Publications by authors named "Vanessa Souza-Mello"

47 Publications

A rise in Proteobacteria is an indicator of gut-liver axis-mediated nonalcoholic fatty liver disease in high-fructose-fed adult mice.

Nutr Res 2021 Jul 21;91:26-35. Epub 2021 May 21.

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

Current evidence suggests that high fructose intake results in gut dysbiosis, leading to endotoxemia and NAFLD onset. Thus, the hypothesis of the study was that an enhanced Proteobacteria proportion in the cecal microbiota could be the most prominent trigger of NAFLD through enhanced endotoxin (LPS) in adult high-fructose-fed C57BL/6 mice. Male C57BL/6 mice received a control diet (n = 10, C: 76% of energy as carbohydrates, 0% as fructose) or high-fructose diet (n = 10, HFRU: 76% of energy as carbohydrate, 50% as fructose) for 12 weeks. Outcomes included biochemical analyses, 16S rDNA PCR amplification, hepatic stereology, and RT-qPCR. The groups showed similar body masses during the whole experiment. However, the HFRU group showed greater water intake and blood pressure than the C group. The HFRU group showed a significantly lower amount of Bacteroidetes and a predominant rise in Proteobacteria, implying increased LPS. The HFRU group also showed enhanced de novo lipogenesis (Chrebp expression), while beta-oxidation was decreased (Ppar-alpha expression). These results agree with the deposition of fat droplets within hepatocytes and the enhanced hepatic triacylglycerol concentrations, as observed in the photomicrographs, where the HFRU group had a higher volume density of steatosis than the C group. Thus, we confirmed that a rise in the Proteobacteria phylum proportion was the most prominent alteration in gut-liver axis-induced hepatic steatosis in HFRU-fed C57BL/6 mice. Gut dysbiosis and fatty liver were observed even in the absence of overweight in this dietary adult mouse model.
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http://dx.doi.org/10.1016/j.nutres.2021.04.008DOI Listing
July 2021

Coronavirus disease 2019 severity in obesity: Metabolic dysfunction-associated fatty liver disease in the spotlight.

World J Gastroenterol 2021 Apr;27(16):1738-1750

Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil.

The coronavirus disease 2019 (COVID-19) outbreak has drawn the scientific community's attention to pre-existing metabolic conditions that could aggravate the infection, causing extended viral shedding, prolonged hospitalization, and high death rates. Metabolic dysfunction-associated fatty liver disease (MAFLD) emerges as a surrogate for COVID-19 severity due to the constellation of metabolic alterations it entails. This review outlines the impact MAFLD exerts on COVID-19 severity in obese subjects, besides the possible mechanistic links to the poor outcomes. The data collected showed that MAFLD patients had poorer COVID-19 outcomes than non-MAFLD obese subjects. MAFLD is generally accompanied by impaired glycemic control and systemic arterial hypertension, both of which can decompensate during the COVID-19 clinical course. Also, MAFLD subjects had higher plasma inflammatory marker concentrations than non-MAFLD subjects, which might be related to an intensified cytokine storm syndrome frequently associated with the need for mechanical ventilation and death. In conclusion, MAFLD represents a higher risk than obesity for COVID-19 severity, resulting in poor outcomes and even progression to non-alcoholic steatohepatitis. Hepatologists should include MAFLD subjects in the high-risk group, intensify preventive measurements, and prioritize their vaccination.
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http://dx.doi.org/10.3748/wjg.v27.i16.1738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072197PMC
April 2021

Consumption of phenolic-rich jabuticaba () powder ameliorates obesity-related disorders in mice.

Br J Nutr 2021 Mar 31:1-9. Epub 2021 Mar 31.

Laboratory for Studies of Interactions between Nutrition and Genetics, LEING, Department of Basic and Experimental Nutrition, Rio de Janeiro State University, Rua São Francisco Xavier, 524, 112.150 bloco F, 20550-900 Rio de Janeiro, Brazil.

