Publications by authors named "Natália Tobar"

18 Publications

  • Page 1 of 1

Fish Oil Diet during Pre-mating, Gestation, and Lactation in Adult Offspring Rats on Cancer Cachexia Prevention.

Mol Nutr Food Res 2021 Mar 2:e2000863. Epub 2021 Mar 2.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, Campinas, Brazil.

Scope: Nutritional supplementation of the maternal diet can modify the cancer susceptibility in adult offspring. Therefore, the authors evaluate the effects of a fish-oil diet administered to a long-term, during pre-mating, gestation, and lactation, in reducing cancer-cachexia damages in adult Walker-256 tumor-bearing offspring.

Methods And Results: Female rats receive control or fish oil diet during pre-mating, gestation, and lactation. After weaning, male offspring are fed the control diet until adulthood and distributed in (C) control adult-offspring; (W) adult tumor-bearing offspring; (OC) adult-offspring of maternal fish oil diet; (WOC) adult tumor-bearing offspring of maternal fish oil diet groups. Fat body mass is preserved, muscle expression of mechanistic target of rapamicin (mTOR) and eukariotic binding protein of eukariotic factor 4E (4E-BP1) is modified, being associated with lower 20S proteasome protein expression, and the liver alanine aminotransferase (ALT) enzyme content maintained in the WOC group. Also, the OC group shows reduced triglyceridemia.

Conclusion: In this experimental model of cachexia, the long-term maternal supplementation is a positive strategy to improve liver function and lipid metabolism, as well as to modify muscle proteins expression in the mTOR pathway and also reduce the 20S muscle proteasome protein, without altering the tumor development and muscle wasting in adult tumor-bearing offspring.
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http://dx.doi.org/10.1002/mnfr.202000863DOI Listing
March 2021

Simultaneous Imaging of Lung Perfusion and Glucose Metabolism in COVID-19 Pneumonia.

Am J Respir Crit Care Med 2021 Feb 26. Epub 2021 Feb 26.

Universidade Estadual de Campinas - Campus Cidade Universitaria Zeferino Vaz, 28132, Endocrinology Division, Department of Internal Medicine, Campinas, Brazil.

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http://dx.doi.org/10.1164/rccm.202007-2944IMDOI Listing
February 2021

The 17β-oestradiol treatment minimizes the adverse effects of protein restriction on bone parameters in ovariectomized Wistar rats: Relevance to osteoporosis and the menopause.

Bone Joint Res 2019 Dec 8;8(12):573-581. Epub 2020 Jan 8.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas (UNICAMP), Campinas, Brazil.

Objectives: Insufficient protein ingestion may affect muscle and bone mass, increasing the risk of osteoporotic fractures in the elderly, and especially in postmenopausal women. We evaluated how a low-protein diet affects bone parameters under gonadal hormone deficiency and the improvement led by hormone replacement therapy (HRT) with 17β-oestradiol.

Methods: Female Wistar rats were divided into control (C), ovariectomized (OVX), and 17β-oestradiol-treated ovariectomized (OVX-HRT) groups, which were fed a control or an isocaloric low-protein diet (LP; 6.6% protein; seven animals per group). Morphometric, serum, and body composition parameters were assessed, as well as bone parameters, mechanical resistance, and mineralogy.

Results: The results showed that protein restriction negatively affected body chemical composition and bone metabolism by the sex hormone deficiency condition in the OVX group. The association between undernutrition and hormone deficiency led to bone and muscle mass loss and increased the fragility of the bone (as well as decreasing relative femoral weight, bone mineral density, femoral elasticity, peak stress, and stress at offset yield). Although protein restriction induced more severe adverse effects compared with the controls, the combination with HRT showed an improvement in minimizing these damaging effects, as it was seen that HRT had some efficacy in maintaining muscle and bone mass, preserving the bone resistance and minimizing some deleterious processes during the menopause.

Conclusion: Protein restriction has adverse effects on metabolism, leading to more severe menopausal symptoms, and HRT could minimize these effects. Therefore, special attention should be given to a balanced diet during menopause and HRT. 2019;8:573-581.
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http://dx.doi.org/10.1302/2046-3758.812.BJR-2018-0259.R2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946913PMC
December 2019

Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats.

