Search

Nescient helix-loop-helix 2 (NHLH2) is a hypothalamic transcription factor that controls the expression of prohormone convertase 1/3, therefore having an impact on the processing of proopiomelanocortin and thus on energy homeostasis. Studies have shown that KO ofNhlh2results in increased body mass, reduced physical activity, and hypogonadism. In humans, a polymorphism of theNHLH2gene is associated with obesity; and in Prader–Willi syndrome, a condition characterized by obesity, hypogonadism and behavioral abnormalities, the expression of NHLH2 is reduced. Despite clinical and experimental evidence suggesting that NHLH2 could be a good target for the treatment of obesity, no previous study has evaluated the impact of NHLH2 overexpression in obesity. Here, in mice fed a high-fat diet introduced right after the arcuate nucleus intracerebroventricular injection of a lentivirus that promoted 40% increase in NHLH2, there was prevention of the development of obesity by a mechanism dependent on the reduction of caloric intake. When hypothalamic overexpression of NHLH2 was induced in previously obese mice, the beneficial impact on obesity-associated phenotype was even greater; thus, there was an 80% attenuation in body mass gain, reduced whole-body adiposity, increased brown adipose tissue temperature, reduced hypothalamic inflammation, and reduced liver steatosis. In this setting, the beneficial impact of hypothalamic overexpression of NHLH2 was a result of combined effects on caloric intake, energy expenditure, and physical activity. Moreover, the hypothalamic overexpression of NHLH2 reduced obesity-associated anxiety/depression behavior. Thus, we provide an experimental proof of concept supporting that hypothalamic NHLH2 is a good target for the treatment of obesity.SIGNIFICANCE STATEMENTObesity is a highly prevalent medical condition that lacks an effective treatment. The main advance provided by this study is the demonstration of the beneficial metabolic and behavioral outcomes resulting from the overexpression of NHLH2 in the hypothalamus. When NHLH2 was overexpressed simultaneously with the introduction of a high-fat diet, there was prevention of obesity by a mechanism dependent on reduced caloric intake. Conversely, when NHLH2 was overexpressed in previously obese mice, there was reduction of the obese phenotype because of a combination of reduced caloric intake, increased physical activity, and increased thermogenesis. In addition, the overexpression of NHLH2 reduced anxiety/depression-like behavior. Thus, NHLH2 emerges as a potential target for the combined treatment of obesity and its associated anxiety/depression-like behavior.

The search for strategies to develop resilience against metabolic and neuropsychiatric disorders has motivated the clinical and experimental assessment of early life interventions such as lifestyle-based and use of unconventional pharmacological compounds. In this study, we assessed the effects of voluntary physical activity and 7,8-Dihydroxy-4-methylcoumarin (DHMC), independently or in combination, over mice physiological and behavioral parameters, adult hippocampal and hypothalamic neurogenesis, and neurotrophic factors expression in the hypothalamus. C57Bl/6J mice were submitted to a 29-day treatment with DHMC and allowed free access to a running wheel. We found that DHMC treatment alone reduced fasting blood glucose levels. Moreover, physical activity showed an anxiolytic effect in the elevated plus maze task and DHMC produced additional anxiolytic behavior, evidenced by reduced activity during the light cycle in the physical activity group. Although we did not find any differences in hypothalamic or hippocampal adult neurogenesis, DHMC increased gene expression levels of VEGF, which was correlated to the reduced fasting glucose levels. In conclusion, our data emphasize the potential of physical activity in reducing development of neuropsychiatric conditions, such as anxiety, and highlights DHMC as an attractive compound to be investigated in future studies addressing neuropsychiatric disorders associated with metabolic conditions.

Obesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction. While the TLR4 activation by dietary fats is a well-characterized pathway involved in the neuronal and glial inflammation, the role of its accessory proteins in diet-induced hypothalamic inflammation remains unknown. Here, we demonstrate that the knockdown of TLR4-interactor with leucine-rich repeats (Tril), a functional component of TLR4, resulted in reduced hypothalamic inflammation, increased whole-body energy expenditure, improved the systemic glucose tolerance and protection from diet-induced obesity. The POMC-specific knockdown of Tril resulted in decreased body fat, decreased white adipose tissue inflammation and a trend toward increased leptin signaling in POMC neurons. Thus, Tril was identified as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental obesity and its inhibition in the hypothalamus may represent a novel target for obesity treatment.

DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.

Interleukin-17 (IL-17) is expressed in the intestine in response to changes in the gut microbiome landscape and plays an important role in intestinal and systemic inflammatory diseases. There is evidence that dietary factors can also modify the expression of intestinal IL-17. Here, we hypothesized that, similar to several other gut-produced factors, IL-17 may act in the hypothalamus to modulate food intake. We confirm that food intake increases IL-17 expression in the mouse ileum and human blood. There is no expression of IL-17 in the hypothalamus; however, IL-17 receptor A is expressed in both pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. Upon systemic injection, IL-17 promoted a rapid increase in hypothalamic POMC expression, which was followed by a late increase in the expression of AgRP. Both systemic and intracerebroventricular injections of IL-17 reduced calorie intake without affecting whole-body energy expenditure. Systemic but not intracerebroventricular injection of IL-17 increase brown adipose tissue temperature. Thus, IL-17 is a gut-produced factor that is controlled by diet and modulates food intake by acting in the hypothalamus. Our findings provide the first evidence of a cytokine that is acutely regulated by food intake and plays a role in the regulation of eating.

Obesity affects approximately 45–55% of persons with schizophrenia and is more difficult to manage in these individuals than in the general population, apart from being an additional factor for morbidity and premature mortality. Although bariatric surgery is considered the most effective long-term treatment for severe obesity, there are few reports on the outcomes of this procedure in persons with schizophrenia. This study aimed to evaluate weight loss and psychiatric symptoms in persons with obesity and schizophrenia after bariatric surgery. Five persons with schizophrenia and moderate to severe obesity who underwent bariatric surgery were followed up for 2 years. Anthropometric data were collected, and psychiatric symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS), which assessed the pre- and postoperative occurrence and severity of symptoms of schizophrenia. The mean body mass index before surgery was 43.5 ± 5.2 kg/m2 and decreased to 28.1 ± 1.9 kg/m2 1 year postoperatively. The mean percentage of total postoperative weight loss was 30.7 ± 6.8% after 6 months, 34.7 ± 7.9% after 1 year, and 34.3 ± 5.5% after 2 years. Before surgery, all subjects were in remission based on the PANSS. Postoperative evaluations showed that the participants had no relapse of psychiatric symptoms (p > 0.05 for the three PANSS dimensions throughout the follow-up period). There were no considerable changes in their medication regimens. These findings suggest that bariatric surgery may be a viable treatment option for stable patients with schizophrenia if they have a preoperative assessment and close management and involvement by mental health professionals throughout the course of treatment.

Genome-wide association studies (GWASs) have identified SNPs of the fat mass and obesity (FTO) gene as the most important risk alleles for obesity. However, how the presence of risk alleles affect phenotype is still a matter of intense investigation. In 2014, a study revealed that long-range enhancers from the intronic regions of the FTO gene regulate iroquois-class homeobox protein (IRX)3 expression. IRX3 is expressed in hypothalamic pro-opiomelanocortin (POMC) neurons and changes in its expression levels affect body adiposity by modifying food intake and energy expenditure. These findings have placed IRX3 as a potential target for the treatment of obesity. Here, we review studies that evaluated the roles of IRX3 in development, neurogenesis, and body energy homeostasis.