Accumulating evidence indicates that dietary phenolic compounds can prevent obesity-related disorders. We investigated whether the consumption of polyphenol-rich jabuticaba peel and seed powder (JPSP) could ameliorate the progression of diet-induced obesity in mice. Male mice were fed a control diet or a high-fat (HF) diet for 9 weeks. After this period, mice were fed control, HF or HF diets supplemented with 5 % (HF-J5), 10 % (HF-J10) or 15 % (HF-J15) of JPSP, for 4 additional weeks. Supplementation with JPSP not only attenuated HF-induced weight gain and fat accumulation but also ameliorated the pro-inflammatory response associated with obesity, as evidenced by the absence of mast cells in the visceral depot accompanied by lower IL-6 and TNF-α at the tissue and circulating levels. JPSP-supplemented mice also exhibited smaller-sized adipocytes, reduced levels of leptin and higher levels of adiponectin, concomitant with improved glucose metabolism and insulin sensitivity. The magnitude of the observed effects was dependent on JPSP concentration with HF-J10- and HF-J15-fed mice showing metabolic profiles similar to control. This study reveals that the consumption of JPSP protects against the dysfunction of the adipose tissue and metabolic disturbances in obese mice. Thus, these findings indicate the therapeutic potential of the phenolic-rich JPSP in preventing obesity-related disorders.
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http://dx.doi.org/10.1017/S0007114521001136DOI Listing
March 2021

Endoplasmic reticulum stress as the basis of obesity and metabolic diseases: focus on adipose tissue, liver, and pancreas.

Eur J Nutr 2021 Mar 19. Epub 2021 Mar 19.

Laboratory of Morphometry, Metabolism, and Cardiovascular Diseases, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Av 28 de Setembro 87 fds, Rio de Janeiro, RJ, 20551-030, Brazil.

Obesity challenges lipid and carbohydrate metabolism. The resulting glucolipotoxicity  causes endoplasmic reticulum (ER) dysfunction, provoking the accumulation of immature proteins, which triggers the unfolded protein reaction (UPR) as an attempt to reestablish ER homeostasis. When the three branches of UPR fail to correct the unfolded/misfolded proteins, ER stress happens. Excessive dietary saturated fatty acids or fructose exhibit the same impact on the ER stress, induced by excessive ectopic fat accumulation or rising blood glucose levels, and meta-inflammation. These metabolic abnormalities can alleviate through dietary interventions. Many pathways are disrupted in adipose tissue, liver, and pancreas during ER stress, compromising browning and thermogenesis, favoring hepatic lipogenesis, and impairing glucose-stimulated insulin secretion within pancreatic beta cells. As a result, ER stress takes part in obesity, hepatic steatosis, and diabetes pathogenesis, arising as a potential target to treat or even prevent metabolic diseases. The scientific community seeks strategies to alleviate ER stress by avoiding inflammation, apoptosis, lipogenesis suppression, and insulin sensitivity augmentation through pharmacological and non-pharmacological interventions. This comprehensive review aimed to describe the contribution of excessive dietary fat or sugar to ER stress and the impact of this adverse cellular environment on adipose tissue, liver, and pancreas function.
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http://dx.doi.org/10.1007/s00394-021-02542-yDOI Listing
March 2021

Gut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin.

J Endocrinol 2020 10;247(1):11-24

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.

Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fructose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPAR-alpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha activation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression.
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http://dx.doi.org/10.1530/JOE-20-0139DOI Listing
October 2020

PPAR-α activation counters brown adipose tissue whitening: a comparative study between high-fat- and high-fructose-fed mice.

Nutrition 2020 10 6;78:110791. Epub 2020 Mar 6.

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

Objectives: To examine the effects of a selective peroxisome proliferator-activated receptor (PPAR-α) agonist treatment on interscapular brown adipose tissue (iBAT) whitening, focusing on thermogenic, lipolysis, and lipid oxidation markers in mice fed a high-fat or high-fructose diet.

Methods: Fifty animals were randomly assigned to receive a control diet (C, 10% lipids as energy), high-fat diet (HF, 50% lipids as energy), or high-fructose diet (HFRU, 50% fructose as energy) for 12 wk. Each group was redivided to begin the 5-wk treatment, totaling five experimental groups: C, HF, HF-a, HFRU, and HFRU-a. The drug was mixed with diet at the dose of 3.5 mg/kg body mass.