Sci Rep 2019 10 29;9(1):15529. Epub 2019 Oct 29.

Laboratory of Nutrition and Cancer, Department of Structural and Functional Biology, Biology Institute, University of Campinas, Campinas, SP, Brazil.

Leucine can stimulate protein synthesis in skeletal muscle, and recent studies have shown an increase in leucine-related mitochondrial biogenesis and oxidative phosphorylation capacity in muscle cells. However, leucine-related effects in tumour tissues are still poorly understood. Thus, we described the effects of leucine in both in vivo and in vitro models of a Walker-256 tumour. Tumour-bearing Wistar rats were randomly distributed into a control group (W; normoprotein diet) and leucine group (LW; leucine-rich diet [normoprotein + 3% leucine]). After 20 days of tumour evolution, the animals underwent -fludeoxyglucose positron emission computed tomography (F-FDG PET-CT) imaging, and after euthanasia, fresh tumour biopsy samples were taken for oxygen consumption rate measurements (Oroboros Oxygraph), electron microscopy analysis and RNA and protein extraction. Our main results from the LW group showed no tumour size change, lower tumour glucose (F-FDG) uptake, and reduced metastatic sites. Furthermore, leucine stimulated a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, higher mRNA and protein expression of oxidative phosphorylation components, and enhanced mitochondrial density/area even though the leucine-treated tumour had a higher number of apoptotic nuclei with increased oxidative stress. In summary, a leucine-rich diet directed Walker-256 tumour metabolism to a less glycolytic phenotype profile in which these metabolic alterations were associated with a decrease in tumour aggressiveness and reduction in the number of metastatic sites in rats fed a diet supplemented with this branched-chain amino acid.
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http://dx.doi.org/10.1038/s41598-019-52112-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820796PMC
October 2019

The absence of lactation after pregnancy induces long-term lipid accumulation in maternal liver of mice.

Life Sci 2019 Jan 15;217:261-270. Epub 2018 Dec 15.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 13084-971 Campinas, Brazil. Electronic address:

Aims: The present investigation evaluated whether pregnancy followed by lactation exerts long-term impacts on maternal hepatic lipid metabolism.

Main Methods: Female mice were subjected to two pregnancies, after which they were either allowed to breastfeed their pups for 21 days (L21) or had their litter removed (L0). Age-matched virgin mice were used as controls (CTL). Three months after the second delivery, serum was collected for lipid profiling, and fragments of liver were used to assess lipid content and to evaluate the key steps of de novo non-esterified fatty acid (NEFA) synthesis, esterification and β-oxidation, very low density lipoprotein (VLDL) assembly and secretion and autophagy.

Key Findings: L0 exhibited a significant increase in hepatic TG and reduced apolipoprotein B-100 (ApoB-100) expression. L21 mice had increased ATP citrate lyase (ACLY) activity and reduced acetyl-CoA carboxylase (ACC) phosphorylation but no increased hepatic TG. On the other hand, L21 mice had reduced hepatic sequestosome 1 (SQSTM1/p62) levels. Increased high density lipoprotein (HDL) cholesterol and hepatic apolipoprotein A-1 (ApoA-1) expression were found exclusively in L21.

Significance: The present study reveals that long-term hepatic lipid accumulation is induced by the history of pregnancy without lactation. On the other hand, reduced SQSTM1/p62 levels indicate that increased autophagic flux during life may prevent hepatic fat in dams subjected to lactation. Lactation after pregnancy is also obligatory for a long-term increase in maternal HDL. The present data may contribute to the understanding of the mechanisms leading to elevated cardiometabolic risk in women limited to short periods of lactation.
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http://dx.doi.org/10.1016/j.lfs.2018.12.026DOI Listing
January 2019

Probiotics modulate gut microbiota and improve insulin sensitivity in DIO mice.

J Nutr Biochem 2017 12 26;50:16-25. Epub 2017 Aug 26.