Worldwide, and especially in Western civilizations, most of the staple diets contain high amounts of fat and refined carbohydrates, leading to an increasing number of obese individuals. In addition to inducing metabolic disorders, energy dense food intake has been suggested to impair brain functions such as cognition and mood control. Here we demonstrate an impaired memory function already 3 days after the start of a high-fat diet (HFD) exposure, and depressive-like behavior, in the tail suspension test, after 5 days. These changes were followed by reduced synaptic density, changes in mitochondrial function and astrocyte activation in the hippocampus. Preceding or coinciding with the behavioral changes, we found an induction of the proinflammatory cytokines TNF-α and IL-6 and an increased permeability of the blood–brain barrier (BBB), in the hippocampus. Finally, in mice treated with a TNF-α inhibitor, the behavioral and BBB alterations caused by HFD-feeding were mitigated suggesting that inflammatory signaling was critical for the changes. In summary, our findings suggest that HFD rapidly triggers hippocampal dysfunction associated with BBB disruption and neuroinflammation, promoting a progressive breakdown of synaptic and metabolic function. In addition to elucidating the link between diet and cognitive function, our results might be relevant for the comprehension of the neurodegenerative process., Graphical Abstract An illustrative scheme summarizing the main outcomes in Swiss mice fed high-fat diet (HFD), with their exact time of onset of changes in the hippocampus. An increase in the expression of proinflammatory cytokines, together with the permeability of the blood–brain barrier was detected after 2 days of HFD. Even in the first week of dietary intervention, memory and learning impairment, depressive-like behavior, and synaptic changes were observed at 3, 5, and 7 days, respectively. Later hippocampal alterations (after 4 weeks of HFD consumption) include mitochondrial dysfunction and astrocytic activation.

Objetivos: A ativação da hemostasia é um elemento crítico da patogênese da Covid-19. Microvesículas (MVs) são partículas de bicamada lipídica liberadas de diferentes células e que medeiam a tromboinflamação. Ademais, MVs já se mostraram ser biomarcadores relevantes em outras doenças infecciosas, incluindo pneumonias virais. Dessa forma, os objetivos desse estudo foram quantificar as MVs circulantes originadas de plaquetas, células endoteliais e eritrócitos; avaliar sua atividade pró-coagulante dependente de fator tecidual (APC-FT) e explorar sua relação com marcadores hemostáticos e desfechos clínicos na Covid-19. Material e métodos: Amostras de pacientes com Covid-19 internados devido a necessidade de oxigenoterapia foram coletadas em até 24h do diagnóstico, como parte de um estudo clínico. As amostras usadas neste estudo foram obtidas antes de qualquer intervenção terapêutica. MVs foram extraídas de plasma livre de plaquetas por ultracentrifugação, quantificadas por citometria de fluxo e a APC-FT foi determinada por meio de ensaio coagulométrico de um estágio. Marcadores de ativação da hemostasia foram quantificados por métodos imunológicos ou funcionais conforme indicados. Resultados: Foram incluídos 30 pacientes e 30 indivíduos saudáveis pareados por idade e sexo. O tempo médio de internação (TI) foi de 2,9±9,8 dias, 12 pacientes (40%) necessitaram de cuidados intensivos (UTI) e 28/30 pacientes sobreviveram. As contagens totais de MVs de plaquetas e células endoteliais estavam aumentadas em pacientes comparado com controles, ao passo que entre as MVs com expressão de fator tecidual (FT), apenas as de origem endotelial estavam aumentadas. A APC-FT mostrou-se aumentada em pacientes quando comparado com controles (p = 0,0007). Não observamos associações significativas entre as contagens de MVs ou APC-FT com desfechos clínicos como tempo de internação e tempo de UTI. Em contraste, observamos correlações significativas envolvendo MVs e outros marcadores de ativação da hemostasia a saber tais como MVs (totais) derivadas de plaquetas com fibrinogênio, F VIII:C, FVW e uPAR solúvel, e MV (FT+) derivadas de células endotelial com FVIII:C e FVW. Discussão e conclusão: O entendimento dos mecanismos pelos quais a hemostasia é ativada na Covid-19 é fundamental para o desenvolvimento de estratégias terapêuticas mais eficazes contra esta e outras doenças infecciosas associadas a aumento de eventos tromboembólicos e imunotrombose. Nossos resultados mostram que a Covid-19 moderada e grave se associa a aumento da contagem de MVs, e que uma fração destas MVs se associa a ativação da hemostasia. Novos ensaios para avaliação funcional da APC-FT serão necessários para definir a associação destes parâmetros com desfechos de gravidade na Covid-19.

Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control, including energy expenditure1, food consumption2, glucose homeostasis2, etc. Here we demonstrated that Interleukin-6 (IL6) activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mice skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1-2 axis is closely associated with firing-rate-related genes in the hypothalamus and with fatty acid oxidation- and mitochondrial-related genes in skeletal muscle of genetically diverse BXD mice strains and humans. Using surgical denervation, pharmacological approaches, and transgenic mice, we showed that the hypothalamic IL6/ERK1/2 pathway requires the a2-adrenergic pathway to modify the fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuitry is required to underpin AMPK/ACC signaling activation and fatty acid oxidation post-exercise. Once the selective downregulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle post-exercise. Altogether, these data demonstrated that IL6/ERK axis in VMH controls fatty acid metabolism in mice skeletal muscle.

This study aimed to evaluate the effect of pioglitazone on brown adipose tissue function and hypothalamic gliosis in humans. Brown adipose tissue and the hypothalamus are regarded as important potential pharmacological targets to metabolic diseases, and defining the impact of current therapies on their structure and/or function could provide therapeutic advance in this field. Six patients with type 2 diabetes were treated for 24 weeks with pioglitazone 30 mg/day as an add-on therapy. Brown adipose tissue glucose uptake and volume were determined using 18F-FDG PET/CT scans; hypothalamic gliosis was determined using MRI scans; blood was collected for hormone and biochemistry measurements. All tests were performed at inclusion and six months after pioglitazone introduction. Pioglitazone treatment led to a significant 3% body mass increase. There were neither changes in cold-induced brown adipose tissue glucose uptake and volume nor changes in hypothalamic gliosis. This is a proof-of-concept study that provides clinical evidence for a lack of action of a thiazolidinedione, pioglitazone, to promote homogeneous and measurable changes in brown adipose tissue volume and also in hypothalamic gliosis after 6 months of treatment.