Results: HF group was the heaviest group, and the HF and HFRU groups had glucose intolerance. PPAR-α activation alleviated these metabolic constraints. HF and HFRU groups had negative vascular endothelial growth factor A (VEGF-A) immunostaining, but only the HF group had a pattern of lipid droplet accumulation that resembled the white adipose tissue, characterizing the whitening phenomenon. Whitening in the HF group was accompanied by decreased expression of genes related to thermogenesis, β-oxidation, and antiinflammatory effects. All of them were augmented by the PPAR-α activation in HF-a and HFRU-a groups, countering the whitening in the HF-a group. Treated groups also had a lower respiratory exchange ratio than untreated groups, suggesting that lipids were used as fuel for the enhanced thermogenesis.

Conclusions: The PPAR-α agonist countered iBAT whitening by inducing the thermogenic pathway and reducing the lipid droplet size, in addition to enhanced VEGF-A expression, adrenergic stimulus, and lipolysis in HF-fed mice.
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http://dx.doi.org/10.1016/j.nut.2020.110791DOI Listing
October 2020

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

Morphoquantitative effects of oral β-carotene supplementation on liver of C57BL/6 mice exposed to ethanol consumption.

Int J Clin Exp Pathol 2019 1;12(5):1713-1722. Epub 2019 May 1.

Doctoral Program in Morphological Sciences, Universidad de La Frontera Temuco, Chile.

Alcohol is harmful to the body, causing hepatic steatosis, alcoholic hepatitis and cirrhosis. The effects of alcohol on the liver can be offset using natural antioxidants. This study aimed to evaluate the effects of the administration of oral β-carotene on the morphoquantitative characteristics of mice livers exposed to ethanol consumption. Forty-eight male mice were used, divided into six groups: Control (C), Low-dose alcohol (LA), Moderate-dose alcohol (MA), β-carotene (B), Low-dose alcohol+β-carotene (LA+B) and Moderate-dose alcohol+β-carotene (MA+B). On day 28 the animals were euthanized and the organs were harvested. The morphoquantitative analysis, evaluation of the collagen fiber content and transmission electron microscopy were performed. A one-way ANOVA was used for statistical analysis. There were no differences between N, V, S, V, TV and TM in groups C and the MA+B ( < 0.001). The analysis of type I collagen fibers revealed that the MA+B group presented differences with groups C ( < 0.001), LA ( = 0.046) and LA+B ( = 0.009). The ultrastructural analysis for N, N, NT, V, V, S and TS did not reflect any significant differences between the groups. Our results suggest that the degree of hepatic steatosis produced by different doses of alcohol can be prevented. However, the following factors should be considered: amount of alcohol consumed, exposure time, regulatory mechanisms of alcoholic liver disease and signaling pathways involved in the ingestion of both ethanol and antioxidants.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947120PMC
May 2019

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

Browning is activated in the subcutaneous white adipose tissue of mice metabolically challenged with a high-fructose diet submitted to high-intensity interval training.

J Nutr Biochem 2019 08 25;70:164-173. Epub 2019 May 25.

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

Fructose may induce an endocrine dysfunction in adipose tissue in rodents. Browning is identified by deposits of beige adipocytes in subcutaneous white adipose tissue (sWAT). We study the effects of the high-intensity interval training (HIIT) on the formation of beige adipocytes in the sWAT of mice fed a high-fructose diet. Sixty male mice (3 months old; C57BL/6) were fed two diets for 18 weeks (n=30 each): control diet (C) or high-fructose diet (F). At the 10th week, for an additional 8-week period, the groups were (n=15 each) nontrained (NT) or trained (HIIT): C-NT, C-HIIT, F-NT and F-HIIT. We evaluated body mass, energy expenditure and molecular analyses for browning and thermogenic markers in sWAT. The HIIT groups showed significantly lower body mass and increased energy expenditure. The consumption of fructose was linked with an increased sWAT mass. However, HIIT caused a reduction of sWAT mass compared to the NT groups. Energy intake was parallel in the groups, regardless of the diet type and HIIT. Fructose was related to higher glucose and insulin levels and hypertrophied sWAT adipocytes, but HIIT decreased both glucose and insulin levels and led to the appearance of brown fat-like adipocytes dispersed in sWAT with higher expression of browning markers. Also, fructose reduced the sWAT markers of mitochondrial biogenesis and beta-oxidation, which were enhanced by HIIT. In conclusion, HIIT might stimulate the sWAT browning in mice fed a high-fructose diet associated with beneficial changes in mitochondrial biogenesis and beta-oxidation markers, contributing to a whole-body metabolic improvement.
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http://dx.doi.org/10.1016/j.jnutbio.2019.05.008DOI Listing
August 2019

High dose of linagliptin induces thermogenic beige adipocytes in the subcutaneous white adipose tissue in diet-induced obese C57BL/6 mice.

