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Lejonklou, M. H., Dunder, L., Bladin, E., Pettersson, V., Rönn, M., Lind, L., . . . Lind, P. M. (2017). Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.. Journal of Environmental Health Perspectives, 125(6), Article ID 067018.
Öppna denna publikation i ny flik eller fönster >>Effects of Low-Dose Developmental Bisphenol A Exposure on Metabolic Parameters and Gene Expression in Male and Female Fischer 344 Rat Offspring.
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2017 (Engelska)Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, nr 6, artikel-id 067018Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND: Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive.

OBJECTIVES: The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring.

METHODS: Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to (BPA0.5; ) or (BPA50; ), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring.

RESULTS: Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels ( compared with , females BPA50 ; compared with , males BPA0.5 ) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls ( number of adipocytes/HPF compared with number of adipocytes/HPF; ) and by 123% in BPA0.5 females compared with BPA50 animals ( number of adipocytes/high power field (HPF) compared with number of adipocytes/HPF; ). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals ( number of adipocytes/HPF compared with number of adipocytes/HPF; ). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex.

CONCLUSIONS: Developmental exposure to of BPA, which is 8-10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at were compared with the offspring of unexposed controls.

Nationell ämneskategori
Arbetsmedicin och miljömedicin Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-326311 (URN)10.1289/EHP505 (DOI)000413788400027 ()28657538 (PubMedID)
Tillgänglig från: 2017-07-05 Skapad: 2017-07-05 Senast uppdaterad: 2018-01-31Bibliografiskt granskad
Klint, H., Lejonklou, M. H., Karimullina, E., Rönn, M., Lind, L., Lind, P. M. & Brittebo, E. (2017). Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue. Upsala Journal of Medical Sciences, 122(1), 20-27
Öppna denna publikation i ny flik eller fönster >>Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue
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2017 (Engelska)Ingår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 1, s. 20-27Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVES: Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated.

MATERIALS: Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 10(4) nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR.

RESULTS: Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 10(4) nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response.

CONCLUSIONS: . Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies.

Nyckelord
Angiogenesis, bisphenol A, cardiomyocytes, cardiovascular disease, endocrine disruption, fructose, heart, vascular tone
Nationell ämneskategori
Farmakologi och toxikologi Allmänmedicin
Identifikatorer
urn:nbn:se:uu:diva-311874 (URN)10.1080/03009734.2016.1225870 (DOI)000396476600003 ()27622962 (PubMedID)
Forskningsfinansiär
Forskningsrådet Formas, 216-2009-972
Tillgänglig från: 2017-01-03 Skapad: 2017-01-03 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
Ljunggren, S. A., Iggland, M., Rönn, M., Lind, L., Lind, P. M. & Karlsson, H. (2016). Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A. Toxicology, 347-349, 6-16
Öppna denna publikation i ny flik eller fönster >>Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A
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2016 (Engelska)Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 347-349, s. 6-16Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25 mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.

Nyckelord
Bisphenol A, Endocrine disrupting chemicals, Fructose, Proteomics, Heart tissue
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-297931 (URN)10.1016/j.tox.2016.02.007 (DOI)000375631700002 ()26930160 (PubMedID)
Forskningsfinansiär
Forskningsrådet Formas
Tillgänglig från: 2016-06-28 Skapad: 2016-06-28 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Lejonklou, M. H., Dunder, L., Bladin, E., Rönn, M., Risérus, U., Lind, m. & Waldén, T. (2015). Adipose tissue and metabolic homeostasis in Fischer F344 rats, exposed to developmental low doses of bisphenol A, are affected in a gender specific and non-monotonic manner. Paper presented at 51st Congress of the European-Societies-of-Toxicology (EUROTOX), SEP 13-16, 2015, Portuguese Soc Pharmacol, Sect Toxicol, Porto, PORTUGAL. Toxicology Letters, 238(2), S253-S253
Öppna denna publikation i ny flik eller fönster >>Adipose tissue and metabolic homeostasis in Fischer F344 rats, exposed to developmental low doses of bisphenol A, are affected in a gender specific and non-monotonic manner
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2015 (Engelska)Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, nr 2, s. S253-S253Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-301801 (URN)10.1016/j.toxlet.2015.08.734 (DOI)000370693801572 ()
Externt samarbete:
Konferens
51st Congress of the European-Societies-of-Toxicology (EUROTOX), SEP 13-16, 2015, Portuguese Soc Pharmacol, Sect Toxicol, Porto, PORTUGAL
Tillgänglig från: 2016-08-25 Skapad: 2016-08-25 Senast uppdaterad: 2017-11-28Bibliografiskt granskad
Rönn, M., Lind, L., Örberg, J., Kullberg, J., Söderberg, S., Larsson, A., . . . Lind, P. M. (2014). Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans. Chemosphere, 112, 42-48
Öppna denna publikation i ny flik eller fönster >>Bisphenol A is related to circulating levels of adiponectin, leptin and ghrelin, but not to fat mass or fat distribution in humans
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2014 (Engelska)Ingår i: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 112, s. 42-48Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVE: Since bisphenol A (BPA) has been shown to induce obesity in experimental studies, we explored the associations between BPA and fat mass, fat distribution and circulating levels of adiponectin, leptin and ghrelin in humans.

METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), fat mass and fat distribution were determined in 70-year-old men and women (n=890) by dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) (n=287). Serum levels of BPA were analyzed using isotope liquid chromatography/tandem mass spectrometer (API4000LC-MS/MS). Hormone levels were analyzed with radioimmunoassays (RIA) or enzyme-linked immunosorbent assay (ELISA). Imaging was performed approximately two years following collection of other data.

RESULTS: Serum concentrations of BPA were not related to adipose tissue measurements by DXA or MRI. BPA associated positively with adiponectin and leptin, but negatively with ghrelin, following adjustments for sex, height, fat mass, lean mass, smoking, alcohol consumption, physical activity, energy intake, and educational levels (p<0.001, p=0.009, p<0.001, respectively). The relationship between BPA and ghrelin was stronger in women than in men.

CONCLUSION: Although no relationships between BPA levels and measures of fat mass were seen, BPA associated strongly with the adipokines adiponectin and leptin and with the gut-hormone ghrelin suggesting that BPA may interfere with hormonal control of hunger and satiety.

Nyckelord
BPA; Adiponectin; Leptin; Ghrelin; Adipose tissue
Nationell ämneskategori
Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi
Identifikatorer
urn:nbn:se:uu:diva-229030 (URN)10.1016/j.chemosphere.2014.03.042 (DOI)000340688300006 ()25048886 (PubMedID)
Forskningsfinansiär
VetenskapsrådetForskningsrådet Formas
Anmärkning

Correction in Chemosphere, 2015, vol 139, pp. 1, DOI: 10.1016/j.chemosphere.2015.05.050

Tillgänglig från: 2014-07-27 Skapad: 2014-07-27 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
Lejonklou, M. H., Karimullina, E., Larsson, S., Lind, T., Melhus, H., Jacobson Rasmusson, A., . . . Lind, P. M. (2014). Does developmental exposure to bisphenol A induce bone and adipose tissue disturbances?. Paper presented at 50th Congress of the European-Societies-of-Toxicology, SEP 07-10, 2014, Edinburgh, SCOTLAND. Toxicology Letters, 229, S243-S243
Öppna denna publikation i ny flik eller fönster >>Does developmental exposure to bisphenol A induce bone and adipose tissue disturbances?
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2014 (Engelska)Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, s. S243-S243Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Arbetsmedicin och miljömedicin Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:uu:diva-233968 (URN)10.1016/j.toxlet.2014.06.810 (DOI)000341134000759 ()
Konferens
50th Congress of the European-Societies-of-Toxicology, SEP 07-10, 2014, Edinburgh, SCOTLAND
Tillgänglig från: 2014-10-15 Skapad: 2014-10-13 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Rönn, M., Kullberg, J., Karlsson, H., Berglund, J., Malmberg, F., Örberg, J., . . . Lind, P. M. (2013). Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats. Toxicology, 303(1), 125-132
Öppna denna publikation i ny flik eller fönster >>Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats
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2013 (Engelska)Ingår i: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 303, nr 1, s. 125-132Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND:

Prenatal exposure to bisphenol A (BPA) has been shown to induce obesity in rodents. To evaluate if exposure also later in life could induce obesity or liver damage we investigated these hypothesises in an experimental rat model.

