Marcio Torsoni - Academia.edu (original) (raw)

Papers by Marcio Torsoni

Scientific Reports, Jan 8, 2020

the activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to an... more the activation of nicotinic acetylcholine receptor α7 subunit (α7nAChR) has been associated to anti-inflammatory response in macrophages. High-fat diet (HFD) consumption during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in liver and white adipose tissue of offspring. In order to evaluate the relationship between damage in the cholinergic anti-inflammatory pathway and insulin resistance (IR) development, the liver of offspring of obese dams was investigated. Additionally, the capacity of α7nAChR activation to reduce IR induced by saturated fatty acid was investigated in hepatoma cell line. Initially, female mice were subjected to either standard chow (SC) or HFD during pregnancy and lactation period. After weaning, only male offspring from HFD dams (HFD-O) and SC dams (SC-O) were fed with the SC diet. Hepatic α7nAChR expression was downregulated, and hepatic tnf-α, IL-1β, and pIKK level, but not pJNK, were elevated in the HFD-O compared to Sc-o mice. Besides, hepatic expression of tnf-α in response to lipopolysaccharide (LPS) was higher in HFD-O than SC-O mice. Insulin-stimulated phosphorylation of the AKT was lower in HFD-O compared to Sc-o. Additionally, insulin-stimulated phosphorylation of the AKt in Koα7 Alb-Cre mice fed HFD was lower than WT mice fed HFD. In hepatoma cell line, palmitate increased IL-6 and TNF-α expressions and pJNK level. These effects were accompanied by reduced capacity of insulin to stimulate AKT phosphorylation. PNU or nicotine reduced cytokine expression and JNK activation, but improved insulin resistance induced by palmitate. Our results suggest that maternal obesity impairs hepatic α7nAChR expression and AKT phosphorylation in the offspring. In vitro studies suggest that α7nAChR activation has potential to reduce deleterious effect of saturated fatty acids on insulin signalling.

Journal of Endocrinology, 2020

The mTOR/S6Ks signaling is one of the intracellular pathways important for metabolic control, act... more The mTOR/S6Ks signaling is one of the intracellular pathways important for metabolic control, acting both peripherally and centrally. In the hypothalamus, mTOR/S6Ks axis mediates the action of leptin and insulin and can modulate the expression of neuropeptides. We analyzed the role of different S6Ks isoforms in the hypothalamic regulation of metabolism. We observed decreased food intake and decreased expression of agouti-related peptide (AgRP) following intracerebroventricular (icv) injections of adenoviral-mediated overexpression of three different S6Ks isoforms. Moreover, mice overexpressing p70-S6K1 in undefined periventricular hypothalamic neurons presented changes in glucose metabolism, as an increase in gluconeogenesis. To further evaluate the hypothalamic role of a less-studied S6K isoform, p54-S6K2, we used a Cre-LoxP approach to specifically overexpress it in AgRP neurons. Our findings demonstrate the potential participation of S6K2 in AgRP neurons regulating feeding behavior.

Brain Sciences, Jul 9, 2022

Maternal obesity results in programmed offspring hyperphagia and obesity. The increased offspring... more Maternal obesity results in programmed offspring hyperphagia and obesity. The increased offspring food intake is due in part to the preferential differentiation of hypothalamic neuroprogenitor cells (NPCs) to orexigenic (AgRP) vs. anorexigenic (POMC) neurons. The altered neurogenesis may involve hypothalamic bHLH (basic helix-loop-helix) neuroregulatory factors (Hes1, Mash1, and Ngn3). Whilst the underlying mechanism remains unclear, it is known that mitochondrial function is critical for neurogenesis and is impacted by proinflammatory cytokines such as TNFα. Obesity is associated with the activation of inflammation and oxidative stress pathways. In obese pregnancies, increased levels of TNFα are seen in maternal and cord blood, indicating increased fetal exposure. As TNFα influences neurogenesis and mitochondrial function, we tested the effects of TNFα and reactive oxidative species (ROS) hydrogen peroxide (H 2 O 2 ) on hypothalamic NPC cultures from newborn mice. TNFα treatment impaired NPC mitochondrial function, increased ROS production and NPC proliferation, and decreased the protein expression of proneurogenic Mash1/Ngn3. Consistent with this, AgRP protein expression was increased and POMC was decreased. Notably, treatment with H 2 O 2 produced similar effects as TNFα and also reduced the protein expression of antioxidant SIRT1. The inhibition of STAT3/NFκB prevented the effects of TNFα, suggesting that TNFα mediates its effects on NPCs via mitochondrial-induced oxidative stress that involves both signaling pathways.