Department of Internal Medicine, State University of Campinas, 13081-970, Campinas, SP, Brazil. Electronic address:

Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance.
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http://dx.doi.org/10.1016/j.jnutbio.2017.08.006DOI Listing
December 2017

Inhibition of hypothalamic leukemia inhibitory factor exacerbates diet-induced obesity phenotype.

J Neuroinflammation 2017 Sep 2;14(1):178. Epub 2017 Sep 2.

Laboratory of Cell Signaling, University of Campinas, Campinas, São Paulo, 13084-970, Brazil.

Background: The consumption of large amounts of dietary fats can trigger an inflammatory response in the hypothalamus and contribute to the dysfunctional control of caloric intake and energy expenditure commonly present in obesity. The objective of this study was to identify chemokine-related transcripts that could be involved in the early stages of diet-induced hypothalamic inflammation.

Methods: We used immunoblot, PCR array, real-time PCR, immunofluorescence staining, glucose and insulin tolerance tests, and determination of general metabolic parameters to evaluate markers of inflammation, body mass variation, and glucose tolerance in mice fed a high-fat diet.

Results: Using a real-time PCR array, we identified leukemia inhibitory factor as a chemokine/cytokine undergoing a rapid increase in the hypothalamus of obesity-resistant and a rapid decrease in the hypothalamus of obesity-prone mice fed a high-fat diet for 1 day. We hypothesized that the increased hypothalamic expression of leukemia inhibitory factor could contribute to the protective phenotype of obesity-resistant mice. To test this hypothesis, we immunoneutralized hypothalamic leukemia inhibitory factor and evaluated inflammatory and metabolic parameters. The immunoneutralization of leukemia inhibitory factor in the hypothalamus of obesity-resistant mice resulted in increased body mass gain and increased adiposity. Body mass gain was mostly due to increased caloric intake and reduced spontaneous physical activity. This modification in the phenotype was accompanied by increased expression of inflammatory cytokines in the hypothalamus. In addition, the inhibition of hypothalamic leukemia inhibitory factor was accompanied by glucose intolerance and insulin resistance.

Conclusion: Hypothalamic expression of leukemia inhibitory factor may protect mice from the development of diet-induced obesity; the inhibition of this protein in the hypothalamus transforms obesity-resistant into obesity-prone mice.
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http://dx.doi.org/10.1186/s12974-017-0956-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581454PMC
September 2017

Knocking down amygdalar PTP1B in diet-induced obese rats improves insulin signaling/action, decreases adiposity and may alter anxiety behavior.

Metabolism 2017 05 3;70:1-11. Epub 2017 Feb 3.

School of Applied Sciences, State University of Campinas, UNICAMP, Brazil; Department of Internal Medicine, State University of Campinas, UNICAMP, Brazil. Electronic address:

Objective: Protein tyrosine phosphatase 1B (PTP1B) has been extensively implicated in the regulation of body weight, food intake, and energy expenditure. The role of PTP1B appears to be cell and brain region dependent.

Results: Herein, we demonstrated that chronic high-fat feeding enhanced PTP1B expression in the central nucleus of the amygdala (CeA) of rats compared to rats on chow. Knocking down PTP1B with oligonucleotide antisense (ASO) decreased its expression and was sufficient to improve the anorexigenic effect of insulin through IR/Akt signaling in the CeA. ASO treatment reduces body weight, fat mass, serum leptin levels, and food intake and also increases energy expenditure, without altering ambulatory activity. These changes were explained, at least in part, by the improvement of insulin sensitivity in the CeA, decreasing NPY and enhancing oxytocin expression. There was a slight decline in fasting blood glucose and serum insulin levels possibly due to leanness in rats treated with ASO. Surprisingly, the elevated plus maze test revealed an anxiolytic behavior after reduction of PTP1B in the CeA.

Conclusions: Thus, the present study highlights the deleterious role that the amygdalar PTP1B has on energy homeostasis in obesity states. The reduction of PTP1B in the CeA may be a strategy for the treatment of obesity, insulin resistance and anxiety disorders.
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http://dx.doi.org/10.1016/j.metabol.2017.01.029DOI Listing
May 2017

Hypothalamic S1P/S1PR1 axis controls energy homeostasis in Middle-Aged Rodents: the reversal effects of physical exercise.