METHODS:

From five to fifteen weeks of age, female Fischer 344 rats were exposed to BPA via drinking water (0.025, 0.25 or 2.5mgBPA/L) containing 5% fructose. Two control groups were given either water or 5% fructose solution. Individual weight of the rats was determined once a week. At termination magnetic resonance imaging was used to assess adipose tissue amount and distribution, and liver fat content. After sacrifice the left perirenal fat pad and the liver were dissected and weighed. Apolipoprotein A-I in plasma was analyzed by western blot.

RESULTS:

No significant effects on body weight or the weight of the dissected fad pad were seen in rats exposed to BPA, and MRI showed no differences in total or visceral adipose tissue volumes between the groups. However, MRI showed that liver fat content was significantly higher in BPA-exposed rats than in fructose controls (p=0.04). BPA exposure also increased the apolipoprotein A-I levels in plasma (p<0.0001).

CONCLUSION:

We found no evidence that BPA exposure affects fat mass in juvenile fructose-fed rats. However, the finding that BPA in combination with fructose induced fat infiltration in the liver at dosages close to the current tolerable daily intake (TDI) might be of concern given the widespread use of this compound in our environment.

Nyckelord
MRI, Liver fat, Rat, Bisphenol A, Obesity
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-185549 (URN)10.1016/j.tox.2012.09.013 (DOI)000314856800014 ()23142792 (PubMedID)
Tillgänglig från: 2012-11-08 Skapad: 2012-11-26 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Roos, V., Rönn, M., Salihovic, S., Lind, L., van Bavel, B., Kullberg, J., . . . Lind, P. M. (2013). Circulating Levels of Persistent Organic Pollutants in Relation to Visceral and Subcutaneous Adipose Tissue by Abdominal MRI. Obesity, 21(2), 413-418
Öppna denna publikation i ny flik eller fönster >>Circulating Levels of Persistent Organic Pollutants in Relation to Visceral and Subcutaneous Adipose Tissue by Abdominal MRI
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2013 (Engelska)Ingår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, nr 2, s. 413-418Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We and others have shown relationships between circulating levels of persistent organic pollutants (POPs) and different measures of obesity in both cross-sectional and prospective studies. Since viscerally located fat seems to be the most harmful type, we investigated whether plasma POP levels were more closely related to visceral adipose tissue (VAT) than to subcutaneous adipose tissue (SAT). Thousand hundred and sixteen subjects aged 70 years were investigated in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study; 23 POPs were analyzed using high-resolution gas chromatography/high-resolution mass spectrometry. Abdominal magnetic resonance imaging, measuring VAT and SAT, respectively, was performed in a representative subsample of 287 subjects. The less chlorinated polychlorinated biphenyl (PCB) congeners (105 and 118), and the pesticides dichlorodiphenyldichloroethylene (DDE), hexachlorobenzene (HCB), and trans-nonachlordane (TNC) were positively related to both VAT and SAT, whereas the more highly chlorinated PCBs (153, 156, 157, 169, 170, 180, 194, 206, and 209) were inversely related to both VAT and SAT. PCB189 was related to the VAT/SAT ratio in an inverted U-shaped manner (P = 0.0008). In conclusion, the results were in accordance with our previous studies using waist circumference and fat mass as obesity measure. However, the novel finding that PCB189 was related to the VAT/SAT ratio deserves further investigation since exposure to this PCB congener, which has previously been linked to diabetes development, might thereby play a role in the distribution of abdominal adipose tissue.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-183796 (URN)10.1002/oby.20267 (DOI)000322087300029 ()22627916 (PubMedID)
Tillgänglig från: 2012-11-01 Skapad: 2012-11-01 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Rönn, M. (2013). Environmental Contaminants and Obesity. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Environmental Contaminants and Obesity
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Obesity is a worldwide problem affecting both children and adults. Genetic, physiological, environmental, psychological, social and economic factors interact in varying degrees, influencing body weight and fat distribution and the progress of obesity. Moreover, some anthropogenic chemicals have proven to be endocrine disrupting chemicals (EDCs) with the potential to interfere with different actions of hormones in the body. EDCs may thereby disrupt homeostasis, modifying developmental, behavioral and immune functions in humans and animals, and also promoting adiposity. Because hormones generally act at low concentrations, small changes in the endocrine system may lead to extensive effects. Based on data from experimental and epidemiological studies this thesis elucidates the relationship between a large number of environmental contaminants and obesity.