Scientific Reports, Apr 26, 2021

Nutritional status during gestation may lead to a phenomenon known as metabolic programming, whic... more Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms. The Let-7 family of microRNAs were one of the first to be discovered, and are closely related to metabolic processes. Bioinformatic analysis revealed that Prkaa2, the gene that encodes AMPK α2, is a predicted target of Let-7. Here we aimed to investigate whether Let-7 has a role in AMPKα2 levels in the NAFLD development in the offspring programmed by maternal obesity. Let-7 levels were upregulated in the liver of newborn mice from obese dams, while the levels of Prkaa2 were downregulated. Let-7 levels strongly correlated with serum glucose, insulin and NEFA, and in vitro treatment of AML12 with glucose and NEFA lead to higher Let-7 expression. Transfection of Let-7a mimic lead to downregulation of AMPKα2 levels, while the transfection with Let-7a inhibitor impaired both NEFA-mediated reduction of Prkaa2 levels and the fat accumulation driven by NEFA. The transfection of Let-7a inhibitor in ex-vivo liver slices from the offspring of obese dams restored phospho-AMPKα2 levels. In summary, Let-7a appears to regulate hepatic AMPKα2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams. Adverse conditions during fetal and early postnatal life can have a long-term impact on health and metabolism, a phenomenon known as the Developmental Origins of Health and Disease (DOHaD) or metabolic programming 1 . Maternal obesity and high-fat diet consumption have been shown to drive deleterious effects on the offspring metabolism, predisposing them to the development of obesity, insulin resistance, dyslipidemias, and non-alcoholic fatty liver disease (NAFLD) . NAFLD is considered as a complex interaction of nutritional factors and higher susceptibility due to parental obesity programming of epigenetic mechanisms, and microRNAs (miRNAs) may play an essential role in NAFLD development, progression and diagnostics 7,8 . Let-7 was one of the first miRNAs to be discovered 10 , and processing and maturing of Let-7 can be inhibited by LIN28 9 . Let-7/LIN28 axis is implicated in energy metabolism, and regulates multiple aspects of glucose and lipid metabolism, while Let-7 knockdown using antimir-based approaches appears as a potential strategy for treating metabolic diseases . NAFLD individuals commonly have decreased hepatic AMPK . The maintenance of AMPK levels seems to be beneficial for the liver homeostasis, and the activation of AMPK may be of value for the prevention and treatment of metabolic disorders associated with obesity, such as type 2 diabetes mellitus and NAFLD . Thus, in the present study we sought to investigate whether hepatic Let-7 would have a role in the modulation of AMPKα2 in the context of the NAFLD development in the offspring programmed by maternal obesity during intrauterine life.

PLOS ONE, Sep 30, 2020

This study investigated the effect of non-periodized training performed at 80, 100 and 120% of th... more This study investigated the effect of non-periodized training performed at 80, 100 and 120% of the anaerobic threshold intensity (AnT) and a linear periodized training model adapted for swimming rats on the gene expression of monocarboxylate transporters 1 and 4 (MCT1 and 4, in soleus and gastrocnemius muscles), protein contents, blood biomarkers, tissue glycogen, body mass, and aerobic and anaerobic capacities. Sixty Wistar rats were randomly divided into 6 groups (n = 10 per group): a baseline (BL; euthanized before training period), a control group (GC; not exercised during the training period), three groups exercised at intensities equivalent to 80, 100 and 120% of the AnT (G80, G100 and G120, respectively) at the equal workload and a linear periodized training group (GPE). Each training program lasted 12 weeks subdivided into three periods: basic mesocycle (6 weeks), specific mesocycle (5 weeks) and taper (1 week). Although G80, G100 and G120 groups were submitted to monotony workload (i.e. non-modulation at intensity or volume throughout the training program), rodents were evaluated during the same experimental timepoints as GPE to be able comparisons. Our main results showed that all training programs were capable to minimize the aerobic capacity decrease promoted by age, which were compared to control group. Rats trained in periodization model had reduced levels of lipid blood biomarkers and increased hepatic glycogen stores compared to all other trained groups. At the molecular level, only expressions of MCT1 in the muscle were modified by different training regimens, with MCT1 mRNA increasing in rats trained at lower intensities (G80), and MCT1 protein content showed higher values in non-periodized groups compared to pre-training and GPE. Here, training at different intensities but at same total workload promoted similar adaptations in rats. Nevertheless, our results suggested that periodized training seems to be optimize the physiological responses of rats.