Endocrine 2019 08 3;65(2):252-262. Epub 2019 Jun 3.

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

Purpose: To verify whether the treatment with linagliptin induces the browning of the subcutaneous WAT (sWAT) and thermogenesis in murine diet-induced obesity (DIO) model.

Methods: Forty animals were randomly assigned to receive a control diet (C, 10% lipids as energy) or a high-fat diet (HF, 50% lipids as energy) for 10 weeks. Each group was re-divided to begin the 5-week treatment, totalizing four experimental groups: C, C-L (C plus linagliptin, 30 mg/kg body mass; BM), HF, and HF-L (HF plus linagliptin, 30 mg/kg BM). The drug was mixed with diet.

Results: HF animals showed overweight, glucose intolerance, and a greater cross-sectional area of adipocytes. The treatment with linagliptin was able to normalize the BM, restore the glucose tolerance and the cross-sectional area of adipocytes. These observations comply with the observation of UCP1-positive multilocular adipocytes in the sWAT of treated animals. Both treated groups (C-L and HF-L) showed high expression of thermogenic and type 2 cytokines genes, which agree with the enhanced body temperature and the lower respiratory exchange ratio, implying enhanced thermogenesis with the use of lipids as fuel.

Conclusions: The reduced BM, the enhanced body temperature, and the presence of positive UCP1 beige cells in the sWAT point to the activation of the browning cascade on the sWAT of linagliptin-treated mice, and hence, linagliptin could induce the thermogenic pathway as a pleiotropic effect that can have translational potential.
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http://dx.doi.org/10.1007/s12020-019-01969-yDOI Listing
August 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

Antiadipogenic effects of açai seed extract on high fat diet-fed mice and 3T3-L1 adipocytes: A potential mechanism of action.

Life Sci 2019 Jul 22;228:316-322. Epub 2019 Apr 22.

Laboratory for Studies of Interactions Between Nutrition and Genetics, LEING, Department of Basic and Experimental Nutrition, Rio de Janeiro State University, Rio de Janeiro, Brazil. Electronic address:

Body adiposity is an important risk factor for the development of chronic non-transmissible diseases. Studies on the process of adipogenesis have been extensively performed in vivo and in vitro models to describe the molecular and cellular bases of adipose tissue development and the effect of natural products in this process. The açai seed extract (ASE) has been evidenced as a potential regulator of body mass. In our work high-fat diet-fed mice treated with ASE (300 mg/Kg/d) (HFD-ASE) showed a lower adipose index (-32.63%, p < 0.001) than the high-fat diet-fed mice group (HFD) and the adipocytes from the HFD group were considerably enlarged (p < 0.001) compared to those in the control group (CG) and HFD-ASE group (+175% and +123%, respectively). We also evaluated the effects of ASE on the modulation of adipogenesis in 3T3-L1 cells. ASE exposure (25 and 100 μg/mL) led to a decrease of 26.6 (p < 0.05) in proliferation and also inhibited pre-adipocyte differentiation through the decreasing expression (p < 0.05) of transcription factors and adipogenic proteins such as PPARɣ, SREBP-1, and FAS. These results show that the ASE reduce adipogenesis and suppress lipid accumulation in the in vivo model and in 3T3-L1 adipocytes and reinforce ASE as a potential strategy to modulate adipogenesis.
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http://dx.doi.org/10.1016/j.lfs.2019.04.051DOI Listing
July 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

The renin-angiotensin system as a target to solve the riddle of endocrine pancreas homeostasis.

Biomed Pharmacother 2019 Jan 4;109:639-645. Epub 2018 Nov 4.

