Publications by authors named "Sandra Barbosa-da-Silva"

18 Publications

  • Page 1 of 1

Editorial Comment: Effect of a low-calorie diet on 24-hour urinary parameters of obese adults with idiopathic calcium oxalate kidney stones.

Int Braz J Urol 2021 Nov-Dec;47(6):1148-1149

Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares. Universidade do Estado do Rio de Janeiro - UERJ, Rio de Janeiro, RJ, Brasil.

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http://dx.doi.org/10.1590/S1677-5538.IBJU.2021.0140.1DOI Listing
September 2021

Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice.

Mol Cell Endocrinol 2020 06 4;509:110804. Epub 2020 Apr 4.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address:

Aim: To investigate the effects of linagliptin treatment on hepatic energy metabolism and ER stress in high-fat-fed C57BL/6 mice.

Methods: Forty male C57BL/6 mice, three months of age, received a control diet (C, 10% of lipids as energy, n = 20) or high-fat diet (HF, 50% of lipids as energy, n = 20) for 10 weeks. The groups were randomly subdivided into four groups to receive linagliptin, for five weeks, at a dose of 30 mg/kg/day added to the diets: C, C-L, HF, and HF-L groups.

Results: The HF group showed higher body mass, total and hepatic cholesterol levels and total and hepatic triacylglycerol levels than the C group, all of which were significantly diminished by linagliptin in the HF-L group. The HF group had higher hepatic steatosis than the C group, whereas linagliptin markedly reduced the hepatic steatosis (less 52%, P < 0.001). The expression of Sirt1 and Pgc1a was more significant in the HF-L group than in the HF group. Linagliptin also elicited enhanced GLP-1 concentrations and a reduction in the expression of the lipogenic genes Fas and Srebp1c. Besides, HF-L showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45 coupled with reduced apoptotic nuclei immunostaining.

Conclusion: Linagliptin caused a marked reduction in hepatic steatosis as a secondary effect of its glucose-lowering property. NAFLD countering involved reduced lipogenesis, increased beta-oxidation, and relief in endoplasmic reticulum stress, leading to reduced apoptosis and better preservation of the hepatic structure. Therefore, linagliptin may be used, preferably in diabetic patients, to avoid the progression of hepatic steatosis.
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http://dx.doi.org/10.1016/j.mce.2020.110804DOI Listing
June 2020

Empaglifozin mitigates NAFLD in high-fat-fed mice by alleviating insulin resistance, lipogenesis and ER stress.

Mol Cell Endocrinol 2019 12 13;498:110539. Epub 2019 Aug 13.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Institute of Biology, State University of Rio de Janeiro, RJ, Brazil. Electronic address:

Aim: To evaluate the pleiotropic effects of empagliflozin in the liver through lipogenesis, beta-oxidation, and endoplasmic reticulum stress pathways.

Methods: Male C57Bl/6 mice, 3 months of age, received a control diet (C, 10% lipids, n = 20) or high-fat diet (HF, 50% lipids, n = 20) for 10 weeks, after that, the groups were subdivided to receive empagliflozin, during 5 weeks at a dose of 10 mg/kg/day added to the diets, totalizing four groups: C, C-EMPA, HF, and HF-EMPA. We performed biochemical analyzes, oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA-IR), indirect calorimetry, liver stereology, western blotting, RT-qPCR for genes related to beta-oxidation, lipogenesis, and endoplasmic reticulum stress.

Results: After the treatment with empagliflozin, there was a 4% increase in energy expenditure, a 5% reduction in body mass, improvement in glucose tolerance and insulin sensitivity and insulin resistance. The expression of Ppar alpha was greater in the HF-EMPA group with a concomitant reduction in the expression of the lipogenic genes Fas, Srebp1c and Ppar gamma, according to protein expression. In addition, HF-EMPA showed a reduction in the genes related to endoplasmic reticulum stress Chop, Atf4, and Gadd45.

Conclusion: Empagliflozin mitigates the development of NAFLD, confirmed through reduced expression of the genes involved in hepatic lipogenesis and genes involved in endoplasmic reticulum stress. Thus, empagliflozin may be an important tool to treat the progression of hepatic steatosis.
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http://dx.doi.org/10.1016/j.mce.2019.110539DOI Listing
December 2019

Beneficial effects of losartan or telmisartan on the local hepatic renin-angiotensin system to counter obesity in an experimental model.

