Palmitate Compromises C6 Astrocytic Cell Viability and Mitochondrial Function.

Consumption of high-fat diets (HFD) is associated with brain alterations, including changes in feeding behavior, cognitive decline, and dementia. Astrocytes play a role in HFD-induced neuroinflammation and brain dysfunction; however, this process is not entirely understood. We hypothesized that exposure to saturated fatty acids can compromise astrocyte viability and mitochondrial function. The C6 (astrocytes) cell line was treated with palmitate or stearate (200 µM and 400 µM) for 6 h. Cell viability, morphology, inflammatory markers, and oxidative stress were evaluated. To assess mitochondrial function, various parameters were measured (membrane potential, mass, respiration, and complex activities). We observed that 6 h of treatment with 400 µM palmitate decreased cell viability, and treatment with 200 µM palmitate changed the astrocyte morphology. Palmitate increased inflammatory markers (TNF-α and IL6) but did not induce oxidative stress. Palmitate significantly decreased the mitochondrial membrane potential and mitochondrial mass. Complex I activity also decreased in palmitate-treated cells; however, no changes were observed in mitochondrial respiration. In conclusion, palmitate, a saturated fatty acid, induces inflammation and impairs mitochondrial function, leading to reduced astrocytic cell viability and changes in cellular morphology. Our study provides valuable insights into the potential mechanisms underlying the relationship between saturated fatty acids, astrocytes, and mitochondrial function in obesity-related brain dysfunction.

Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis.

This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia.

Obesity-Induced Brain Neuroinflammatory and Mitochondrial Changes.

Obesity is defined as abnormal and excessive fat accumulation, and it is a risk factor for developing metabolic and neurodegenerative diseases and cognitive deficits. Obesity is caused by an imbalance in energy homeostasis resulting from increased caloric intake associated with a sedentary lifestyle. However, the entire physiopathology linking obesity with neurodegeneration and cognitive decline has not yet been elucidated. During the progression of obesity, adipose tissue undergoes immune, metabolic, and functional changes that induce chronic low-grade inflammation. It has been proposed that inflammatory processes may participate in both the peripheral disorders and brain disorders associated with obesity, including the development of cognitive deficits. In addition, mitochondrial dysfunction is related to inflammation and oxidative stress, causing cellular oxidative damage. Preclinical and clinical studies of obesity and metabolic disorders have demonstrated mitochondrial brain dysfunction. Since neuronal cells have a high energy demand and mitochondria play an important role in maintaining a constant energy supply, impairments in mitochondrial activity lead to neuronal damage and dysfunction and, consequently, to neurotoxicity. In this review, we highlight the effect of obesity and high-fat diet consumption on brain neuroinflammation and mitochondrial changes as a link between metabolic dysfunction and cognitive decline.

The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin.

GPR139 is an orphan G-protein-coupled receptor that is expressed in restricted areas of the nervous system, including the hypothalamus. In this study, we hypothesized that GPR139 could be involved in the regulation of energy balance and metabolism. In the first part of the study, we confirmed that GPR139 is expressed in the hypothalamus and particularly in proopiomelanocortin and agouti-related peptide neurons of the mediobasal hypothalamus. Using a lentivirus with a short-hairpin RNA, we inhibited the expression of GPR139 bilaterally in the mediobasal hypothalamus of mice. The intervention promoted a 40% reduction in the hypothalamic expression of GPR139, which was accompanied by an increase in body mass, a reduction in fasting blood glucose levels, and an increase in insulin levels. In the hypothalamus, inhibition of GPR139 was accompanied by a reduction in the expression of orexin. As previous studies using a pharmacological antagonist of orexin showed a beneficial impact on type 2 diabetes and glucose metabolism, we propose that the inhibition of hypothalamic GPR139 could be acting indirectly through the orexin system to control systemic glucose and insulin. In conclusion, this study advances the characterization of GPR139 in the hypothalamus, demonstrating its involvement in the regulation of body mass, blood insulin, and glycemia.

The orphan receptor GPR68 is expressed in the hypothalamus and is involved in the regulation of feeding.