In experimental obesity, the hypothalamus is affected by an inflammatory response activated by dietary saturated fats. This inflammation is triggered as early as one day after exposure to a high-fat diet, and during its progression, there is recruitment of inflammatory cells from the systemic circulation. The objective of the present study was identifying chemokines potentially involved in the development of hypothalamic diet-induced inflammation. In order to identify chemokines potentially involved in this process, we performed a real-time PCR array that determined Ackr2 as one of the transcripts undergoing differential regulation in obese-prone as compared to obese-resistant mice fed a high-fat diet for three days. ACKR2 is a decoy receptor that acts as an inhibitor of the signals generated by several CC inflammatory chemokines. Our results show that Ackr2 expression is rapidly induced after exposure to dietary fats both in obese-prone and obese-resistant mice. In immunofluorescence studies, ACKR2 was detected in hypothalamic neurons expressing POMC and NPY and also in microglia and astrocytes. The lentiviral overexpression of ACKR2 in the hypothalamus reduced diet-induced hypothalamic inflammation; however, there was no change in spontaneous caloric intake and body mass. Nevertheless, the overexpression of ACKR2 resulted in improvement of glucose tolerance, which was accompanied by reduced insulin secretion and increased whole body insulin sensitivity. Thus, ACKR2 is a decoy chemokine receptor expressed in most hypothalamic cells that is modulated by dietary intervention and acts to reduce diet-induced inflammation, leading to improved glucose tolerance due to improved insulin action.

Obesity and aging lead to abnormal transforming growth factor-β1 (TGF-β1) signaling in the hypothalamus, triggering the imbalance on glucose metabolism and energy homeostasis. Here, we determine the effect of acute exercise on TGF-β1 expression in the hypothalamus of two models of obesity in mice. The bioinformatics analysis was performed to evaluate the correlation between hypothalamic Tgf-β1 messenger RNA (mRNA) and genes related to thermogenesis in the brown adipose tissue (BAT) by using a large panel of isogenic BXD mice. Thereafter, leptin-deficient (ob/ob) mice and obese C57BL/6 mice fed on a high-fat diet (HFD) were submitted to the acute exercise protocol. Transcriptomic analysis by using BXD mouse reference population database revealed that hypothalamic Tgf-β1 mRNA is negatively correlated with genes related to thermogenesis in brown adipose tissue of BXD mice, such as peroxisome proliferator-activated receptor gamma coactivator and is positively correlated with respiratory exchange ratio. In agreement with these results, leptin-deficient (ob/ob) and HFD-fed mice displayed high levels of Tgf-β1 mRNA in the hypothalamus and reduction of Pgc1α mRNA in BAT. Interestingly, an acute exercise session reduced TGF-β1 expression in the hypothalamus, increased Pgc1α mRNA in the BAT and reduced food consumption in obese mice. Our results demonstrated that acute physical exercise suppressed hypothalamic TGF-β1 expression, increasing Pgc1α mRNA in BAT in obese mice.

Background: Inflammation is the most relevant mechanism linking obesity with insulin-resistance and metabolic disease. It impacts the structure and function of tissues and organs involved in metabolism, such as the liver, pancreatic islets and the hypothalamus. Brown adipose tissue has emerged as an important component of whole body energy homeostasis, controlling caloric expenditure through the regulation of non-shivering thermogenesis. However, little is known about the impact of systemic inflammation on the structure and function of brown adipose tissue. Methods: The relations between IL10 and mitochondria structure/function and also with thermogenesis were evaluated by bioinformatics using human and rodent data. Real-time PCR, immunoblot, fluorescence and transmission electron microscopy were employed to determine the effect of IL10 in the brown adipose tissue of wild type and IL10 knockout mice. Findings: IL10 knockout mice, a model of systemic inflammation, present severe structural abnormalities of brown adipose tissue mitochondria, which are round-shaped with loss of cristae structure and increased fragmentation. IL10 deficiency leads to newborn cold intolerance and impaired UCP1-dependent brown adipose tissue mitochondrial respiration. The reduction of systemic inflammation with an anti-TNFα monoclonal antibody partially rescued the structural but not the functional abnormalities of brown adipose tissue mitochondria. Using bioinformatics analyses we show that in both humans and mice, IL10 transcripts correlate with mitochondrial lipid metabolism and caspase gene expression. Interpretation: IL10 and systemic inflammation play a central role in the regulation of brown adipose tissue by controlling mitochondrial structure and function. Fund: Sao Paulo Research Foundation grant 2013/07607-8. Keywords: Interleukin-10, Inflammation, Thermogenesis, Mitochondria, Respiration, Obesity

Background The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity. Methods Bioinformatics tools were used to evaluate the correlations between hypothalamic Irx3 and neurotransmitters, markers of thermogenesis and obesity related phenotypes. Droplet-sequencing analysis in >20,000 hypothalamic cells was used to explore the types of hypothalamic cells expressing Irx3. Lentivirus was used to inhibit hypothalamic Irx3 and the resulting phenotype was studied. Findings IRX3 is expressed predominantly in POMC neurons. Its expression is inhibited during prolonged fasting, as well as when mice are fed a high-fat diet. The partial inhibition of hypothalamic Irx3 using a lentivirus resulted in increased diet-induced body mass gain and adiposity due to increased caloric intake and reduced energy expenditure. Interpretation Contrary to the results obtained when lean mice are submitted to complete inhibition of Irx3, partial inhibition of hypothalamic Irx3 in obese mice causes an exacerbation of the obese phenotype. These data suggest that at least some of the Irx3 functions in the hypothalamus are regulated according to a hormetic pattern, and modulation of its expression can be a novel approach to modifying the body's energy-handling regulation. Fund Sao Paulo Research Foundation grants 2013/07607-8 (LAV) and 2017/02983-2 (JDJ); NIH grants R01DK083567 (YBK).

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Background Interleukin-6 (IL6) produced in the context of exercise acts in the hypothalamus reducing obesity-associated inflammation and restoring the control of food intake and energy expenditure. In the hippocampus, some of the beneficial actions of IL6 are attributed to its neurogenesis-inducing properties. However, in the hypothalamus, the putative neurogenic actions of IL6 have never been explored, and its potential to balance energy intake can be an approach to prevent or attenuate obesity. Methods Wild-type (WT) and IL6 knockout (KO) mice were employed to study the capacity of IL6 to induce neurogenesis. We used cell labeling with Bromodeoxyuridine (BrdU), immunofluorescence, and real-time PCR to determine the expression of markers of neurogenesis and neurotransmitters. We prepared hypothalamic neuroprogenitor cells from KO that were treated with IL6 in order to provide an ex vivo model to further characterizing the neurogenic actions of IL6 through differentiation assays. In addition, we analyzed single-cell RNA sequencing data and determined the expression of IL6 and IL6 receptor in specific cell types of the murine hypothalamus. Results IL6 expression in the hypothalamus is low and restricted to microglia and tanycytes, whereas IL6 receptor is expressed in microglia, ependymocytes, endothelial cells, and astrocytes. Exogenous IL6 reduces diet-induced obesity. In outbred mice, obesity-resistance is accompanied by increased expression of IL6 in the hypothalamus. IL6 induces neurogenesis-related gene expression in the hypothalamus and in neuroprogenitor cells, both from WT as well as from KO mice. Conclusion IL6 induces neurogenesis-related gene expression in the hypothalamus of WT mice. In KO mice, the neurogenic actions of IL6 are preserved; however, the appearance of new fully differentiated proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons is either delayed or disturbed.

