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Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Machi, Altilio, Qi, Morales, Silvestre, Hernandez, Da Costa-Santos, Santana, Neghabi, Nategh, Castro, Werneck-de-Castro, Ranji, Evangelista, Vazquez-Padron, Bernal-Mizrachi and Rodrigues.)

After 2 years of the COVID-19 pandemic, the protocols used to control infection lack attention and analysis. We present data about deposits of complete genomic sequences of SARS-CoV-2 in the Global Initiative on Sharing All Influenza Data (GISAID) database made between January 2021 and May 31, 2022. We build the distribution profile of SARS-CoV-2 variants across South America, highlighting the contribution and influence of each variant over time. Monitoring the genomic sequences in GISAID illustrates negligence in the follow up of infected patients in South America and also the discrepancies between the number of complete genomes deposited throughout the pandemic by developed and developing countries. While Europe and North America account for more than 9 million of the genomes deposited in GISAID, Africa and South America deposited less than 400 000 genome sequences. Genomic surveillance is important for detecting early warning signs of new circulating viruses, assisting in the discovery of new variants and controlling pandemics.

Since the first reported case of COVID-19 in Brazil, the public and private educational system started to close. Up to November 2020, scientific discussions about the return of schooling activities have been rarely performed by the national scientific community and police-makers. The great delay of school returning in Brazil contrasts with successful international strategies of school reopening worldwide and seems counterintuitive with the reopening of non-essential activities. Here, important issues to be considered before and during school reopening are reviewed and discussed. COVID-19 testing is essential to avoid disease spreading, but high cost of individual RT-qPCRs impairs an extensive testing strategy for school returning. To reduce costs and increase the speed of diagnosis, we tested the efficiency of a pooled-sample PCR strategy in a cohort of the educational staff in the city of Macaé/RJ, finding five asymptomatic individuals (0,66%) among the 754 people tested. Thus, a polled-sample PCR testing strategy of the educational staff might prevent infection spreading in schools at a reasonable cost. We discuss how our test strategy could be coupled with internationally recognized safety rules to allow for a safe school return and how countries from different world regions are dealing with educational activities during COVID-19 pandemic.

The Brazilian strategy to overcome the spread of COVID-19 has been particularly criticized due to the lack of a national coordinating effort and an appropriate testing program. Here, a successful approach to control the spread of COVID-19 transmission is described by the engagement of public (university and governance) and private sectors (hospitals and oil companies) in Macaé, state of Rio de Janeiro, Brazil, a city known as the National Oil Capital. In 2020 between the 17th and 38th epidemiological week, over two percent of the 206,728 citizens were subjected to symptom analysis and RT-qPCR testing by the Federal University of Rio de Janeiro, with positive individuals being notified up to 48 h after swab collection. Geocodification and spatial cluster analysis were used to limit COVID-19 spreading in Macaé. Within the first semester after the outbreak of COVID-19 in Brazil, Macaé recorded 1.8% of fatalities associated with COVID-19 up to the 38th epidemiological week, which was at least five times lower than the state capital (10.6%). Overall, considering the successful experience of this joint effort of private and public engagement in Macaé, our data suggest that the development of a similar strategy countrywise could have contributed to a better control of the COVID-19 spread in Brazil. Quarantine decree by the local administration, comprehensive molecular testing coupled to scientific analysis of COVID-19 spreading, prevented the catastrophic consequences of the pandemic as seen in other populous cities within the state of Rio de Janeiro and elsewhere in Brazil., (© 2021. The Author(s).)

Mechanistic target of rapamycin complex 1 (mTORC1) deficiency or chronic hyperactivation in pancreatic β-cells leads to diabetes. mTORC1 complexes with La-related protein 1 (LARP1) to specifically regulate the expression of 5' terminal oligopyrimidine tract (5'TOP) mRNAs which encode proteins of the translation machinery and ribosome biogenesis. Here we show that LARP1 is the most expressed LARP in mouse islets and human β-cells, being 2-4-fold more abundant than LARP1B, a member of the family that also interacts with mTORC1. Interestingly, β-cells from diabetic patients have higher LARP1 and LARP1B expression. However, specific deletion of Larp1 gene in β-cells (β-Larp1KO mice) did not impair insulin secretion and glucose metabolism in male and female mice. High fat or high branched-chain amino acid (BCAA) diets did not disturb glucose homeostasis compared to control littermates up to 8 weeks; BCAA diet slightly impaired glucose tolerance in the β-Larp1KO mice at 16 weeks. However, no differences in plasma insulin levels, non-fasting glycemia and β-cell mass were observed in the β-Larp1KO mice. In conclusion, LARP1 is the most abundant LARP in mouse islets and human β-cells, and it is upregulated in diabetic subjects. However, genetically disruption of Larp1 gene did not impact glucose homeostasis in basal and diabetogenic conditions, suggesting no major role for LARP1 in β-cells.