World J Hepatol 2019 Apr;11(4):359-369

Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Departamento de Anatomia, Instituto de Biologia Roberto Alcântara Gomes, Rio de Janeiro 20551-030, Brazil.

Background: Obesity has been associated with hepatic overexpression of the renin-angiotensin system (RAS).

Aim: To evaluate the action of two angiotensin II (ANGII) receptor blockers (losartan or telmisartan) on the modulation of local hepatic RAS and the resulting metabolic effects in a diet-induced obesity murine model.

Methods: Twenty C57BL/6 mice were randomly divided into two nutritional groups for 10 wk: control group (C, = 5, 10% of energy as fat) or high-fat group (HF, = 15, 50% of energy as fat). After treatment started, the HF group was randomly divided into three groups: untreated HF group ( = 5), HF treated with losartan (HFL, = 5) and HF treated with telmisartan (HFT, = 5). The treatments lasted for 5 wk, and the dose was 10 mg/kg body mass.

Results: HF diet induced body mass gain (+28%, < 0.0001), insulin resistance (+69%, = 0.0079), high hepatic triacylglycerol (+127%, = 0.0004), and overexpression of intrahepatic angiotensin-converting enzyme (ACE) 1/ ANGII type 1 receptor (AT1r) (+569.02% and +141.40%, respectively, < 0.0001). The HFL and HFT groups showed higher ACE2/rMAS gene expression compared to the HF group (ACE2: +465.57%, = 0.0002 for HFL and +345.17%, = 0.0049 for HFT; rMAS: +711.39%, < 0.0001 for HFL and +539.75%, < 0.0001 for HFT), followed by reduced insulin/glucose ratio (-30% for HFL and -33% for HFT, = 0.0181), hepatic triacylglycerol levels (-28%, = 0.0381 for HFL; and -45%, = 0.0010 for HFT, and Plin2 expression.

Conclusion: Modulation of the intrahepatic RAS, with favored involvement of the ACE2/rMAS axis over the ACE1/AT1r axis after losartan or telmisartan treatments, caused hepatic and metabolic beneficial effects as demonstrated by reduced hepatic triacylglycerol levels coupled with reduced PLIN 2 expression and improved glycemic control.
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http://dx.doi.org/10.4254/wjh.v11.i4.359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504859PMC
April 2019

Beneficial effects of intermittent fasting on steatosis and inflammation of the liver in mice fed a high-fat or a high-fructose diet.

Nutrition 2019 09 28;65:103-112. Epub 2019 Mar 28.

Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address:

Objective: Intermittent fasting (IF) is a nutritional intervention with significant metabolic effects on the liver that are not yet fully understood. The aim of this study was to investigate the effects of IF on body mass, lipid profile, glucose metabolism, liver lipogenesis, β-oxidation, and inflammation.

Methods: We used cellular and molecular techniques to investigate the effects of IF on 3-mo-old male C57 BL/6 mice that were fed control (10% kcal fat), high-fat (HF; 50% kcal fat), or high-fructose (HFr; 50% kcal fructose) diets for 8 wk. Half of the animals were submitted to IF (1 d fed, 1 d fast) for an additional 4 wk.

Results: Although food intake on the fed day did not differ between the groups, mice in the HF and HFr groups showed diminished body mass, total cholesterol, and triacylglycerol levels. Also, plasma adiponectin increased in the HFr group and leptin decreased in the HF mice. Oral glucose tolerance test and insulin were ameliorated by IF, regardless of the diet consumed (HF or HFr), and decreased hepatic lipogenesis and increased β-oxidation markers, resulting in a reduction of the hepatic steatosis and inflammation.

Conclusions: There were beneficial effects of IF even with the continuity of the obesogenic diet and proinflammatory diet in mice. It is recommended that based on the beneficial effects of IF on glucose and liver metabolism and inflammation that IF be a coadjutant factor in the treatment of hepatic metabolic issues and steatosis.
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http://dx.doi.org/10.1016/j.nut.2019.02.020DOI Listing
September 2019

Intermittent fasting exerts beneficial metabolic effects on blood pressure and cardiac structure by modulating local renin-angiotensin system in the heart of mice fed high-fat or high-fructose diets.