Background Common variable immunodeficiency is the most prevalent symptomatic primary immunodeficiency in adults. Affected patients fail to mount an appropriate humoral response against community acquired infectious diseases and recent reports have provided data supporting the increased susceptibility of these patients to severe SARS-CoV-2 infections. In this context, the infusion of COVID-19 convalescent plasma could represent an effective therapeutic strategy. Case presentation 25-year old woman diagnosed with common variable immunodeficiency in 2013, developed severe COVID-19 that rapidly progressed to pneumonia presenting with multiple bilateral lung opacities that were both central and peripheral and presented as ground-glass and consolidation types involving all lobes, bilaterally. As blood oxygen saturation decayed and lung abnormalities were not responsive to large spectrum antibiotics and corticosteroids, patient was placed on mechanical ventilation and compassionate-use of approved COVID-19 convalescent donor plasma was introduced. The patient presented a rapid response to the approach and mechanical ventilation could be interrupted 24 h after first dose of COVID-19 convalescent donor plasma. As a whole, the patient received four doses of 200 mL convalescent plasma during a period of 6 days. There was rapid improvement of clinical status, with interruption of supplemental oxygen therapy after 6 days and reduction of lung abnormalities as evidence by sequential computed tomography scans. Conclusions This is a single patient report that adds to other few reports on common variable immunodeficiency and agammaglobulinemia, suggesting that COVID-19 convalescent donor plasma could be a valuable therapeutic approach to treat patients affected by dysgammaglobulinemias and presenting severe COVID-19.

As the worldwide vaccination, it is imperative to minimize vaccine wastage by effectively using all doses available. Vaccine wastage can occur at multiple points during the vaccination process, but it is mainly because the device dead space and the filling process technique. However, there are no studies discussing the waste volume effect of COVID-19 vaccines in clinical practice. There is an increasing COVID-19 vaccine demand that we estimate up to several billion dual doses. The objective of this study was to assess the number of 0.3mL doses obtained from a multiple-dose vial using 1ml and 3ml syringes with different type of needles replicating the first COVID-19 vaccination protocol.Our results suggest that it is possible to obtain six or seven doses from each vial instead five. We provide evidence to optimize between 20% and 40% additional vaccine doses per vial if the current 5-dose vials are used, making scarce supplies go further.It is our duty, as researchers, to ensure the efficacy and efficiency of the worldwide COVID-19 vaccination process. However, if standard syringes-needles and technique are used, there may not be sufficient volume to draw extra doses from a single vial.

Interoceptive signals from gut and adipose tissue and sensory cues from the environment are integrated by hubs in the brain to regulate feeding behavior and maintain homeostatic control of body weight. In vivo neural recordings have revealed that these signals control the activity of multiple layers of hunger neurons and eating is not only the result of feedback correction to a set point, but can also be under the influence of anticipatory regulations. A series of recent technical developments have revealed how peripheral and sensory signals, in particular, from the gut are conveyed to the brain to integrate neural circuits. Here, we describe the mechanisms involved in gastrointestinal stimulation by nutrients and how these signals act on the hindbrain to generate motivated behaviors. We also consider the organization of multidirectional intra- and extrahypothalamic circuits and how this has created a framework for understanding neural control of feeding.

Dear Editor,COVID-19 was first reported in December, 2019 in Wuhan, China, and rapidly spread across the globe 1. It has affected more than 6.4 million people and has led to the death of over 370 thousand as of June 2, 2020 (www.who.org). Severely affected patients present fever, dry cough, dyspnea, and fatigue, which are commonly associated with the development of pneumonia and acute respiratory distress syndrome (ARDS) 2. Advanced age, ischemic and congestive heart disease, hypertension, diabetes, and chronic obstructive pulmonary disease (COPD) are the most important independent predictors of death 2,3. As with other infectious diseases affecting the respiratory tract, asthma has been cited as a potential risk factor for severe COVID-194-6; however, no previous study has addressed this specific question.Here, we systematically reviewed all papers published on COVID-19 since its emergence in December 2019 to May 18, 2020, looking into the description of asthma as a premorbid condition and its putative association with severe progression of the disease.Two authors, NFM and CPJ, independently identified cross-sectional and longitudinal studies published before May 18, 2020, that reported on the prevalence of asthma as a premorbid condition of severe COVID-19 by systematically searching PubMed-NCBI database. We restricted the search for PubMed-NCBI because COVID-19 is a new medical condition and, currently, PubMed-NCBI covers more than 90% of MEDLINE providing a widely accessible biomedical resource 7. For database searches, language of the article was restricted to English. Search terms included the following: COVID-19 (COVID, COVID 19) ornCov or novel coronavirus or Sars-Cov-2 in the title and clinical characteristics or asthma anywhere in the text. Three authors, EM, EPA, and LAV, resolved eventual discrepancies by discussion and adjudication.We found 458 articles that met the initial inclusion search criteria (Supplementary Figure 1). All articles were assessed by authors and 290 were excluded (Supplementary Table 1) due to one or more of the following criteria: editorials; metanalyses; systematic reviews; commentaries; letters to the Editor; no description of patient’s clinical characteristics or premorbid conditions; and main text in a language other than English.The remaining 150 articles were included in the study. Supplementary Table 2 depicts the details of all articles analyzed. As a whole, the articles described the clinical aspects of 36,072 COVID-19 patients. One hundred and seven studies mentioned the existence of other respiratory premorbidities except for asthma. Asthma was mentioned as a premorbid condition in only eighteen studies (Table 1). There was a total of 8,690 patients included in the studies mentioning asthma, and 655 patients were previously diagnosed with asthma. In most of the studies describing other respiratory illnesses, COPD was the leading diagnosis.Based on the current medical records, we conclude that 7.5% of patients included in articles describing the clinical characteristics of COVID-19 patients and citing asthma were previously diagnosed with asthma. If all studies providing any clinical description of COVID-19 comorbidities are taken into consideration, asthma was present in only 1.8% of patients. These numbers are far less than expected considering the prevalence of asthma in the world. According to the World Asthma Report (http://www.globalasthmareport.org), there were as many as 339 million people living with asthma in the world in 2018, which corresponds to 4.4% of the world’s population.In conclusion, asthma does not seem to be an important premorbid condition in COVID-19 patients; or, conversely, it could be a protective factor, as previously proposed 8. The findings herein reported could be an epidemiological truth that should be further explored in mechanistic studies or could be due to the fact that researchers are not properly investigating and describing the premorbidities in COVID-19 patients. Whatever the reasons, the medical community should be aware of the implications of missing the diagnosis of a potentially severe respiratory disease such as asthma that could worsen the prognosis of COVID-19 patients.Acknowledgements. NFM was supported by The Sao Paulo Research Foundation (grant: 2016/17810-3), and CPJ was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) grant: 1744875 and 88882.434715/2019-01. EM, LAV and EPA are supported by grants from Sao Paulo Research Foundation (grants: 2013/07607-8 and 2020/) and Brazilian National Council of Scientific and Technological Development (CNPq).Ethics. The study does not require ethical approval because the systematic review is based on published research and the original data are anonymous.