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

Local renin-angiotensin system (RAS) in the pancreas is linked to the modulation of glucose-stimulated insulin secretion (GSIS) in beta cells and insulin sensitivity in target tissues, emerging as a promising tool in the prevention and/or treatment of obesity, diabetes, and systemic arterial hypertension. Insulin resistance alters pancreatic islet cell distribution and morphology and hypertrophied islets exhibit upregulated angiotensin II type 1 receptor, which drives oxidative stress, apoptosis, and fibrosis, configuring beta cell dysfunction and diminishing islet lifespan. Pharmacological modulation of RAS has shown beneficial effects in diet-induced obesity model, mainly related to the translational potential that angiotensin receptor blockers and ECA2/ANG (1-7)/MAS receptor axis modulation have when it comes to islet preservation and type 2 diabetes prevention and/or treatment. This review describes the existing evidence for different approaches to blocking RAS elements in the management of insulin resistance and diabetes and focuses on islet remodeling and GSIS in rodents and humans.
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http://dx.doi.org/10.1016/j.biopha.2018.10.191DOI Listing
January 2019

GW0742 (PPAR-beta agonist) attenuates hepatic endoplasmic reticulum stress by improving hepatic energy metabolism in high-fat diet fed mice.

Mol Cell Endocrinol 2018 10 23;474:227-237. Epub 2018 Mar 23.

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

Endoplasmic reticulum (ER) stress and hepatic steatosis are intertwined with insulin resistance. PPARs are at the crossroads of these pathways. This study aimed to investigate the effects of GW0742 (PPAR-beta agonist) on hepatic energy metabolism and ER stress in a murine diet-induced obesity model. HF diet caused overweight, hyperinsulinemia, hepatic inflammation (increased NF-kB, TNF-alpha, and IL-6 protein expression) and favored hepatic lipogenesis, leading to ER stress, with ultrastructural and molecular alterations, ending up in proapoptotic stimulus. GW0742 rescued the overweight and the glucose tolerance, tackled hepatic inflammation and favored hepatic beta-oxidation over lipogenesis. These results comply with ER ultrastructure improvement, reducing ER stress and apoptosis in treated animals. Our results indicate that the PPAR-beta/delta activation alleviated the ER stress by improving the insulin sensitivity and maximizing the hepatic energy metabolism with a shift towards beta-oxidation. PPAR-beta/delta activation could be an essential tool to avoid the NAFLD progression and other obesity constraints.
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http://dx.doi.org/10.1016/j.mce.2018.03.013DOI Listing
October 2018

Differential actions of PPAR-α and PPAR-β/δ on beige adipocyte formation: A study in the subcutaneous white adipose tissue of obese male mice.

PLoS One 2018 19;13(1):e0191365. Epub 2018 Jan 19.

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

Background And Aims: Obesity compromises adipocyte physiology. PPARs are essential to adipocyte plasticity, but its isolated role in the browning phenomenon is not clear. This study aimed to examine whether activation of PPAR-α or PPAR-β/δ could induce beige cell depots in the subcutaneous white adipose tissue of diet-induced obese mice.

Material And Methods: Sixty animals were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for ten weeks. Then each group was re-divided to begin the treatments that lasted 4 weeks, totalizing six groups: C, C-α (C plus PPAR-α agonist, 2.5 mg/kg BM), C-β (C plus PPAR-β/δ agonist, 1 mg/kg BM), HF, HF-α (HF plus PPAR-α agonist), HF-β (HF plus PPAR-β/δ agonist).

Results: HF animals presented with overweight, glucose intolerance and subcutaneous white adipocyte hypertrophy. Both treatments significantly attenuated these parameters. Browning, verified by UCP1 positive beige cells and enhanced body temperature, was just observed in PPAR-α treated groups. PPAR-α agonism also elicited an enhanced gene expression of the thermogenesis effector UCP1, the beige-selective gene TMEM26 and the PRDM16, an essential gene for brown-like phenotype maintenance in the beige adipocytes when compared to their counterparts. The enhanced CIDEA and the reduced UCP1 gene levels might justify the white phenotype predominance after the treatment with the PPAR-β/δ agonist.

Conclusions: This work provides evidence that the PPAR-β/δ agonist ameliorated metabolic disorders through enhanced beta-oxidation and better tolerance to glucose, whereas the PPAR-α agonism was confirmed as a promising therapeutic target for treating metabolic diseases via beige cell induction and enhanced thermogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774787PMC
March 2018

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

Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice.

Biochimie 2017 Sep 12;140:106-116. Epub 2017 Jul 12.