Nutr Res 2019 03 13;63:51-62. Epub 2018 Dec 13.

Institute of Biology, State University of Rio de Janeiro, RJ, Brazil. Electronic address:

Intermittent fasting (IF) sets the preference for fats as fuel and is linked to beneficial metabolic outcomes; however, the effects in the renin-angiotensin system (RAS) in the heart remains to be determined. We hypothesized that IF improves blood pressure and lipid profiles due to a less activated local RAS in the left ventricle of mice, irrespective of the dietary scheme. This study aimed to evaluate the effects of intermittent fasting on cardiovascular parameters and local RAS in the left ventricle (LV) of mice fed either a high-fat (HF) or high-fructose diet (HFru). Metabolic alterations were induced in C57BL/6 mice by providing them free access to a high-fat or a high-fructose (HFru) diet for 8 weeks. Following the 8-week metabolic alteration period, the mice were subjected to the IF protocol in which mice were deprived of food for 24 hours, every other day, for a period of 4 weeks. The IF protocol caused significant reduction in body weight, systolic blood pressure, blood glucose, total cholesterol, and triacylglycerol levels, in addition to augmenting the plasma and urinary uric acid levels, irrespective of the diet. Post IF protocol, beneficial LV remodeling was observed in animals fed either diet and included reduced LV mass, thickness, and cardiomyocyte cross-sectional area. These results comply with the improved RAS modulation, which favored ACE2/MAS receptor axis over the renin/ACE/AT1 axis. In conclusion, the significant decrease in weight brought about as a result of the IF protocol lead to modulation of the local RAS, with the consequential benefit of LV remodeling and reduction in blood pressure, irrespective of the diet.
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http://dx.doi.org/10.1016/j.nutres.2018.12.005DOI Listing
March 2019

Liver and Metformin: Lessons of a fructose diet in mice.

Biochim Open 2017 Jun 3;4:19-30. Epub 2017 Feb 3.

Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil.

Studies show that the continuous consumption of fructose can lead to nonalcoholic fatty liver disease (NAFLD) and steatohepatitis. We aimed to investigate the role of Metformin in an animal model of liver injury caused by fructose intake, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses. Male three months old C57BL/6 mice were divided into control group (C) and fructose group (F, 47% fructose), maintained for ten weeks. After, the groups received Metformin or vehicle for a further eight weeks: control (C), control + Metformin (CM), fructose (F), and fructose + Metformin (FM). Fructose resulted in hepatic steatosis, insulin resistance and lower insulin sensitivity in association with higher mRNA levels of proteins linked with lipogenesis and increased lipid peroxidation. Fructose diminished mRNA expression of antioxidant enzymes, and of proteins responsible for mitochondrial biogenesis. Metformin reduced lipogenesis and increased the expression of proteins related to mitochondrial biogenesis, thereby increasing beta-oxidation and decreasing lipid peroxidation. Also, Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in triglyceride accumulation in the liver, steatosis and lipid peroxidation was observed in the FM group. In conclusion, fructose increases lipogenesis, reduces the antioxidant defenses, and diminishes mitochondrial biogenesis. After an extended period of fructose intake, Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states.
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http://dx.doi.org/10.1016/j.biopen.2017.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801827PMC
June 2017

High-intensity interval training has beneficial effects on cardiac remodeling through local renin-angiotensin system modulation in mice fed high-fat or high-fructose diets.

Life Sci 2017 Nov 8;189:8-17. Epub 2017 Sep 8.

Institute of Biology, State University of Rio de Janeiro, RJ, Brazil. Electronic address:

Aims: HIIT (high-intensity interval training) has the potential to reduce cardiometabolic risk factors, but the effects on cardiac remodeling and local RAS (renin-angiotensin system) in mice fed high-fat or high-fructose diets still need to be fully addressed.

Main Methods: Sixty male C57BL/6 mice (12weeks old) were randomly divided into three groups, control (C), High-fat (HF), or High-fructose diet (HRU) and were monitored for eight weeks before being submitted to the HIIT. Each group was randomly assigned to 2 subgroups, one subgroup was started on a 12-week HIIT protocol (T=trained group), while the other subgroup remained non-exercised (NT=not-trained group).