The experimental studies demonstrated that fructose supplementation in the drinking water resulted in unfavorable metabolic alterations such as a higher liver somatic index (LSI), an increase in plasma triglycerides and increased plasma levels of apo A-I. Fructose in combination with exposure to bisphenol A (BPA) increased liver fat content and plasma levels of apo A-I in juvenile female Fischer 344 rats. The experimental studies also showed that the retro-peritoneal fat, which in rats is a distinct fat depot easy to distinguish and dissect, correlated well with the measurements of total fat mass analyzed with MRI, and could therefore be used as a substitute for total fat mass in rats.

The epidemiological studies showed that circulating levels of persistent organic pollutants (POPs) were related to fat mass measured by DXA. OCDD, HCB, TNC, DDE and the less chlorinated PCBs were positively related to fat mass, while the more highly chlorinated PCBs showed a negative association. Further, circulating levels of BPA were positively associated with levels of the hormones adiponectin and leptin, but negatively related with ghrelin, hormones which are involved in the regulation of hunger and satiety. However, serum BPA levels were not related to measures of fat mass in the elderly individuals in the PIVUS cohort.

This thesis concludes that environmental contaminants such as BPA and POPs most likely are contributors, along with genetic, social and behavioral factors, to the development of obesity.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2013. s. 67
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 949
Nyckelord
Fischer 344, rat, obesity, adipose tissue, persistent organic pollutants, POPs, bisphenol A, BPA, pesticides, dioxin, PCB, DDT, apo A-I, adiponectin, leptin, ghrelin
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-209807 (URN)978-91-554-8798-0 (ISBN)
Disputation
2013-12-13, Frödingsalen, Ulleråkersvägen 40 A, Uppsala, 13:15 (Svenska)
Opponent
Handledare
Tillgänglig från: 2013-11-20 Skapad: 2013-10-26 Senast uppdaterad: 2016-11-04
Rönn, M., Lind, M. P., Karlsson, H., Cvek, K., Berglund, J., Malmberg, F., . . . Kullberg, J. (2013). Quantification of total and visceral adipose tissue in fructose-fed rats using water-fat separated single echo MRI. Obesity, 21(9), E388-E395
Öppna denna publikation i ny flik eller fönster >>Quantification of total and visceral adipose tissue in fructose-fed rats using water-fat separated single echo MRI
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2013 (Engelska)Ingår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, nr 9, s. E388-E395Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objective: The aim of this study was to setup a rodent model for modest weight gain and an MRI-based quantification of body composition on a clinical 1.5 T MRI system for studies of obesity and environmental factors and their possible association. Design and Methods: Twenty-four 4-week-old female Fischer rats were divided into two groups: one exposed group (n=12) and one control group (n 12). The exposed group was given drinking water containing fructose (5% for 7 weeks, then 20% for 3 weeks). The control group was given tap water. Before sacrifice, whole body MRI was performed to determine volumes of total and visceral adipose tissue and lean tissue. MRI was performed using a clinical 1.5 T system and a chemical shift based technique for separation of water and fat signal from a rapid single echo acquisition. Fat signal fraction was used to separate adipose and lean tissue. Visceral adipose tissue volume was quantified using semiautomated segmentation. After sacrifice, a perirenal fat pad and the liver were dissected and weighed. Plasma proteins were analyzed by Western blot. Results: The weight gain was 5.2% greater in rats exposed to fructose than in controls (P=0.042). Total and visceral adipose tissue volumes were 5.2 cm(3) (P=0.017) and 3.1 cm(3) (P=0.019) greater, respectively, while lean tissue volumes did not differ. The level of triglycerides and apolipoprotein A-I was higher (P=0.034, P=0.005, respectively) in fructose-exposed rats.

Nationell ämneskategori
Medicinsk bildbehandling Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-209508 (URN)10.1002/oby.20229 (DOI)000325426600007 ()
Tillgänglig från: 2013-10-21 Skapad: 2013-10-21 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
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