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

Non-alcoholic fatty liver disease (NAFLD) presents with growing prevalence worldwide, though its pharmacological treatment remains to be established. This study aimed to evaluate the effects of a PPAR-alpha agonist on liver tissue structure, ultrastructure, and metabolism, focusing on gene and protein expression of de novo lipogenesis and gluconeogenesis pathways, in diet-induced obese mice. Male C57BL/6 mice (three months old) received a control diet (C, 10% of lipids, n = 10) or a high-fat diet (HFD, 50% of lipids, n = 10) for ten weeks. These groups were subdivided to receive the treatment (n = 5 per group): C, C-alpha (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the control diet), HFD and HFD-alpha group (PPAR-alpha agonist, 2.5 mg/kg/day mixed in the HFD). The effects were compared with biometrical, biochemical, molecular biology and transmission electron microscopy (TEM) analyses. HFD showed greater body mass (BM) and insulinemia than C, both of which were tackled by the treatment in the HFD-alpha group. Increased hepatic protein expression of glucose-6-phosphatase, CHREBP and gene expression of PEPCK in HFD points to increased gluconeogenesis. Treatment rescued these parameters in the HFD-alpha group, eliciting a reduced hepatic glucose output, confirmed by the smaller GLUT2 expression in HFD-alpha than in HFD. Conversely, favored de novo lipogenesis was found in the HFD group by the increased expression of PPAR-gamma, and its target gene SREBP-1, FAS and GK when compared to C. The treatment yielded a marked reduction in the expression of all lipogenic factors. TEM analyses showed a greater numerical density of mitochondria per area of tissue in treated than in untreated groups, suggesting an increase in beta-oxidation and the consequent NAFLD control. PPAR-alpha activation reduced BM and treated insulin resistance (IR) and NAFLD by increasing the number of mitochondria and reducing hepatic gluconeogenesis and de novo lipogenesis protein and gene expressions in a murine obesity model.
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http://dx.doi.org/10.1016/j.biochi.2017.07.003DOI Listing
September 2017

Hepatic structural enhancement and insulin resistance amelioration due to AT1 receptor blockade.

World J Hepatol 2017 Jan;9(2):74-79

Vanessa Souza-Mello, Biomedical Centre, Institute of Biology, Department of Anatomy, State University of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil.

Over the last decade, the role of renin-angiotensin system (RAS) on the development of obesity and its comorbidities has been extensively addressed. Both circulating and local RAS components are up-regulated in obesity and involved in non-alcoholic fatty liver disease onset. Pharmacological manipulations of RAS are viable strategies to tackle metabolic impairments caused by the excessive body fat mass. Renin inhibitors rescue insulin resistance, but do not have marked effects on hepatic steatosis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) yield beneficial hepatic remodeling. ARBs elicit body mass loss and normalize insulin levels, tackling insulin resistance. Also, this drug class increases adiponectin levels, besides countering interleukin-6, tumoral necrosis factor-alpha, and transforming growth factor-beta 1. The latter is essential to prevent from liver fibrosis. When conjugated with peroxisome proliferator-activated receptor (PPAR)-alpha activation, ARB fully rescues fatty liver. These effects might be orchestrated by an indirect up-regulation of MAS receptor due to angiotensin II receptor type 1 (AT1R) blockade. These associations of ARB with PPAR activation and ACE2-angiotensin (ANG) (1-7)-MAS receptor axis deserve a better understanding. This editorial provides a brief overview of the current knowledge regarding AT1R blockade effects on sensitivity to insulin and hepatic structural alterations as well as the intersections of AT1R blockade with peroxisome proliferator-activated receptor activation and ACE2-ANG (1-7) - MAS receptor axis.
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http://dx.doi.org/10.4254/wjh.v9.i2.74DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241531PMC
January 2017

Browning of white adipose tissue: lessons from experimental models.

Horm Mol Biol Clin Investig 2017 Jan 18;31(1). Epub 2017 Jan 18.