Key Findings: HIIT reduced BM and systolic blood pressure in high-fat groups, while enhanced insulin sensitivity after high-fat or high-fructose intake. Moreover, HIIT reduced left ventricular hypertrophy in HF-T and HFRU-T. Notably, HIIT modulated key factors in the local left ventricular renin-angiotensin-system (RAS): reduced protein expression of renin, ACE (Angiotensin-converting enzyme), and (Angiotensin type 2 receptor) AT2R in HF-T and HFRU-T groups but reduced (Angiotensin type 1 receptor) AT1R protein expression only in the high-fat trained group. HIIT modulated ACE2/Ang (1-7)/Mas receptor axis. ACE2 mRNA gene expression was enhanced in HF-T and HFRU-T groups, complying with elevated Mas (Mas proto-oncogene, G protein-coupled receptor) receptor mRNA gene expression after HIIT.

Significance: This study shows the effectiveness of HIIT sessions in producing improvements in insulin sensitivity and mitigating LV hypertrophy, though hypertension was controlled only in the high-fat-fed submitted to HIIT protocol. Local RAS system in the heart mediates these findings and receptor MAS seems to play a pivotal role when it comes to the amelioration of cardiac structural and functional remodeling due to HIIT.
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http://dx.doi.org/10.1016/j.lfs.2017.09.012DOI Listing
November 2017

AT1 receptor antagonist induces thermogenic beige adipocytes in the inguinal white adipose tissue of obese mice.

Endocrine 2017 Mar 23;55(3):786-798. Epub 2016 Dec 23.

Laboratory of Morphometry, Metabolism and Cardiovascular disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Purpose: To evaluate whether losartan is able to induce beige adipocytes formation, focusing on the thermogenic gene expression and adipocyte remodeling in the subcutaneous white adipose tissue of diet-induced obese mice.

Methods: Male C57BL/6 mice received a control diet (10% energy as lipids) or a high-fat diet (50% energy as lipids) for 10 weeks, followed by a 5-week treatment with losartan: control group, control-losartan group (10 mg/Kg/day), high-fat group and high-fat-losartan group (10 mg/Kg/day). Biochemical, morphometrical, stereological and molecular approaches were used to evaluate the outcomes.

Results: The high-fat diet elicited overweight, insulin resistance and adipocyte hypertrophy in the high-fat group, all of which losartan rescued in the high-fat-losartan group. These effects comply with the induction of beige adipocytes within the inguinal fat pads in high-fat-losartan group as they exhibited the greatest energy expenditure among the groups along with the presence uncoupling protein 1 positive multilocular adipocytes with enhanced peroxisome proliferator-activated receptor gamma coactivator 1-alpha and PR domain containing 16 mRNA levels, indicating a significant potential for mitochondrial biogenesis and adaptive thermogenesis.

Conclusions: Our results show compelling evidence that losartan countered diet-induced obesity in mice by enhancing energy expenditure through beige adipocytes induction. Reduced body mass, increased insulin sensitivity, decreased adipocyte size and marked expression of uncoupling protein 1 by ectopic multilocular adipocytes support these findings. The use of losartan as a coadjutant medicine to tackle obesity and its related disorders merits further investigation.
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http://dx.doi.org/10.1007/s12020-016-1213-1DOI Listing
March 2017

Differential effects of angiotensin receptor blockers on pancreatic islet remodelling and glucose homeostasis in diet-induced obese mice.