Aging (Albany NY) 2016 12;9(1):142-155

School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.

Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.
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http://dx.doi.org/10.18632/aging.101138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310661PMC
December 2016

Therapy with resveratrol attenuates obesity-associated allergic airway inflammation in mice.

Int Immunopharmacol 2016 Sep 22;38:298-305. Epub 2016 Jun 22.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address:

Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property.
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http://dx.doi.org/10.1016/j.intimp.2016.06.017DOI Listing
September 2016

Fractalkine (CX3CL1) is involved in the early activation of hypothalamic inflammation in experimental obesity.

Diabetes 2014 Nov 19;63(11):3770-84. Epub 2014 Jun 19.

Laboratory of Cell Signaling, University of Campinas, Campinas, Brazil

Hypothalamic inflammation is a common feature of experimental obesity. Dietary fats are important triggers of this process, inducing the activation of toll-like receptor-4 (TLR4) signaling and endoplasmic reticulum stress. Microglia cells, which are the cellular components of the innate immune system in the brain, are expected to play a role in the early activation of diet-induced hypothalamic inflammation. Here, we use bone marrow transplants to generate mice chimeras that express a functional TLR4 in the entire body except in bone marrow-derived cells or only in bone marrow-derived cells. We show that a functional TLR4 in bone marrow-derived cells is required for the complete expression of the diet-induced obese phenotype and for the perpetuation of inflammation in the hypothalamus. In an obesity-prone mouse strain, the chemokine CX3CL1 (fractalkine) is rapidly induced in the neurons of the hypothalamus after the introduction of a high-fat diet. The inhibition of hypothalamic fractalkine reduces diet-induced hypothalamic inflammation and the recruitment of bone marrow-derived monocytic cells to the hypothalamus; in addition, this inhibition reduces obesity and protects against diet-induced glucose intolerance. Thus, fractalkine is an important player in the early induction of diet-induced hypothalamic inflammation, and its inhibition impairs the induction of the obese and glucose intolerance phenotypes.
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http://dx.doi.org/10.2337/db13-1495DOI Listing
November 2014

Low-power laser irradiation fails to improve liver regeneration in elderly rats at 48 h after 70 % resection.

Lasers Med Sci 2015 Sep 1;30(7):2003-8. Epub 2014 Jun 1.

Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, 13081-970, Brazil,

The liver regeneration is an important clinical issue after major hepatectomies. Unfortunately, many organs (including the liver) exhibit age-related impairments regarding their regenerative capacity. Recent studies found that low-power laser irradiation (LPLI) has a stimulatory effect on the liver regeneration process. However, its effects in elderly remain unknown. Thus, this study aimed to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized elderly rats exposed to LPLI. The effects of 15 min of LPLI (wavelength of 632.8 nm; fluence of 0.97 J/cm(2); total energy delivered of 3.6 J) were evaluated in hepatectomized elderly Wistar male rats. Afterwards, through immunoblotting approaches, the protein expression and phosphorylation levels of hepatocyte growth factor (HGF), Met, Akt and Erk 1/2 signaling pathways as well as the proliferating cell nuclear antigen (PCNA) were investigated. It was observed that LPLI was not able to improve liver regeneration in elderly rats as evidenced by the lack of improvement of HGF and PCNA protein expression or phosphorylation levels of Met, Akt and Erk 1/2 in the remnant livers. In sum, this study demonstrated that the main molecular pathway, i.e. HGF/Met → Akt and Erk 1/2 → PCNA, involved in the hepatic regeneration process was not improved by LPLI in elderly hepatectomized rats, which in turn rules out LPLI as an adjuvant therapy, as observed in this protocol of liver regeneration evaluation (i.e. at 48 h after 70 % resection), in elderly.
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http://dx.doi.org/10.1007/s10103-014-1598-0DOI Listing
September 2015

Liver regeneration following partial hepatectomy is improved by enhancing the HGF/Met axis and Akt and Erk pathways after low-power laser irradiation in rats.