Background The brown adipose tissue (BAT) is a potential target for the treatment of obesity and metabolic disorders. Its activation by cold exposure or adrenergic drugs can increase systemic insulin sensitivity and improve lipid metabolism; however, little is known about the effects of specific dietary components on BAT activity. Objectives We asked if a short-term (4 weeks) dietary intervention with olive oil could modify BAT activity in lean and overweight/obese volunteers. Design This was a 4-week open clinical trial in which all participants underwent a dietary intervention with extra-virgin olive oil supplementation. As the initial intake of olive oil was controlled all the participants were controls of themselves. Results The intervention resulted in significant increase in blood monounsaturated fatty acid levels, which was accompanied by increased BAT activity in lean but not in overweight/obese volunteers. In the lean group, an increase in leptin was detected after the intervention, and low leptin values at the beginning of the study were predictive of greater BAT activity after intervention. In addition, increase in leptin concentration was associated with increased BAT activity. Three known endogenous mediators of BAT activity, secretin, fibroblast growth factor 21 (FGF21), and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were increased by intervention in lean, whereas only secretin and FGF21 were increased in subjects with excessive weight. Conclusion This study provides clinical evidence for the impact of monounsaturated fatty acids on BAT activity and an advance in the understanding of the beneficial health effects of olive oil.

In a public dataset of transcripts differentially expressed in selected neuronal subpopulations of the arcuate nucleus, we identified TLR4-interactor with leucine-rich repeats (Tril) as a potential candidate for mediating the harmful effects of a high-fat diet in proopiomelanocortin (POMC) neurons. The non-cell-specific inhibition of Tril in the arcuate nucleus resulted in reduced hypothalamic inflammation, protection against diet-induced obesity associated with increased whole-body energy expenditure and increased systemic glucose tolerance. The inhibition of Tril, specifically in POMC neurons, resulted in a trend for protection against diet-induced obesity, increased energy expenditure and increased hypothalamic sensitivity to leptin. Thus, Tril emerges as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental diet-induced obesity.

Chronic HFD intake induces low-grade inflammation in the hypothalamus, which is characterized by proinflammatory cytokine overproduction. This process occurs, at least in part, via TLR4 activation by circulant saturated fatty acids. The TLR4 signaling in the brain is mediated by the TLR4 interactor with leucine-rich repeats (TRIL), an upstream accessory protein. Our main purpose was to determine the putative involvement of TRIL in diet-induced hypothalamic inflammation. We employed male, 8-12 week-old C57BL and POMCCRE mice fed on chow or HFD. The mRNA levels in the hypothalamus were measured by RT-PCR, western blot analyses was used for determination of protein content and immunofluorescence microscopy for evaluate the distribution of TRIL in arcuate nucleus (ARC) of hypothalamus and leptin signaling in POMC-expressing neurons. Finally, bilateral viral injections were performed to non-specific knockdown of TRIL in ARC using shRNA-based lentivirus and Cre-dependent AAV to knockdown TRIL specifically in POMC neurons. The non-specific knockdown of TRIL in the ARC of mice fed on HFD attenuated body weight gain despite no alterations in food intake, improved glucose homeostasis and increased energy expenditure. Moreover, nlrp3, il1β and hspa5 mRNA expression were decreased upon knockdown of TRIL. POMC-specific knockdown of TRIL reduced body fat with no changes in food intake or body weight gain in mice fed on HFD for 8 weeks. The inhibition of TRIL in POMC neurons resulted in a trend of improved leptin signaling in those neurons. We also found increased expression of thermogenic genes in the iBAT and improved fasting glucose. POMC-specific inhibition of TRIL in mice fed on HFD for long-term (24 weeks) did not prevent POMC loss or diminishes cleaved-caspase 3 in ARC. Collectively our results suggest that TRIL is involved in the TLR4-mediated early response to dietary fats and TRIL targeting counteract hypothalamic inflammation and partially restores metabolic homeostasis. Disclosure A. Moura-Assis: None. J. Junior: None. J.M. Gaspar: None. L. Velloso: None. P.S. Nogueira: None. Funding São Paulo Research Foundation (2016/01245-5)

Excessive fat consumption increases the level of fatty acids (FAs) in the blood, which reach the hypothalamus and damage the circuit related to energy balance. In the present study, we used palmitate in a primary culture of purified astrocytes to mimic the fat-rich environment found in obesity. Our results showed increased glial fibrillary acidic protein (GFAP) reactivity in hypothalamic astrocytes compared to cortical astrocytes. In addition, palmitate-treated astrocytes showed no significant changes in cytokine expression and an upregulation of glutathione in the culture medium that may serve as an intrinsic neuroprotective property against excess FA. Additionally, purified hypothalamic neurons were incubated with palmitate-treated astrocyte-conditioned medium (MPAL). MPAL treated-neurons exhibited a reduction in excitatory synapses and enhanced neuritogenesis. Our results suggest that hypothalamic astrocytes react to palmitate differently than cortical astrocytes and influence the behavior of the neural network related to energy balance. Our work brings a better understanding of the interactions among hypothalamic neurons in a high FA environment, similarly to obesity induced by a high-fat diet.

Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO). We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days. The expression of HIF-1alpha and HIF-1beta was measured by PCR and western blotting and its hypothalamic distribution was evaluated by fluorescence microscopy. Inhibition of HIF-1beta in arcuate nucleus of hypothalamus was performed using stereotaxic injection of shRNA lentiviral particles and animals were grouped under normal chow diet or high fat diet for 14 days. Using bioinformatics, we show that in humans, the levels of HIF-1 transcripts are directly correlated with those of hypothalamic transcripts for proteins involved in inflammation, regulation of apoptosis, autophagy, and the ubiquitin/proteasome system; furthermore, in rodents, hypothalamic HIF-1 expression is directly correlated with the phenotype of increased energy expenditure. In mice, DIO was accompanied by increased HIF-1 expression. The inhibition of hypothalamic HIF-1 by injection of an shRNA resulted in a further increase in body mass, a decreased basal metabolic rate, increased hypothalamic inflammation, and glucose intolerance. Thus, hypothalamic HIF-1 is increased during DIO, and its inhibition worsens the obesity-associated metabolic phenotype. Thus, hypothalamic HIF-1 emerges as a target for therapeutic intervention against obesity.

Hypothalamic sphingosine-1-phosphate receptor 1 (S1PR1), the G protein-coupled receptor 1 of sphingosine-1-phosphate, has been described as a modulator in the control of energy homeostasis in rodents. However, this mechanism is still unclear. Here, we evaluate the role of interleukin 6 (IL-6) associated with acute physical exercise in the control of the hypothalamic S1PR1-signal transducer and activator of transcription 3 (STAT3) axis. Acute exercise session and an intracerebroventricular IL-6 injection increased S1PR1 protein content and STAT3 phosphorylation in the hypothalamus of lean and obese mice accompanied by a reduction in food consumption. Transcriptome analysis indicated a strong positive correlation between Il-6 and S1pr1 messenger RNA in several tissues of genetically diverse BXD mice strains and humans, including in the hypothalamus. Interestingly, exercise failed to stimulate the S1PR1-STAT3 axis in IL-6 knockout mice and the disruption of hypothalamic-specific IL-6 action blocked the anorexigenic effects of exercise. Taken together, our results indicate that physical exercise modulates the S1PR1 protein content in the hypothalamus, through the central action of IL-6.