Mol Cell Endocrinol 2017 01 22;439:54-64. Epub 2016 Oct 22.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Centre, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address:

Obesity leads to adverse endocrine pancreas remodelling, reduced islet lifespan and early type 2 diabetes onset. AT1R blockade shows beneficial pleiotropic effects. This study sought to compare the effects of losartan and telmisartan on pancreatic islets remodelling and glucose homeostasis in diet-induced obese mice. High-fat diet yielded overweight, insulin resistance, islet apoptosis and hypertrophy. Suitable insulin levels and preserved endocrine pancreas structure were correlated to adequate AKT-FOXO1 pathway functioning in losartan-treated animals. Conversely, telmisartan yielded enhanced PDX1 and GLP-1 islet expression along with greater GLP-1 levels, with the consequent better islet glucose sensing and uptake. Greater islet vascularisation coupled with reduced apoptosis and macrophage infiltration seems to underlie the beneficial findings in both treatments. In conclusion, these results provide compelling evidence that two antihypertensive drugs (telmisartan and losartan) ameliorate pancreatic islet structure, glucose handling, and vascularisation in obese mice. Although only telmisartan countered overweight, both drugs yielded reduced apoptosis and islet preservation, with translational potential.
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http://dx.doi.org/10.1016/j.mce.2016.10.021DOI Listing
January 2017

Rosuvastatin limits the activation of hepatic stellate cells in diet-induced obese mice.

Hepatol Res 2017 Aug 27;47(9):928-940. Epub 2016 Oct 27.

Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Aim: The aim of this study was to investigate the effects of rosuvastatin in a model of diet-induced obesity and non-alcoholic fatty liver disease, with attention to the activation of hepatic stellate cells (HSCs).

Method: Male C57BL/6 mice received a control diet (C; 10% energy as lipids) or a high-fat diet (HF; 50% energy as lipids) for 12 weeks, followed by 7 weeks of treatment. Group CR received control diet + rosuvastatin; group HFR received high-fat diet + rosuvastatin.

Results: The HF group showed higher insulin, total cholesterol, triacylglycerol, and leptin levels than the C group, all of which were significantly diminished by rosuvastatin in the HFR group. The HF group had greater steatosis and activated HSCs than the C group, whereas rosuvastatin diminished the steatosis (less 21%, P < 0.001) and significantly inhibited the activation of the HSCs in the HFR group compared to the HF group. The sterol regulatory element-binding protein-1 and the peroxisome proliferator-activated receptor (PPAR)-γ protein expressions were increased in HF animals and reduced after treatment in the HFR group. By contrast, low PPAR-α and carnitine palmitoyltransferase-1 expressions were found in the HF group, and were restored by rosuvastatin treatment in the HFR group.

Conclusion: Rosuvastatin mitigated hepatic steatosis by modulating PPAR balance, favoring PPAR-α over PPAR-γ downstream effects. The effects were accompanied by a diminishing of insulin resistance, the anti-inflammatory adipokine profile, and HSC activation, avoiding non-alcoholic fatty liver disease progression and non-alcoholic steatohepatitis onset in this model.
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http://dx.doi.org/10.1111/hepr.12821DOI Listing
August 2017

Maternal vitamin D-restricted diet has consequences in the formation of pancreatic islet/insulin-signaling in the adult offspring of mice.

Endocrine 2016 Oct 3;54(1):60-69. Epub 2016 May 3.

Laboratorio de Morfometria, Metabolismo e Doenca Cardiovascular, Centro Biomedico, Instituto de Biologia, Universidade do Estado de Rio de Janeiro - UERJ, Av. 28 de Setembro, 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil.

The maternal deficiency of vitamin D can act on organogenesis in mice offspring, being a risk factor for chronic diseases in adulthood. This study investigates the effects of maternal deficiency of vitamin D on structural islet remodeling and insulin-signaling pathway in the offspring. We studied male C57Bl/6 offspring at 3-month old (n = 10/group) from mother fed one of the two diets: control diet (C) or vitamin D-restricted diet (VitD). After weaning, offspring only fed the control diet ad libitum. In the offspring, we studied insulin production, islet remodeling, and islet protein expression of the insulin-signaling pathway (Western blotting, isolated islet, n = 5/group). VitD offspring showed greater glycemia (P = 0.012), smaller beta-cell mass (P = 0.014), and hypoinsulinemia (P = 0.024) than C offspring. Comparing VitD offspring with C offspring, we observed lower protein levels in islet of insulin (P = 0.003), insulin receptor substrate-1 (P = 0.025), phosphatidylinositol-3-kinases (P = 0.045), 3-phosphoinositide-dependent protein kinase 1 (P = 0.017), protein kinase B (P = 0.028), with reduced expression of pancreas/duodenum homeobox-1 (PDX-1) (P = 0.016), glucose transporter-2 (P = 0.003), and glucokinase (P = 0.045). The maternal vitamin D-restricted diet modifies the development of the pancreas of the offspring, leading to islet remodeling and altered insulin-signaling pathway. The decrease of PDX-1 is probably significant to the changes in the beta-cell mass and insulin secretion in adulthood.
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http://dx.doi.org/10.1007/s12020-016-0973-yDOI Listing
October 2016

Differences and similarities in hepatic lipogenesis, gluconeogenesis and oxidative imbalance in mice fed diets rich in fructose or sucrose.