Brain Sciences

Food Chemistry: Molecular Sciences, 2021

Although beet stalks and leaves are not consumed and are usually discarded, they are an important... more Although beet stalks and leaves are not consumed and are usually discarded, they are an important source of bioactive flavonoids possessing antioxidant and anti-inflammatory activity. The aim of this study was to assess the effect of supplementation with beet stalks and leaves on metabolic parameters and glucose homeostasis in mice exposed to a high-fat diet. Six-week-old male Swiss mice were randomly divided into five experimental groups submitted to either standard diet (CT) or high-fat diet (HF), and HF-fed mice were subdivided into three treatment groups supplemented with oven-dehydrated beet stalks and leaves (SL), lyophilized beet stalks and leaves (Ly) or beet stalk and leaf extract (EX). Supplementation with SL promoted a mild improvement in the glucose homeostasis and decreased the protein levels of TNFα with no alterations in hepatic triglyceride content. It remains to be clarified if the enhancement in the glucose homeostasis observed in HFSL could be a consequence of improvement in pancreatic insulin secretion and/or glucose uptake from skeletal muscle and white adipose tissues.

Background Although beet stalks and leaves are not consumed and are usually discarded, they are a... more Background Although beet stalks and leaves are not consumed and are usually discarded, they are an important source of bioactive flavonoids possessing antioxidant and anti-inflammatory activity, which could be explored to prevent metabolic disorders associated with an unhealthy diet. The aim of this study was to assess the effect of supplementation with beet (Beta vulgaris L.) stalks and leaves on metabolic parameters and glucose homeostasis in mice exposed to a high-fat diet.Methods Six-week-old male Swiss mice were randomly divided into five experimental groups submitted to either standard diet (CT) or high-fat diet (HF), and HF-fed mice were subdivided into three treatment groups supplemented with oven-dehydrated beet stalks and leaves (SL), lyophilized beet stalks and leaves (Ly) or beet stalk and leaf extract (EX).Results Supplementation with SL was able to ameliorate glucose homeostasis (P < 0.05) with no alteration in hepatic triglyceride content. It remains to be clarifie...

Scientific Reports, 2021

Frontiers in Immunology, 2019

i.p. or i.c.v.) reduced the levels of inflammatory markers in the hypothalamus following LPS inje... more i.p. or i.c.v.) reduced the levels of inflammatory markers in the hypothalamus following LPS injection. Nevertheless, when the i.c.v. injection of PNU-282987 was performed the anti-inflammatory effect was much smaller in HFD-fed mice than SC-fed mice. Here, we provide evidence that a short-term HFD impairs early α7nAChR expression in central and peripheral tissues, contributing to a higher probability of death in sepsis.

Scientific Reports, 2020

Diet is an important factor in both the pathogenesis and in the clinical course of Crohn’s diseas... more Diet is an important factor in both the pathogenesis and in the clinical course of Crohn’s disease (CD). However, data on dietary patterns of CD patients are rather limited in the literature. This cross-sectional study included 60 patients with CD, aged 18–60 years. Dietary intake was assessed using a validated food frequency questionnaire to measure food consumption patterns by principal component analysis (PCA). Multiple regression analysis was performed to investigate the association between dietary patterns and clinical and demographic variables. Three dietary patterns were identified: “Traditional + FODMAP” was associated with symptoms, gender, previous surgeries, and duration of the disease. “Fitness style” was positively associated with physical activity and negatively associated with body mass index and smoking. “Snacks and processed foods” was positively associated with duration of the disease and negatively associated with age. According to the weekly food consumption anal...

Clinical Science, 2019

There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To so... more There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To solve this problem, we used 2 different approaches: (1) FAT-1 transgenic mice, capable of producing endogenous ω-3 FA; (2) wild-type (WT) mice orally supplemented with DHA-enriched fish oil. FAT-1 mice had higher systemic (serum) and local (skin tissue) ω-3 FA levels, mainly docosahexaenoic acid (DHA), in comparison with WT mice. FAT-1 mice had increased myeloperoxidase (MPO) activity and content of CXCL-1 and CXCL-2, and reduced IL-10 in the skin wound tissue three days after the wound induction. Inflammation was maintained by an elevated TNF-α concentration and presence of inflammatory cells and edema. Neutrophils and macrophages, isolated from FAT-1 mice, also produced increased TNF-α and reduced IL-10 levels. In these mice, the wound closure was delayed, with a wound area 6-fold bigger in relation with WT group, on the last day of analysis (14 days post-wounding). This was associated w...