Currently, up to 35% off all drugs approved for the treatment of human diseases belong to the G-protein-coupled receptor (GPCR) family. Out of the almost 800 existing GPCRs, 25% have no known endogenous ligands and are regarded as orphan receptors; many of these are currently under investigation as potential pharmacological targets. Here, we hypothesised that orphan GPCRs expressed in the hypothalamus could be targets for the treatment of obesity and other metabolic diseases. Using bioinformatic tools, we identified 78 class A orphan GPCRs that are expressed in the hypothalamus of mice. Initially, we selected two candidates and determined their responsivities to nutritional interventions: GPR162, the GPCR with highest expression in the hypothalamus, and GPR68, a GPCR with intermediate expression in the hypothalamus and that has never been explored for its potential involvement in metabolic regulation. GPR162 expression was not modified by fasting/feeding or by the consumption of a high-fat diet, and was therefore not subsequently evaluated. Conversely, GPR68 expression increased in response to the consumption of a high-fat diet and reduced under fasting conditions. Using immunofluorescence, GPR68 was identified in both proopiomelanocortin-expressing and agouti-related peptide-expressing neurons in the hypothalamic arcuate nucleus. Acute inhibition of GPR68 with an allosteric modulator promoted an increase in the expression of the orexigenic agouti-related peptide and neuropeptide Y, whereas 4- and 12-h inhibition of GPR68 resulted in increased caloric intake. Thus, GPR68 has emerged as an orphan GPCR that is expressed in the hypothalamus and is involved in the regulation of feeding.

1α,25-(OH)2 vitamin D3 prevents insulin resistance and regulates coordinated exocytosis and insulin secretion.

Vitamin D3 is associated with improvements in insulin resistance and glycemia. In this study, we investigated the short-term effect of 1α,25(OH)2 Vitamin D3 (1,25-D3) and cholecalciferol (vitamin D3) on the glycemia and insulin sensitivity of control and dexamethasone-induced insulin-resistance rats. 45Ca2+ influx responses to 1,25-D3 and its role in insulin secretion were investigated in isolated pancreatic islets from control rats. In vivo, 5 d treatment with 1,25-D3 (i.p.) prevented insulin resistance in dexamethasone-treated rats. Treatment with 1,25-D3 improved the activities of hepatic enzymes, serum lipids and calcium concentrations in insulin-resistant rats. 25-D3 (o.g.) does not affect insulin resistance. In pancreatic islets, 1,25-D3 increased insulin secretion and stimulated rapid response 45Ca2+ influx. The stimulatory effect of 1,25-D3 on 45Ca2+ influx was decreased by diazoxide, apamine, thapsigargin, dantrolene, 2-APB, nifedipine, TEA, PKA, PKC, and cytoskeleton inhibitor, while it was increased by glibenclamide and N-ethylmaleimide. The stimulatory effect of 1,25-D3 on 45Ca2+ influx involves the activation of L-type VDCC, K+-ATP, K+-Ca2+, and Kv channels, which augment cytosolic calcium. These ionic changes mobilize calcium from stores and downstream activation of PKC, PKA tethering vesicle traffic and fusion at the plasma membrane for insulin secretion. This is the first study highlighting the unprecedented role of 1,25-D3 (short-term effect) in the regulation of glucose homeostasis and on prevention of insulin resistance. Furthermore, this study shows the intracellular ß-cell signal transduction of 1,25-D3 through the modulation of pivotal ionic channels and proteins exhibiting a coordinated exocytosis of vesicles for insulin secretion.

Exercise improves the social and behavioral skills of children and adolescent with autism spectrum disorders.

Background: Currently, there is no standard treatment for Autism Spectrum Disorders (ASD), but there are many ways to minimize the symptoms and maximize abilities. Some studies suggest that exercise and other physical activities with children with ASD may be beneficial. In this study, we hypothesized that a physical exercise program (48-week exercise-intervention) could improve symptomatology dyad among children and adolescents with ASD. Our main aim was to examine the effects of physical activity on the primary clinical symptoms and associated comorbidities in children and adolescents with ASD. Methods: We allocated 229 children with ASD, ranging in age from 2.3-17.3 years (M = 7.8, SD = 3.2), into three groups: (a) exercise- intervention group, (b) control group from the same institution, and (c) control group from another institution. The exercise program was performed at moderate intensity in a 30 min section twice a week for 48 weeks. We used Bayesian multilevel regression modeling to examine participant outcomes and responses to the exercise-intervention. Results: Our results showed that a 48-week exercise-intervention substantially decreased ASD social interaction problems, attention deficit, emotional reactivity, stereotypical verbal and motor behavior, and sleep disturbances. However, physical exercise did not affect eye contact and food selectivity. We also observed that ASD severity and socioeconomic status influence eye contact, attention deficit, and sleep disturbance responses. Conclusion: In conclusion, children and adolescents with ASD exposed to a 48-week physical exercise-intervention program had important improvements in ASD symptoms. This study highlights that structured exercise programs can be a powerful complementary therapy for the ASD population.