Food Funct 2015 May;6(5):1684-91

Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, RJ, Brazil.

Changes in feeding habits are the primary environmental factors (though modifiable) commonly correlated with increase in diseases such as obesity and associated comorbidities. Diets rich in fructose and sucrose have been related to the epidemic of obesity. Three groups of mice were studied during 15 weeks of consuming standard chow (SC), a high-fructose diet (HFru) and a high-sucrose diet (HSu). The animals did not present significant differences in food intake, energy intake, or body mass evolution at the end of the experiment. Although the findings in the HFru and HSu animals were not equal in magnitude, in comparison with the SC mice, the HFru and HSu animals showed hyperglycemia, hyperinsulinemia and hyperleptinemia as well as high levels of inflammatory adipokines, low adiponectin, and high levels of total cholesterol, triacylglycerol, and liver enzymes. The liver of HFru (more) and HSu (less) groups showed fatty infiltration and areas of necroinflammation, which are characteristic of the transition from nonalcoholic fatty liver disease to nonalcoholic steatohepatitis. In addition, the HFru and HSu groups showed increased lipogenesis, gluconeogenesis, reduced beta-oxidation and antioxidant imbalance compared with the SC animals. In conclusion, current findings demonstrate comparable adverse effects on carbohydrate metabolism, inflammatory profile, antioxidant imbalance and NAFLD in the mice of the C57BL/6 strain fed a diet rich in sucrose or rich in fructose.
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http://dx.doi.org/10.1039/c5fo00251fDOI Listing
May 2015

Singular effects of PPAR agonists on nonalcoholic fatty liver disease of diet-induced obese mice.

Life Sci 2015 Apr 4;127:73-81. Epub 2015 Mar 4.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address:

Aims: To assess the effects of peroxisome proliferator-activated receptor (PPAR) agonists on glucose tolerance and hepatic lipid metabolism in diet-induced obese mice.

Main Methods: Male C57BL/6 mice received a standard chow diet (SC, 10% energy as lipids) or high-fat diet (HF, 50% energy as lipids) for 10 weeks, after which treatment was initiated, forming the groups: SC group, HF group, HF-BZ group (HF + bezafibrate, pan-PPAR agonist), HF-WY group (HF + WY-14643, PPARalpha agonist) and HF-GW group (HF + GW1929, PPARgamma agonist). Treatments lasted for four weeks. Insulin resistance and liver remodeling were evaluated by biochemical and molecular approaches.

Key Findings: The HF and HF-GW mice were overweight. Conversely, the HF-BZ and HF-WY mice presented with body masses equal to those of the SC mice. All treatments restored insulin sensitivity and blood lipid and adiponectin levels. Hepatic steatosis was prevented in the HF-WY and HF-BZ mice as shown by the elevated mRNA levels of PPARalpha and Carnitine palmitoyl transferase-1a in both groups, which favored enhanced beta-oxidation. Marked decreases in liver triacylglycerol levels confirmed these findings. In contrast, the HF-GW mice exhibited increased PPARgamma and fatty acid translocase/CD136 mRNA levels, contributing to enhanced hepatic lipogenesis.

Significance: The WY14643 and bezafibrate treatments most effectively improved the adverse metabolic and hepatic effects caused by obesity and IR. The results reinforce the central role of PPARalpha, as well as its contrary relationship to PPARgamma in the regulation of metabolic homeostasis and lipolytic pathways in the liver.
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http://dx.doi.org/10.1016/j.lfs.2015.02.003DOI Listing
April 2015

The inflammatory profile and liver damage of a sucrose-rich diet in mice.