Cellular Physiology and Biochemistry, 2019

This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 I... more This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Journal of Endocrinology, 2019

Endocrinology, Jan 12, 2016

A temporary and reversible inhibition of the hypothalamo-pituitary-gonadal (HPG) axis is adaptive... more A temporary and reversible inhibition of the hypothalamo-pituitary-gonadal (HPG) axis is adaptive when energy reserves are diminished, allowing individual survival and energy accumulation for eventual reproduction. The AMP-activated protein kinase (AMPK) works as a cellular sensor of the AMP/ATP ratio and ultimately of energy availability. Activation of AMPK suppresses ATP-consuming processes and stimulates ATP-producing pathways. The AMPK α2 catalytic subunit is expressed in multiple hypothalamic nuclei including those associated with reproductive control, i.e., the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (Arc). Subsets of Kiss1 neurons in the AVPV (20% in females) and Arc (45% in males and 65% in females) coexpress AMPKα2 mRNA. Using the Cre-loxP approach, we assessed if AMPKα2 in Kiss1 cells is required for body weight and reproductive function. The AMPKα2-deleted mice show no difference in body weight and time for sexual maturation compared to contro...

PLOS ONE, 2016

Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities i... more Modern lifestyle has resulted in an increase in the prevalence of obesity and its comorbidities in pregnant women and the young population. It has been well established that the consumption of a high-fat diet (HFD) has many direct effects on glucose metabolism. However, it is important to assess whether maternal consumption of a HFD during critical periods of development can lead to metabolic changes in the offspring metabolism. This study evaluated the potential effects of metabolic programming on the impairment of insulin signalling in recently weaned offspring from obese dams. Additionally, we investigated if early exposure to an obesogenic environment could exacerbate the impairment of glucose metabolism in adult life in response to a HFD. Swiss female mice were fed with Standard Chow (SC) or a HFD during gestation and lactation and tissues from male offspring were analysed at d28 and d82. Offspring from obese dams had greater weight gain and higher adiposity and food intake than offspring from control dams. Furthermore, they showed impairment in insulin signalling in central and peripheral tissues, which was associated with the activation of inflammatory pathways. Adipose tissue was ultimately the most affected in adult offspring after HFD rechallenge; this may have contributed to the metabolic deregulation observed. Overall, our results suggest that diet-induced maternal obesity leads to increased susceptibility to obesity and impairment of insulin signalling in offspring in early and late life that cannot be reversed by SC consumption, but can be aggravated by HFD re-exposure.

PLOS ONE, 2015

Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional ... more Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell-line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity.

British Journal of Nutrition, 2014

Maternal consumption of a high-fat diet (HFD) during pregnancy and lactation is closely related t... more Maternal consumption of a high-fat diet (HFD) during pregnancy and lactation is closely related to hepatic lipid accumulation, insulin resistance and increased serum cytokine levels in offspring and into their adulthood. MicroRNA (miRNA) have been implicated in cholesterol biosynthesis and fatty acid metabolism. We evaluated the modulation of hepatic fatty acid synthesis (de novo), β-oxidation pathways, and miRNA-122 (miR-122) and miRNA-370 (miR-370) expression in recently weaned offspring (day 28) of mouse dams fed a HFD (HFD-O) or a standard chow (SC-O) during pregnancy and lactation. Compared with SC-O mice, HFD-O mice weighed more, had a larger adipose tissue mass and were more intolerant to glucose and insulin (P< 0·05). HFD-O mice also presented more levels of serum cholesterol, TAG, NEFA and hepatic IκB kinase and c-Jun N-terminal kinase phosphorylation compared with SC-O mice (P< 0·05). Protein levels of fatty acid synthase, acetyl-CoA carboxylase and 3-hydroxy-3-methy...

The Journal of Physiology, 2005

The exposure of homeothermic animals to a cold environment leads to a powerful activation of orex... more The exposure of homeothermic animals to a cold environment leads to a powerful activation of orexigenic signalling which is accompanied by molecular and functional resistance to insulin-induced inhibition of feeding. Recent evidence suggests that AMPK participates in nutrient-dependent control of satiety and adiposity. The objective of the present study was to evaluate the effect of cold exposure upon the molecular activation of AMPK signalling in the hypothalamus of rats. Immunoblotting demonstrated that cold exposure per se is sufficient for inducing, on a time-dependent basis, the molecular activation of the serine/threonine kinase AMP-activated protein kinase (AMPK) and inactivation of the acetyl-CoA carboxylase (ACC). These molecular phenomena were accompanied by resistance to nutrient-induced inactivation of AMPK and activation of ACC. Moreover, cold-exposure led to a partial inhibition of a feeding-induced anorexigenic response, which was paralleled by resistance to insulin-induced suppression of feeding. Finally, cold exposure significantly impaired insulin-induced inhibition of AMPK through a mechanism dependent on the molecular cross-talk between phosphatidylinositol-3(PI 3 )-kinase/Akt and AMPK. In conclusion, increased feeding during cold exposure results, at least in part, from resistance to insulin-and nutrient-dependent anorexigenic signalling in the hypothalamus.

PLoS ONE, 2013

Background: Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose ... more Background: Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability. Methodology/Principal Findings: In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation. Conclusion/Significance: Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.