Background The consumption of large amounts of dietary fats activates an inflammatory response in the hypothalamus, damaging key neurons involved in the regulation of caloric intake and energy expenditure. It is currently unknown why the mediobasal hypothalamus is the main target of diet-induced brain inflammation. We hypothesized that dietary fats can damage the median eminence blood/spinal fluid interface. Methods Swiss mice were fed on a high-fat diet, and molecular and structural studies were performed employing real-time PCR, immunoblot, immunofluorescence, transmission electron microscopy, and metabolic measurements. Results The consumption of a high fat diet was sufficient to increase the expression of inflammatory cytokines and brain-derived neurotrophic factor in the median eminence, preceding changes in other circumventricular regions. In addition, it led to an early loss of the structural organization of the median eminence β1-tanycytes. This was accompanied by an increase in the hypothalamic expression of brain-derived neurotrophic factor. The immunoneutralization of brain-derived neurotrophic factor worsened diet-induced functional damage of the median eminence blood/spinal fluid interface, increased diet-induced hypothalamic inflammation, and increased body mass gain. Conclusions The median eminence/spinal fluid interface is affected at the functional and structural levels early after introduction of a high-fat diet. Brain-derived neurotrophic factor provides an early protection against damage, which is lost upon a persisting consumption of large amounts of dietary fats. Electronic supplementary material The online version of this article (10.1186/s12974-017-1046-8) contains supplementary material, which is available to authorized users.

This study hypothesized that polyphenol- and fiber-rich Brazilian fruits could elicit preventive effects in inflammatory bowel diseases (IBDs), even when applied to obese subjects. Therefore, the purpose was to investigate the implications of the consumption of acai pulp and jaboticaba peel on obese mice with dextran sodium sulfate (DSS)-induced colitis. First, obesity was induced by a high-fat diet for 13 weeks, followed by the inclusion of DSS in the water for five days. Animals received during the whole experiment a standard or high-fat diet, with the last one containing or not 5% (w/w) freeze-dried acai or jaboticaba. The diets added with the fruits had a higher content in total phenolic compounds (1.1 mg GAE/g) and an increased antioxidant capacity (up to 25.32 μmol TE/g). The high-fat diet promoted weight gain starting from the eighth week of the experiment. While jaboticaba delayed and reduced body weight gain, acai highly exacerbated it, also increasing the accumulation of fats. Colitis was successfully induced as seen by the clinical signs and damaged colonic mucosa. The high-fat diets did not increase the severity of colitis in comparison with the standard regimen, despite promoting additional weight gain. Animals that received acai or jaboticaba did not have many symptoms of colitis and showed a grand recovery in colonic histological parameters. Additionally, acai increased the expression of tight-junction-related molecules. Despite being included in a high-fat diet, the fruits still managed to promote healing effects in colitis, therefore indicating their potential for trials with IBD patients.

Pressure ulcers (PrUs)* are chronic wounds caused by a combination of factors, such as repetitive ischemia perfusion injury, bacterial colonization of the wound bed, local tissue hypoxia, or an altered cellular and systemic stress response. The objectives of this study were to analyze fragments of devitalized tissue of Stages III and IV PrUs and compare them with healthy tissue to evaluate the expression of the genes involved in wound inflammation. Samples of healthy skin from patients undergoing plastic surgery (n = 3) were collected, as well as from patients with devitalized tissue from Stages III and IV PrUs (n = 3) by means of sharp debridement. Gene expression analysis identified 5 up-regulated genes and 6 down-regulated genes in the devitalized tissue. Fibroblast cultures treated with devitalized tissue extract showed less attraction and cellular growth compared with the control group. Western blotting analysis showed a tendency of 3 particular genes to decrease in cell cultures treated with devitalized tissue extract. This study demonstrates that all of these mediators stimulate and promote inflammation in the wound bed and that a better understanding of the mechanisms of chronic wound development could lead to novel therapeutic strategies.

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. Electronic supplementary material The online version of this article (10.1186/s12974-017-0956-9) contains supplementary material, which is available to authorized users.

Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-β (TGF-β1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-β1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-β1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-β1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-β1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.

The activity of brown/beige adipose tissue (B/BAT) is inversely proportional to body adiposity. Studies have shown that obese subjects submitted to distinct approaches aimed at reducing body mass present an increase of B/BAT activation. However, it is unknown if this beneficial effect of body mass reduction applies to patients with type 2 diabetes mellitus. In this study, we evaluated the impact of massive body mass reduction obtained as a consequence of bariatric surgery in the cold-induced activation of B/BAT in obese non-diabetic (OND) and obese diabetic (OD) subjects. This is an observational study. Fourteen OND, 14 OD and 11 subjects were included in the study. All obese subjects were submitted to Roux-in-Y gastric bypass and measurements were performed before and 8 months after surgery. B/BAT was evaluated by (18F)-FDG-PET/CT scan and determination of signature transcript expression in specimens obtained in biopsies. Before surgery, mean B/BAT activity and the expression of signature transcripts were similar between OND and OD groups. Eight months after surgery, body mass reduction was similar between the obese groups. Nevertheless, the activity of B/BAT was increased in OND and unchanged in OD subjects. This effect was correlated with a more pronounced improvement of insulin resistance, as evaluated by the hyperinsulinemic, euglycemic clamp, in OND subjects as compared with OD subjects. Body mass reduction has a more efficient effect to induce the activation of B/BAT in non-diabetic than in diabetic subjects. This effect is accompanied by more pronounced insulin sensitivity and serine 473 phosphorylation of Akt in B/BAT of non-diabetic than in diabetic subjects.

Background The endoplasmic reticulum (ER) is responsible for the synthesis and processing of secretory and membrane proteins. In some cases, proteins cannot reach their final conformation and they remain unfolded in the ER lumen. The accumulation of unfolded proteins leads to a state of stress in the ER (ER stress) that is considered toxic to the cells. As a result, cells may respond by driving the proteins to degradation, pausing the transcription process, or even inducing apoptosis.1 ER stress has recently been linked to the exacerbation of the inflammatory process in the pathogenesis of Crohn’s disease (CD).2 Therefore, our aim was to evaluate the effect of a chemical inhibitor on the activation of ER stress pathways and its modulation of pro-inflammatory cytokines. Methods After approval of a local Ethics Committee, biopsies of intestinal mucosa were collected by colonoscopy from patients with CD (CD group) and from patients without inflammatory bowel diseases (control group). Explant culture was performed to evaluate the occurrence of ER stress and was treated with a chemical ER stress inhibitor. Non-parametric tests were performed for statistical analysis adopting p < 0.05 as significant value. Results Samples were collected from 10 patients with active CD (CDEIS ≥5) and six control patients. After cell culture, a significant difference was observed in the activation of the main ER stress pathway in the CD group when compared with control group. After treatment with a chemical inhibitor, there was significant decrease in the expression of genes responsible for the activation of ER stress. In addition, a decrease in the expression of inflammatory cytokines was observed after treatment. Conclusion The use of a chemical inhibitor has been shown to be effective in significantly decreasing the activation of ER stress and to modulate the inflammation in CD. The activation of the main ER stress pathways may contribute to the inflammatory process in CD, and its blockade suggests a potential new target in the treatment of CD. References

Energy homeostasis can be regulated by peripheral signals acting on the central nervous system, including the hypothalamus. The bile acid TUDCA has neuroprotective functions, reducing the major pathological markers of Alzheimer's diasease (AD) in animal models. However, its role in the hypothalamus of AD brains is still unclear. Here we reported that C57BL/6 mice submitted to intracerebroventricular injection of streptozotocin, experimental model of AD, and treated during 10 days with TUDCA presented reduced hypothalamic inflammation and hypothalamic mRNA levels of the orexigenic markers NPY and AgRP, resulting in decreased food intake and fat depots. Furthermore, this treatment also improved glucose tolerance and insulin sensitivity, as well as mice cognition. Our findings indicate that AD affect the hypothamalus, suggesting that hypothalamic dysfunction are directly involved with metabolic disorders observed in AD, and that the systemic administration of TUDCA attenuates these effects.