J Nutr Biochem 2014 Feb 15;25(2):193-200. Epub 2013 Nov 15.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address:

Unlabelled: It is still unclear if an isoenergetic, sucrose-rich diet leads to health consequences.

Aims: To investigate the effects of excessive sucrose within an isoenergetic diet on metabolic parameters in male C57BL/6 mice.

Methods: Animals were fed a control diet (10% fat, 8% sucrose - SC group), a high-sucrose diet (10% fat, 32% sucrose - HSu group), a high-fat diet (42% fat, 8% sucrose - HF group) or a high-fat/high-sucrose diet (42% fat, 32% sucrose - HF/HSu group) for 8 weeks.

Results: Mice fed HF and HF/HSu diets gained more body mass (BM) and more body adiposity than SC- or Hsu-fed mice. Despite the unchanged BM and adiposity indices, HSu mice presented adipocyte hypertrophy, which was also observed in the HF and HF/HSu groups (P<.0001). The HF, HSu and HF/HSu mice were glucose intolerant and had elevated serum insulin levels (P<.05). The levels of leptin, resistin and monocyte chemotactic protein-1 increased, while the serum adiponectin decreased in the HF, HSu and HF/HSu groups (P<.05). In the adipose tissue, the HF, HSu and HF/HSu groups showed higher levels of leptin expression and lower levels of adiponectin expression in comparison with the SC group (P<.05). Liver steatosis was higher in the HF, HSu and HF/HSu groups than in the SC group (P<.0001). Hepatic cholesterol was higher in the HF and HF/HSu groups, while hepatic TG was higher in the HSu and HF/HSu groups (P<.05). In hepatic tissue, the sterol receptor element-binding protein-1c expression was increased in the HF, HSu and HF/HSu groups, unlike the peroxisome proliferator-activated receptor-alpha expression that decreased in the HF, HSu and HF/HSu groups in comparison with the SC group (P<.05).

Conclusion: A sucrose-rich diet does not lead to a state of obesity but has the potential to cause changes in the adipocytes (hypertrophy) as well as glucose intolerance, hyperinsulinemia, hyperlipidemia, hepatic steatosis and increases in the number of inflammatory cytokines. The deleterious effects of a sucrose-rich diet in an animal model, even when the sucrose replaces starch isocalorically in the feed, can have far-reaching consequences for health.
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http://dx.doi.org/10.1016/j.jnutbio.2013.10.006DOI Listing
February 2014

Liver damage is not reversed during the lean period in diet-induced weight cycling in mice.

Hepatol Res 2014 Apr 22;44(4):450-9. Epub 2013 May 22.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Aim: Weight cycling (WC) is frequent in obesity treatment. We evaluated the degree of regression of the liver damage in WC.

Methods: C57BL/6 male mice received standard chow (SC, 10% energy from lipids) or high-fat diet (HF, 60% energy from lipids) for 6 months (SC6 or HF6) or a diet that alternated every 2 months (SC2/HF2/SC2 or HF2/SC2/HF2).

Results: The body mass gain followed the HF intake and induced WC in the animals. The liver alanine aminotransferase, triglyceride and cholesterol levels were higher in the groups receiving the HF diet for any period. The plasma insulin and glucose levels were the highest in the HF6 and HF2/SC2/HF2 groups. Any HF intake increased the liver mass. All the groups had some degree of liver steatosis, with the SC6 group exhibiting the lowest level (∼23% compared with 50-70%). The activated hepatic stellate cells were sparse throughout the liver sections from the HF6 and HF2/SC2/HF2 groups. The lowest sterol regulatory element-binding protein-1c (SREBP-1c) level was detected in the SC6 group. The peroxisome proliferator-activated receptor (PPAR)-α expression was higher in the SC6 and SC2/HF2/SC2 groups than in the HF6 and HF2/SC2/HF2 groups that showed reduced expression.

Conclusion: WC induced by diet leads to adverse response in the liver, including biochemical and molecular alterations that are not reversed during the lean period of the WC, which must be maintained for a long period to allow the liver to recover from the damage associated with obesity.
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http://dx.doi.org/10.1111/hepr.12138DOI Listing
April 2014

Weight cycling enhances adipose tissue inflammatory responses in male mice.