Background: Myogenesis is positively regulated by thyroid hormone (triiodothyronine [T3]), which is amplified by the type 2 deiodinase (D2) activation of thyroxine to T3. Global inactivation of the Dio2 gene impairs skeletal muscle (SKM) differentiation and regeneration in response to muscle injury. Given that newborn and adult mice with late developmental SKM Dio2 disruption do not develop a significant phenotype, it was hypothesized that D2 plays an early role in this process., Methods: This was tested in mice with SKM disruption of Dio2 driven by two early developmental promoters: MYF5 and MYOD., Results: MYF5 myoblasts in culture differentiate normally into myotubes, despite loss of almost all D2 activity. Dio2 mRNA levels in developing SKM obtained from MYF5-D2KO embryos (E18.5) were about 54% of control littermates, but the expression of the T3-responsive genes Myh1 and 7 and Atp2a1 and 2 were not affected. In MYF5-D2KO and MYOD-D2KO neonatal hind-limb muscle, the expression of Myh1 and 7 and Atp2a2 remained unaffected, despite 60-70% loss in D2 activity and/or mRNA. Only in MYOD-D2KO neonatal muscle was there a 40% reduction in Atp2a1 mRNA. Postnatal growth of both mouse models and SKM function as assessed by exercise capacity and measurement of muscle strength were normal. Furthermore, an analysis of the adult soleus revealed no changes in the expression of T3-responsive genes, except for an about 18% increase in MYOD-D2KO SOL Myh7 mRNA., Conclusion: Two mouse models of early developmental disruption of Dio2 in myocyte precursor exhibit no significant SKM phenotype.

Key Points: In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a β-adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression. Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice., Abstract: Thyroid hormone promotes expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3'-triiodothyronine (T3 ), the active thyroid hormone. To test whether D2-generated T3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20 min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1 mg (100 g body weight)(-1) propranolol or 6 mg (100 g body weight)(-1) iopanoic acid (5.9- vs. 2.8-fold; P < 0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9- vs. 2.8-fold; P < 0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1 μm forskolin (2.2- vs. 1.3-fold; P < 0.05). Chronic exercise training (6 weeks) increased soleus muscle PGC-1a mRNA levels (∼25%) and the mitochondrial enzyme citrate synthase (∼20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by ∼30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a β-adrenergic receptor-dependent mechanism. The accelerated conversion of T4 to T3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Objective: Investigate the differences in cardiopulmonary (CP) capacity and Quality of Life (QOL) between healthy elderly (≥ 65 years) with different TSH levels (< 1.0 and ≥ 1.0 μIU/mL) both within the normal range. Also, evaluate the effects of TSH elevation on CP test and QOL, by administering methimazole to subjects with initial lower-normal TSH, in order to elevate it to superior-normal limit., Materials and Methods: Initially, a cross-sectional study was performed to compare CP capacity at peak exercise and QOL (using WHOQOL-OLD questionnaire) between healthy seniors (age ≥ 65 years) with TSH < 1.0 μIU/mL vs. TSH ≥1.0 μIU/mL. In the second phase, participants with TSH < 1.0 μIU/mL were included in a non-controlled-prospective-interventional study to investigate the effect of TSH elevation, using methimazole, on QOL and CP capacity at peak exercise., Results: From 89 elderly evaluated, 75 had TSH ≥ 1 μIU/mL and 14 TSH < 1 μIU/mL. The two groups had similar basal clinical characteristics. No difference in WHOQOL-OLD scores was observed between groups and they did not differ in terms of CP function at peak exercise. QOL and CP variables were not correlated with TSH levels. Twelve of 14 participants with TSH < 1.0 μIU/mL entered in the prospective study. After one year, no significant differences in clinical caracteristics, QOL, and CP variables were detected in paired analysis before and after methimazole intervention., Conclusions: We found no differences in CP capacity and QOL between health elderly with different TSH levels within normal range and no impact after one year of methimazole treatment. More prospective-controlled-randomized studies are necessary to confirm or not the possible harm effect in normal low TSH.

