 desaturation; oleic acid repressed the desaturation rate more potently than trans-11 vaccenic acid, whereas trans-9 elaidic acid increased the delta-9 desaturation rate. We then correlated the delta-9 desaturation rate with the expression of scd1 protein and mRNA. We showed that C18:1 fatty acids controlled the expression of scd1 at the transcriptional level in HASMC, leading to an increase in scd1 mRNA content by trans-9 elaidic acid treatment, whereas a decrease in scd1 mRNA content was observed with cis-9 oleic acid and trans-11 vaccenic acid treatments. Altogether, this work highlights a differential capability of C18:1 fatty acid isomers to control scd1 gene expression, which presumes of different consequent effects on cell functions.
PMCID: PMC3316751  PMID: 22057664
Stearoyl-CoA desaturase; trans fatty acids; Oleic acid; Vascular smooth muscle cells; Atherosclerosis
25.  Fatty acid distribution of cord and maternal blood in human pregnancy: special focus on individual trans fatty acids and conjugated linoleic acids 
Maternal nutrition in pregnancy has a crucial impact on the development of the fetus. Dietary trans fatty acids (tFA) are known to have adverse health effects, especially during pregnancy. However, the distribution of tFA produced via partial hydrogenation of vegetable oils (mainly elaidic acid; t9) differs compared to ruminant-derived tFA (mainly vaccenic acid; t11). Recent findings indicate that they may have different impact on human health.
Therefore, in this study, plasma and erythrocytes of mother-child pairs (n = 55) were sampled to investigate the distribution of tFA, including individual trans C18:1 fatty acids and conjugated linoleic acids (CLA) in fetal related to maternal lipids; with additional consideration of maternal dairy fat intake.
Portion of t9 and t11, but also of c9,t11 CLA was higher in maternal than in fetal blood lipids. The portion of t9 in maternal and fetal lipids differed only slightly. In contrast, the portion of fetal t11 was only half of that in maternal blood. This led to a fetal t9/t11-index in plasma and erythrocytes being twice as high compared to the maternal values. A high dairy fat intake resulted in elevated portions of t11 and its Δ9-desaturation product c9,t11 CLA in maternal blood. In contrast, in the respective fetal blood lipids only c9,t11 CLA, but not t11 was increased. Nevertheless, a positive association between maternal and fetal plasma exists for both t11 and c9,t11 CLA. Furthermore, in contrast to t9, t11 was not negatively associated with n-3 LC-PUFA in fetal blood lipids.
Fetal blood fatty acid composition essentially depends on and is altered by the maternal fatty acid supply. However, in addition to dietary factors, other aspects also contribute to the individual fatty acid distribution (oxidation, conversion, incorporation). The lower portion of fetal t11 compared to maternal t11, possibly results from Δ9-desaturation to c9,t11 CLA and/or oxidation. Based on the fatty acid distribution, it can be concluded that t11 differs from t9 regarding its metabolism and their impact on fetal LC-PUFA.
PMCID: PMC3295739  PMID: 22208621
trans octadecenoic acids; trans fatty acids; vaccenic acid; elaidic acid; conjugated linoleic acids; omega-3 LC-PUFA; t9/t11-index; fetus; pregnancy; dairy fat

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