Publications by authors named "Flavia Silva-Veiga"

6 Publications

  • Page 1 of 1

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 07 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

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

Eur J Nutr 2021 Sep 19;60(6):2949-2960. 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
September 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

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
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