Background:Studies have shown significant benefits of exercise therapy in heart failure (HF) with a reduced ejection fraction (HFrEF) and HF with a preserved ejection fraction (HFpEF). The mechanisms responsible for the beneficial effect of exercise in HFrEF and HFpEF are still unclear. We hypothesized that the effect of exercise on myocardial remodeling may explain its beneficial effect.Methods:IMAGING-REHAB-HF is a single-center, randomized, controlled clinical trial using cardiac magnetic resonance imaging, vasomotor endothelial function, cardiac sympathetic activity imaging and serum biomarkers to compare the effect of exercise therapy in HFpEF (LVEF ≥ 45%) and HFrEF (LVEF < 45%). Subjects will be assessed at baseline and after 4 months. The exercise program will consist of three 60-min exercise sessions/week. The primary endpoints are the effect of exercise on myocardial extracellular volume (ECV), left ventricular (LV) systolic function, LV mass, LV mass-to-volume and LV cardiomyocyte volume. Secondary endpoints include the effect of exercise on vasomotor endothelial function, cardiac sympathetic activity and plasmatic biomarkers. Patients will be allocated in a 2:1 fashion to supervised exercise program or usual care. A total sample size of 90 patients, divided into two groups according to LVEF:HFpEF group (45 patients:30 in the intervention arm and 15 in the control arm) and HFrEF group (45 patients:30 in the intervention arm and 15 in the control arm) – will be necessary to achieve adequate power.Conclusion:This will be the first study to evaluate the benefits of a rehabilitation program on cardiac remodeling in HF patients. The unique design of our study may provide unique data to further elucidate the mechanisms involved in reverse cardiac remodeling after exercise in HFpEF and HFrEF patients.

The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this situation, fatty acids cause inflammation via TLR4 (toll like receptor 4) and the nuclei become less responsive to the hormones leptin and insulin, contributing to the development of obesity. In this work, these nuclei were analyzed in animals fed with high-fat diet and submitted to swimming without and with load for two months. For this, frontal sections of the hypothalamus were immunolabelled with GFAP (glial fibrillary acidic protein), synaptophysin, IL-6 (interleukin 6) and TLR4. Also, proteins extracted from the hypothalamus were analyzed using Western blotting (GFAP and synaptophysin), fluorometric analysis for caspases 3 and 7, and CBA (cytometric bead array) for Th1, Th2, and Th17 profiles. The high-fat diet significantly caused overweight and, in the hypothalamus, decreased synapses and increased astrocytic reactivity. The swimming with load, especially 80 % of the maximum load, reduced those consequences. The high-fat diet increased TLR4 in the arcuate nucleus and the swimming exercise with 80 % of the maximum load showed a tendency of reducing this expression. Swimming did not significantly influence the inflammatory or anti-inflammatory cytokines in the hypothalamus or in plasma. The high-fat diet in sedentary animals increased the expression of caspases 3 and 7 and swimming practice reduced this increment to levels compatible with animals fed on a normal diet. The set of results conclude that the impact of swimming on the damage caused in the hypothalamus by a high-fat diet is positive. The different aspects analyzed in here point to better cellular viability and conservation of the synapses in the hypothalamic nuclei of overweight animals that practiced swimming with a load.

In outbred mice, susceptibility or resistance to diet-induced obesity is associated with rapid changes in hypothalamic proopiomelanocortin (POMC) levels. Here, we evaluated 3 hypotheses that potentially explain the development of the different obesity phenotypes in outbred Swiss mice. First, rapid and differential changes in the gut microbiota in obesity-prone (OP) and obesity-resistant (OR) mice fed on a high-fat diet (HFD) might cause differential efficiencies in fatty acid harvesting leading to changes in systemic fatty acid concentrations that in turn affect POMC expression and processing. Second, independently of the gut microbiota, OP mice might have increased blood fatty acid levels after the introduction of a HFD, which could affect POMC expression and processing. Third, fatty acids might act directly in the hypothalamus to differentially regulate POMC expression and/or processing in OP and OR mice. We evaluated OP and OR male Swiss mice using 16S rRNA sequencing for the determination of gut microbiota; gas chromatography for blood lipid determination; and immunoblot and real-time polymerase chain reaction for protein and transcript determination and indirect calorimetry. Some experiments were performed with human pluripotent stem cells differentiated into hypothalamic neurons. We did not find evidence supporting the first 2 hypotheses. However, we found that in OP but not in OR mice, palmitate induces a rapid increase in hypothalamic POMC, which is followed by increased expression of proprotein convertase subtilisin/kexin type 1 PC1/3. Lentiviral inhibition of hypothalamic PC1/3 increased caloric intake and body mass in both OP and OR mice. In human stem cell-derived hypothalamic cells, we found that palmitate potently suppressed the production of POMC-derived peptides. Palmitate directly regulates PC1/3 in OP mice and likely has a functional impact on POMC processing.

BACKGROUND/OBJECTIVES: Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). SUBJECTS/METHODS: Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. RESULTS: Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. CONCLUSION: T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss.

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent disorders in the elderly population. Studies suggest that people with T2DM have higher risk of developing AD. Likewise, AD brains presents Insulin resistance resulting in low capacity of glucose uptake. There is a growing evidence that insulin resistance and downstream abnormalities in the insulin signaling pathway are present in the AD brain and contribute to the development of cognitive dysfunction. Here we reported that C57BL/6 mice submitted to intracerebroventricular injection of streptozotocin, model of AD, and treated during 10 days with the bile acid TUDCA presented reduced accumulation of Aβ oligomer in the hippocampus and higher insulin secretion and glucose tolerance, besides improvement in memory test, suggesting that TUDCA treatment interferes with glucose-insulin homeostasis in brain and consequently attenuates AD.