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Beige or brite (brown-in-white) adipocytes are present in white adipose tissue (WAT) and have a white fat-like phenotype that when stimulated acquires a brown fat-like phenotype, leading to increased thermogenesis. This phenomenon is known as browning and is more likely to occur in subcutaneous fat depots. Browning involves the expression of many transcription factors, such as PR domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor (PPAR)-γ, and of uncoupling protein (UCP)-1, which is the hallmark of thermogenesis. Recent papers pointed that browning can occur in the WAT of humans, with beneficial metabolic effects. This fact indicates that these cells can be targeted to treat a range of diseases, with both pharmacological and nutritional activators. Pharmacological approaches to induce browning include the use of PPAR-α agonist, adrenergic receptor stimulation, thyroid hormone administration, irisin and FGF21 induction. Most of them act through the induction of PPAR-γ coactivator (PGC) 1-α and the consequent mitochondrial biogenesis and UCP1 induction. About the nutritional inducers, several compounds have been described with multiple mechanisms of action. Some of these activators include specific amino acids restriction, capsaicin, bile acids, Resveratrol, and retinoic acid. Besides that, some classes of lipids, as well as many plant extracts, have also been implicated in the browning of WAT. In conclusion, the discovery of browning in human WAT opens the possibility to target the adipose tissue to fight a range of diseases. Studies have arisen showing promising results and bringing new opportunities in thermogenesis and obesity control.
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http://dx.doi.org/10.1515/hmbci-2016-0051DOI Listing
January 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

Fish oil diet modulates epididymal and inguinal adipocyte metabolism in mice.

Food Funct 2016 Mar;7(3):1468-76

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

We aimed to investigate the impact of different high-fat diets containing fish oil on adiposity and white adipose tissue (WAT) function in mice, comparing the effects on epididymal (eWAT) and subcutaneous (sWAT) depots. For this, we used C57BL/6 male mice fed four types of diets for eight weeks: standard chow (SC), high-fat lard (HF-L), high-fat lard plus fish oil (HF-L + FO), and high-fat fish oil (HF-FO). The HF-L group had a greater body mass (BM) gain, insulin resistance, increased gene expression related to lipogenesis (CD36, aP2, SREBP1c, and FAS), decreased gene expression of perilipin in both eWAT and sWAT, and reduced expression of genes related to beta-oxidation (CPT-1a) and to mitochondrial biogenesis (PGC1alpha, NRF1, and TFAM) in eWAT and sWAT. On the other hand, the HF-L + FO and HF-FO groups showed a smaller BM gain and adiposity, and normalization of insulin resistance and lipogenic genes in both eWAT and sWAT. These animals also showed decreased perilipin gene expression and elevated expression of beta-oxidation and mitochondrial biogenesis genes in eWAT and sWAT. 'Beige' adipocytes were identified in sWAT of the HF-FO animals. In conclusion, fish oil intake has anti-obesity effects through modulation of both eWAT and sWAT metabolism in mice and is relevant in diminishing the BM gain, adiposity, and insulin resistance even in combination with a high-fat lard diet in mice.
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http://dx.doi.org/10.1039/c5fo00909jDOI Listing
March 2016

Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring.

Physiol Behav 2016 Jan 17;153:47-55. Epub 2015 Oct 17.

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

We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood.
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http://dx.doi.org/10.1016/j.physbeh.2015.10.019DOI Listing
January 2016

Adverse effects of vitamin D deficiency on the Pi3k/Akt pathway and pancreatic islet morphology in diet-induced obese mice.

Mol Nutr Food Res 2016 Feb 26;60(2):346-57. Epub 2015 Oct 26.

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

Scope: To investigate the impact of vitamin D deficiency on insulin resistance and abnormal glucose homeostasis in obesity.

Methods And Results: Sixty male C57BL/6 mice (3 months old) were fed a control diet (C-10% energy as fat) or a high-fat diet (HF-50% energy as fat), with or without vitamin D, for 8 weeks. There was no difference in body mass between the HF and HF/VitD- groups. Vitamin D deficiency (VitD) in the diet-induced obese mice increased hyperinsulinemia (p = 0.04), hyperleptinemia (p = 0.0002), insulin resistance (HOMA-IR, p = 0.04), and islet changes, including alpha and beta cell disarray. In the insulin signaling pathway, insulin receptor substrate 2 expression was upregulated in the C/VitD- group (p = 0.001) and downregulated in the HF/VitD- group (p = 0.009). Interestingly, forkhead box protein O1 expression was higher in the HF/VitD- group than in the HF group (p = 0.03), and pancreatic and duodenal homeobox 1 expression was lower in the HF/VitD-group than in the HF group (p = 0.025), indicating that the HF diet and vitamin D deficiency influenced the downregulation of the expression of these proteins (two-way ANOVA, p < 0.0001).