Growth hormone (GH) regulates whole body metabolism, and physical exercise is the most potent stimulus to induce its secretion in humans. The mechanisms underlying GH secretion after exercise remain to be defined. The aim of this study was to elucidate the role of estrogen and pituitary type 1 deiodinase (D1) activation on exercise-induced GH secretion. Ten days after bilateral ovariectomy, animals were submitted to 20 min of treadmill exercise at 75% of maximum aerobic capacity and tissues were harvested immediately or 30 min after exercise. Non-exercised animals were used as controls. A significant increase in D1 activity occurred immediately after exercise (~60%) in sham-operated animals and GH was higher (~6-fold) 30 min after exercise. Estrogen deficient rats exhibited basal levels of GH and D1 activity comparable to those found in control rats. However, after exercise both D1 activity and serum GH levels were blunted compared to sedentary rats. To understand the potential cause-effect of D1 activation in exercise-induced GH release, we pharmacologically blocked D1 activity by propylthiouracil (PTU) injection into intact rats and submitted them to the acute exercise session. D1 inhibition blocked exercise-induced GH secretion, although basal levels were unaltered. In conclusion, estrogen deficiency impairs the induction of thyroid hormone activating enzyme D1 in the pituitary, and GH release by acute exercise. Also, acute D1 activation is essential for exercise-induced GH response.

Unlabelled: The glucagon stimulation test (GST) is a reliable measure for assessing growth hormone (GH) and adrenocorticotropic hormone (ACTH) secretion. The GST is considered to be a safe test, with few mild side effects, especially in adults and in the elderly in whom underlying co-morbidities may be present., Objective: To describe the side effects of the GST in elderly people., Design and Setting: The study was performed with patients of the geriatric ambulatory of our hospital who were recruited to voluntarily participate in a research study concerning the GH and ACTH axis in the elderly people. Forty-two subjects (n=5 males and 37 females) aged 67-88 years, without hypothalamic-pituitary disease, were submitted to the GST. The GST was performed by intramuscular injection of 1mg of glucagon. Blood samples were collected at baseline, and 90, 120, 150, and 180 min after glucagon injection for GH and cortisol measurements., Results: During the test, 9 subjects (21.4%) had side effects, which included: nausea (14.2%), indisposition (11.9%), hypotension (9.5%), vomiting (7.1%), sweating (4.7%), and dizziness (2.3%). There were four cases of severe symptomatic hypotension, with inaudible blood pressure in two cases. In one case of severe hypotension, the subject suffered two episodes of generalized tonic seizures. Patients who had side effects at GST had statistically higher peak of cortisol (28.9 ± 6.67 μg/dL) and a statistical trend to higher GH peak (8.74 ± 5.96 μg/L). In the group of patients who did not have side effects, the mean cortisol and GH peak were 19.05 ± 5.36 μg/dL and 5.32 ± 3.52 μg/L, respectively., Conclusion: Although the GST is a reliable alternative test to the ITT, it should be cautiously used in the elderly because this population may have co-morbidities including vascular and cardiac diseases that could be potentiated with side effects of the test, such as severe hypotension., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Ovariectomy leads to significant increase in body weight, but the possible peripheral mechanisms involved in weight gain are still unknown. Since exercise and thyroid hormones modulate energy balance, we aimed to study the effect of swimming training on body weight gain and brown adipose tissue (BAT) type 2 iodothyronine deiodinase responses in ovariectomized (Ox) or sham-operated (Sh) rats. Rats were submitted to a period of 8-week training, 5 days per week with progressive higher duration of exercise protocol. Swimming training program did not totally prevent the higher body mass gain that follows ovariectomy in rats (16.5% decrease in body mass gain in Ox trained rats compared to 22% decrease in sham operated trained animals, in relation to the respective sedentary groups), but training of Ox animals impaired the accumulation of subcutaneous fat pads. Interestingly, swimming training upregulates pituitary type 1 (p<0.001 vs. all groups) and BAT type 2 iodothyronine deiodinases (p<0.05 vs. ShS and OxS) in sham operated but not in Ox rats, indicating an impaired pituitary and peripheral response to exercise in Ox rats. However, BAT mitochondrial O2 consumption significantly increased by swimming training in both sham and Ox groups, indicating that Ox BAT mitochondria responds normally to exercise stimulus, but does not result in a significant reduction of body weight. In conclusion, increased body mass gain produced by Ox is not completely impaired by 8 weeks of high intensity physical training, showing that these animals sustain higher rate of body mass gain independent of being submitted to higher energy expenditure., (© Georg Thieme Verlag KG Stuttgart · New York.)