Background Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract. Usually, the clinical management are based on sulphasalazine, corticosteroid, immunomodulators, biologics therapy and bioactive small molecules. However, new therapeutic strategies involving the inflammatory process are being proposed as the use of pro-resolution lipid mediators. This study aimed to investigate the potential therapeutical role of Resolvin D2 (RvD2) in the intestinal mucosa of CD patients and its therapeutic potential. Methods The study included 16 CD patients, 8 patients in remission (CDR) and 8 with active disease (CDA) and 6 healthy subjects in the control group (CTR); all were followed up in tertiary referral hospital. Blood sample and colonic biopsies were collected during colonoscopy. Disease activity was determined by the Crohn’s Disease Endoscopic Index of Severity (CDEIS). The serum blood level of RvD2 was determined by enzymatic immunosorption assay (ELISA). Intestinal biopsies were submitted to cell culture and treated with Infliximab (IFX) or RvD2. The expression of inflammatory cytokines was evaluated by real-time PCR and RvD2 levels through the ELISA. A nonparametric test was used for statistical analysis, with adopted p Results The intestinal mucosa of the CDA group showed higher levels of pro-inflammatory markers, such as, IL1β (p=0.008 and p=0.01), IL6 (p=0.002), IL23 (p=0.03) and S100A8 (p=0.004 and p=0.01), compared to CTR and CDR groups, respectively. Although serum RvD2 levels of CDA (p=0.002) and CDR (p=0.004) groups were increased when compared to the CTR group, there is no differences between CDA and CDR groups (p>0.05). However, intestinal explants of the CDA group treated with RvD2 showed a significantly decrease of IL1β expression (p Conclusion The results suggest the participation of RvD2 in the modulation of colonic inflammation associated with CD. RvD2 showed to be as effective as IFX in attenuating the pro-inflammatory response present in the intestinal mucosa of patients with CD and provide insights into pro-resolution lipid mediators approaches to modulate chronic inflammation.

Alzheimer's disease (AD) is a neurodegenerative disorder and the major cause of dementia. According to predictions of the World Health Organization, more than 150 million people worldwide will suffer from dementia by 2050. An increasing number of studies have associated AD with type 2 diabetes mellitus (T2DM), since most of the features found in T2DM are also observed in AD, such as insulin resistance and glucose intolerance. In this sense, some bile acids have emerged as new therapeutic targets to treat AD and metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA), reduces amyloid oligomer accumulation and improves cognition in APP/PS1 mice model of AD, and also improves glucose-insulin homeostasis in obese and type 2 diabetic mice. Herein, we investigated the effect of TUDCA upon glucose metabolism in streptozotocin-induced AD mice model (Stz). The Stz mice that received 300 mg/kg TUDCA during 10 days (Stz + TUDCA), showed improvement in glucose tolerance and insulin sensitivity, reduced fasted and fed glycemia, increased islet mass and β-cell area, as well as increased glucose-stimulated insulin secretion, compared with Stz mice that received only PBS. Stz + TUDCA mice also displayed lower neuroinflammation, reduced protein content of amyloid oligomer in the hippocampus, improved memory test and increased protein content of insulin receptor β-subunit in the hippocampus. In conclusion, TUDCA treatment enhanced glucose homeostasis in the streptozotocin-induced Alzheimer's disease mice model, pointing this bile acid as a good strategy to counteract glucose homeostasis disturbance in AD pathology.

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.

Selected subpopulations of hypothalamic neurons play important roles in the regulation of whole body energy homeostasis. Studies have shown that the saturated fats present in large amounts in western diets can activate an inflammatory response in the hypothalamus, affecting the capacity of such neurons to respond appropriately to satiety and adipostatic signals. In the first part of this review, we will explore the mechanisms behind saturated fatty acid-induced hypothalamic dysfunction. Next, we will present and discuss recent studies that have identified the mechanisms that mediate some of the anti-inflammatory actions of unsaturated fatty acids in the hypothalamus and the potential for exploring these mechanisms to prevent or treat obesity.

OBJECTIVE In adults, hypothalamic gliosis has been documented using quantitative T2 neuroimaging, whereas functional magnetic resonance imaging (fMRI) has shown a defective hypothalamic response to nutrients. No studies have yet evaluated these hypothalamic abnormalities in children with obesity. METHODS Children with obesity and lean controls underwent quantitative MRI measuring T2 relaxation time, along with continuous hypothalamic fMRI acquisition to evaluate early response to glucose ingestion. RESULTS Children with obesity (N = 11) had longer T2 relaxation times, consistent with gliosis, in the mediobasal hypothalamus (MBH) compared to controls (N = 9; P = 0.004). Moreover, there was a highly significant group*region interaction (P = 0.002), demonstrating that signs of gliosis were specific to MBH and not to reference regions. Longer T2 relaxation times correlated with measures of higher adiposity, including visceral fat percentage (P = 0.01). Mean glucose-induced hypothalamic blood oxygen-level dependent signal change did not differ between groups (P = 0.11). However, mean left MBH T2 relaxation time negatively correlated with glucose-induced hypothalamic signal change (P

Summary: Obesity has been associated with cognitive decline, atrophy of brain regions related to learning and memory, and higher risk of developing dementia. However, the molecular mechanisms underlying these neurological alterations are still largely unknown. Here, we investigate the effects of palmitate, a saturated fatty acid present at high amounts in fat-rich diets, in the brain. Palmitate is increased in the cerebrospinal fluid (CSF) of overweight and obese patients with amnestic mild cognitive impairment. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Palmitate induces astroglial and microglial activation in the mouse hippocampus, and its deleterious impact is mediated by microglia-derived tumor necrosis factor alpha (TNF-α) signaling. Our results establish that obesity is associated with increases in CSF palmitate. By defining a pro-inflammatory mechanism by which abnormal levels of palmitate in the brain impair memory, the results further suggest that anti-inflammatory strategies may attenuate memory impairment in obesity. : Obesity has been associated with cognitive decline. Melo et al. show that palmitate levels are increased in the CSF of overweight and obese humans. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Microglial-derived TNF-α mediates the deleterious actions of palmitate in the brain. Keywords: palmitate, memory impairment, obesity, brain inflammation, microglia, TNF-α, insulin signaling

Background Laboratory reports on adipose tissue suggest that fat grafting to the breast may pose an oncologic risk. One possible reason for this is the theoretic chronic inflammation due to adipokynes released by grafted white adipose tissue (WAT). Objectives The aim of this study was to analyze inflammatory activity in lipofilled breast through the use of proinflammatory markers. Methods Fifty-four paired-breasts of female rats were divided into 4 groups: control, sham, and breasts grafted with either autologous subcutaneous (SC) WAT or autologous omentum (OM). The WAT was prepared through centrifugation, and the grafting was performed with the use of 0.9-mm blunt-tip cannula. The rats were killed 8 weeks postoperatively, and their breasts were harvested for immunohistochemical staining for CD68-expressing macrophages, gene expression (real-time PCR) for monocyte chemoattractant protein 1 (MCP-1), F4/80, Cox-2, and IL-6. Results The weights of the rats that underwent a procedure differed from those of the unmanipulated control group (P < 0.01). The macrophage counts of CD68 differed only between breasts lipofilled with OM and control (P < 0.01). MCP-1, F4/80, and Cox-2 were similarly expressed among the groups (P = 0.422, P = 0.143, and P = 0.209, respectively). The expression of IL-6 differed between breast samples grafted with SC and OM WAT (P = 0.015), but not between samples of control and OM (P = 0.752), and control and SC (P = 0.056). Conclusions No inflammation activity was identified in the microenvironment of lipofilled breasts, indicating that chronic inflammation does not seem to be triggered by the breast lipofilling procedure.