Conclusion: Vitamin D deficiency exacerbated the adverse structural and physiological remodeling of pancreatic islets due to obesity, contributing to abnormal glucose homeostasis.
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http://dx.doi.org/10.1002/mnfr.201500398DOI Listing
February 2016

High-intensity interval training beneficial effects on body mass, blood pressure, and oxidative stress in diet-induced obesity in ovariectomized mice.

Life Sci 2015 Oct 15;139:75-82. Epub 2015 Aug 15.

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

Aims: To investigate the possible beneficial effect of high-intensity interval training (HIIT) on skeletal muscle oxidative stress, body mass (BM) and systolic blood pressure (SBP) in ovariectomized mice fed or not fed a high-fat diet.

Main Methods: Three-month-old female C57BL/6 mice were bilaterally ovariectomized (OVX group) or submitted to surgical stress without ovariectomy (SHAM group) and separated into standard chow (SHAM-SC; OVX-SC) and high-fat diet (SHAM-HF; OVX-HF) groups. After 13 weeks, an HIIT program (swimming) was carried out for 8 weeks in non-trained (NT) and trained (T) groups.

Key Findings: The significant reduction of uterine mass and the cytological examination of vaginal smears in the OVX group confirmed that ovariectomy was successful. Before the HIIT protocol, the ovariectomized groups showed a greater BM than the SHAM group, irrespective of the diet they received. The HIIT minimized BM gain in animals fed an HF diet and/or ovariectomized. SBP and total cholesterol were increased in the OVX and HF animals compared to their counterparts, and the HIIT efficiently reduced these factors. In the HF and OVX mice, the muscular superoxide dismutase and catalase levels were low while their glutathione peroxidase and glutathione reductase levels were high and the HIIT normalized these parameters.

Significance: Diet-induced obesity maximizes the deleterious effects of an ovariectomy. The HIIT protocol significantly reduced BM, SBP and oxidative stress in the skeletal muscle indicating that HIIT diminishes the cardiovascular and metabolic risk that is inherent to obesity and menopause.
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http://dx.doi.org/10.1016/j.lfs.2015.08.004DOI Listing
October 2015

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease.

World J Hepatol 2015 May;7(8):1012-9

Vanessa Souza-Mello, Biomedical Centre, Institute of Biology, Department of Anatomy, State University of Rio de Janeiro, Rio de Janeiro 20551-030, Brazil.

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.
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http://dx.doi.org/10.4254/wjh.v7.i8.1012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450178PMC
May 2015

PPAR-α agonist elicits metabolically active brown adipocytes and weight loss in diet-induced obese mice.

Cell Biochem Funct 2015 Jun 11;33(4):249-56. Epub 2015 May 11.

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

Obesity is considered a public health problem worldwide. Fenofibrate, a selective peroxisome proliferator-activated receptor α (PPAR-α) agonist, elicits weight loss in animal models. This study aimed to examine the effects of fenofibrate on energy expenditure, body mass (BM) and gene expression of thermogenic factors in brown adipose tissue of diet-induced obese mice. Male C57BL/6 mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 50% lipids) diet for 10 weeks. Afterwards, groups were subdivided as SC, SC-F, HF and HF-F (n = 10, each). Treatment with fenofibrate (100 mg kg(-1) BM mixed into the diet) lasted 5 weeks. Treated groups had reduced final BM compared with their counterparts (p < 0·05), explained by the increase in energy expenditure, CO2 production and O2 consumption after treatment with fenofibrate (p < 0·05). Similarly, genes involved in thermogenesis as PPAR-α, PPAR-γ coactivator 1α, nuclear respiratory factor 1, mitochondrial transcription factor A (Tfam), PR domain containing 16 (PRDM16), β-3 adrenergic receptor (β3-AR), bone morphogenetic protein 8B and uncoupling protein 1 were significantly expressed in brown adipocytes after the treatment (p < 0·05). All observations ensure that selective PPAR-α agonist can induce thermogenesis by increasing energy expenditure and enhancing the expression of genes involved in the thermogenic pathway. These results suggest fenofibrate as a coadjutant drug for the treatment of obesity.
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http://dx.doi.org/10.1002/cbf.3111DOI Listing
June 2015
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