PLoS One 2012 25;7(7):e39837. Epub 2012 Jul 25.

Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil.

Background: Obesity is associated with low-grade chronic inflammation attributed to dysregulated production, release of cytokines and adipokines and to dysregulated glucose-insulin homeostasis and dyslipidemia. Nutritional interventions such as dieting are often accompanied by repeated bouts of weight loss and regain, a phenomenon known as weight cycling (WC).

Methods: In this work we studied the effects of WC on the feed efficiency, blood lipids, carbohydrate metabolism, adiposity and inflammatory markers in C57BL/6 male mice that WC two or three consecutive times by alternation of a high-fat (HF) diet with standard chow (SC).

Results: The body mass (BM) grew up in each cycle of HF feeding, and decreased after each cycle of SC feeding. The alterations observed in the animals feeding HF diet in the oral glucose tolerance test, in blood lipids, and in serum and adipose tissue expression of adipokines were not recuperated after WC. Moreover, the longer the HF feeding was (two, four and six months), more severe the adiposity was. After three consecutive WC, less marked was the BM reduction during SC feeding, while more severe was the BM increase during HF feeding.

Conclusion: In conclusion, the results of the present study showed that both the HF diet and WC are relevant to BM evolution and fat pad remodeling in mice, with repercussion in blood lipids, homeostasis of glucose-insulin and adipokine levels. The simple reduction of the BM during a WC is not able to recover the high levels of adipokines in the serum and adipose tissue as well as the pro-inflammatory cytokines enhanced during a cycle of HF diet. These findings are significant because a milieu with altered adipokines in association with WC potentially aggravates the chronic inflammation attributed to dysregulated production and release of adipokines in mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039837PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405086PMC
April 2013

Adipose tissue, liver and pancreas structural alterations in C57BL/6 mice fed high-fat-high-sucrose diet supplemented with fish oil (n-3 fatty acid rich oil).

Exp Toxicol Pathol 2010 Jan 30;62(1):17-25. Epub 2009 Jan 30.

Laboratório de Morfometria e Morfologia Cardiovascular, Centro Biomédico, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro 87 (fds) 20551-030 Rio de Janeiro, RJ, Brasil.

Fish oil treatment was used in reversing the morphological and metabolic changes of C57BL/6 mice fed high-fat-high-sucrose (HFHS) diet. Two-month-old male C57BL/6 mice were fed HFHS chow or standard chow (SC). At 3 months of age, HFHS mice were separated into an untreated group (HFHS) and a group treated with fish oil (HFHS-Fo, 1.5g/kg/day). At 4 months of age, HFHS fed mice had an increase in body mass (BM) and total body fat, when the animals were sacrificed. Both parameters were lower in HFHS-Fo than in HFHS mice. Plasma glucose and insulin levels were not affected among the groups, but HFHS and HFHS-Fo animals had higher homeostasis model assessment for insulin resistance HOMA-IR ratio. HFHS and HFHS-FO mice had increased plasma total cholesterol and LDL-C, HFHS-Fo increased plasma HDL-C and decreased triglycerides levels. The liver mass (LM) and the adipocytes' size were larger in HFHS mice, while HFHS-Fo mice had a lower LM and smaller adipocytes. The liver steatosis and hepatocyte binucleation were increased in HFHS mice, while HFHS-Fo mice had reduced liver steatosis and hepatocyte binucleation. HFHS-Fo mice had a lower pancreas mass, while HFHS animals had higher islet pancreatic diameter. The SC group showed strong expression for insulin, glucagon and a glucose transporter type 2 GLUT-2 in all pancreatic islets, while in HFHS mice there was less expression for GLUT-2. However, HFHS-Fo mice showed an increase of GLUT-2 expression. In conclusion, dietary fish oil treatment reduces body mass and fat pad adiposity, and also by reducing plasma TG and pancreatic islet hypertrophy in mice fed high-fat-high-sucrose diet. Furthermore, fish oil improves glucagon and GLUT-2 expressions when it is decreased in insulin, but in hepatocyte binucleation and hepatic steatosis where the effect is reduced.
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http://dx.doi.org/10.1016/j.etp.2008.12.008DOI Listing
January 2010
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