Lasers Med Sci 2013 Nov 20;28(6):1511-7. Epub 2013 Jan 20.

Department of Internal Medicine, State University of Campinas, 13081-970, Campinas, São Paulo, Brazil.

A simple, easy, and safe procedure aiming to improve liver regeneration could be of great clinical benefit in critical situations such as major hepatectomy, trauma, or hemorrhage. Low-power laser irradiation (LPLI) has come into a wide range of use in clinical practice by inducing regeneration in healthy and injured tissues. However, the effect of LPLI on the process of liver regeneration, especially those related to the molecular mechanisms, is not fully understood. Thus, the aim of the present study was to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized rats exposed to LPLI. We used Wistar male rats, which had their remaining liver irradiated or not with LPLI (wavelength of 632.8 nm and fluence of 65 mW/cm(2)) for 15 min after a 70% hepatectomy. We subsequently investigated hepatocyte growth factor (HGF), Met, Akt, and Erk 1/2 signaling pathways through protein expression and phosphorylation analyses along with cell proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67) using immunoblotting and histological studies. Our results show that LPLI can improve liver regeneration as shown by increased HGF protein expression and the phosphorylation levels of Met, Akt, and Erk 1/2 accompanied by higher levels of the PCNA and Ki-67 protein in the remnant livers. In summary, our results suggest that LPLI may play a clinical role as a simple, fast, and easy-to-perform strategy in order to enhance the liver regenerative capacity of a small liver remnant after hepatectomy.
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http://dx.doi.org/10.1007/s10103-013-1264-yDOI Listing
November 2013

Diacerhein improves glucose tolerance and insulin sensitivity in mice on a high-fat diet.

Endocrinology 2011 Nov 6;152(11):4080-93. Epub 2011 Sep 6.

Department of Internal Medicine, State University of Campinas, Campinas, São Paulo, Brazil.

Obesity and type 2 diabetes are characterized by insulin resistance, and the common basis of these events is a chronic and systemic inflammatory process marked by the activation of the c-Jun N-terminal kinase (JNK) and inhibitor-κB kinase (IKKβ)/nuclear factor-κB (NFκB) pathways, up-regulated cytokine synthesis, and endoplasmic reticulum dysfunction. The aim of this study was to evaluate the effects of diacerhein administration, an antiinflammatory drug that reduces the levels of inflammatory cytokines, on insulin sensitivity and signaling in diet-induced obese (DIO) mice. Swiss mice were fed with conventional chow (control group) or a high-fat diet (DIO group). Later, DIO mice were randomly subdivided into a new subgroup (DAR) that received 20 mg/kg diacerhein for 10 d. Western blotting was used to quantify the expression and phosphorylation of insulin receptor, insulin receptor substrate 1, and Akt and of inflammatory mediators that modulate insulin signaling in a negative manner (IKKβ, JNK, and inducible nitric oxide synthase). We show here, for the first time, that the administration of diacerhein in DIO mice improved endoplasmic reticulum stress, reduced JNK and IKKβ phosphorylation, and resulted in a marked improvement in fasting glucose, a decrease in macrophage infiltration in adipose tissue, and a reduced expression and activity of proinflammatory mediators accompanied by an improvement in the insulin signaling mainly in the liver and adipose tissue. Taken together, these results indicate that diacerhein treatment improves insulin sensitivity in obesity, mediated by the reversal of subclinical inflammation, and that this drug may be an alternative therapy for insulin resistance.
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http://dx.doi.org/10.1210/en.2011-0249DOI Listing
November 2011

Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats.

Diabetes 2011 03 31;60(3):784-96. Epub 2011 Jan 31.

Department of Internal Medicine, State University of Campinas, Campinas, SP, Brazil.

Objective: Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling.

Research Design And Methods: The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c-Jun NH(2)-terminal kinase (JNK) and IκB kinase (IKKβ) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats.

Results: The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKKβ phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels.

Conclusions: Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance.
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http://dx.doi.org/10.2337/db09-1907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046839PMC
March 2011