Hippocampal Function Is Impaired by a Short-Term High-Fat Diet in Mice: Increased Blood-Brain Barrier Permeability and Neuroinflammation as Triggering Events.

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.

TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation.

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.

Neuroinflammation in autism spectrum disorders: Exercise as a "pharmacological" tool.

The worldwide prevalence of ASD is around 1%. Although the pathogenesis of ASD is not entirely understood, it is recognized that a combination of genetic, epigenetics, environmental factors and immune system dysfunction can play an essential role in its development. It has been suggested that autism results from the central nervous system derangements due to low-grade chronic inflammatory reactions associated with the immune system activation. ASD individuals have increased microglial activation, density, and increased proinflammatory cytokines in the several brain regions. Autism has no available pharmacological treatments, however there are pedagogical and psychotherapeutic therapies, and pharmacological treatment, that help to control behavioral symptoms. Recent data indicate that exercise intervention programs may improve cognitive and behavioral symptoms in children with ASD. Exercise can also modify inflammatory profiles that will ameliorate associated metabolic disorders. This review highlights the involvement of neuroinflammation in ASD and the beneficial effects of physical exercise on managing ASD symptoms and associated comorbidities.

Laparoscopic treatment of a gastro-gastric fistula after Roux-en-Y gastric bypass-report of two cases.

The most frequently performed bariatric surgery is the laparoscopic Roux-en-Y gastric bypass (LRYGB). An uncommon complication of LRYGB is gastro-gastric fistula (GGF). Possible causes of GGF include incomplete transection of the stomach during the initial surgery, staple-line leaks in the post-operative period and marginal ulcers. The optimal management of GGF is still under debate, with medical, endoscopic and surgical treatment modalities available. The authors present two cases of a GGF successfully managed with a laparoscopic surgical approach, after failed medical and endoscopic treatment.

Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes.

Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB1R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB1R agonists, WIN55212-2 (500 nM) and the CB1R-selective agonist, ACEA (3 µM) while it was exacerbated by the CB1R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB1Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKß levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB1R density within a month after T1D induction resolves previous controversial reports on forebrain CB1R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.

Abdominal Actinomycosis misdiagnosed as liposarcoma

Actinomycosis is an uncommon, endogenous, and chronic infection with varied and nonspecific clinical features such as abdominal, pelvic or cervical masses, ulcerative lesions, abscesses, draining fistula, fibrosis, and constitutional symptoms. The disease ensues when the bacteria disrupt the mucosal barrier, invade, and spread throughout interfascial planes. Currently, the diagnosis of actinomycosis is challenging because of its very low frequency and depending on the clinical presentation it may masquerade malignancies. Therapy consists initially in intravenous penicillin, followed by an oral regimen that may be extended until a year of treatment. A timely diagnosis is crucial to avoid extensive therapeutic attempt as surgery. However, a biopsy or drainage of abscesses and fistula's tract may be required not only as a diagnostic procedure as part of the therapy. We report the case of a 72-year-old woman with an abdominal mass initially misdiagnosed as a liposarcoma. A second biopsy of a skin lesion of the abdominal wall made the diagnosis of actinomycosis, avoiding a major surgical procedure. The patient was treated with a long-term course of antibiotics with favorable outcome. Liposarcoma was ruled out after the patient's full recovery with antibiotics and the misdiagnosis was credit to the overconfidence on the immunohistochemical positivity to MDM2.

Abdominal Actinomycosis misdiagnosed as liposarcoma.

Actinomycosis is an uncommon, endogenous, and chronic infection with varied and nonspecific clinical features such as abdominal, pelvic or cervical masses, ulcerative lesions, abscesses, draining fistula, fibrosis, and constitutional symptoms. The disease ensues when the bacteria disrupt the mucosal barrier, invade, and spread throughout interfascial planes. Currently, the diagnosis of actinomycosis is challenging because of its very low frequency and depending on the clinical presentation it may masquerade malignancies. Therapy consists initially in intravenous penicillin, followed by an oral regimen that may be extended until a year of treatment. A timely diagnosis is crucial to avoid extensive therapeutic attempt as surgery. However, a biopsy or drainage of abscesses and fistula's tract may be required not only as a diagnostic procedure as part of the therapy. We report the case of a 72-year-old woman with an abdominal mass initially misdiagnosed as a liposarcoma. A second biopsy of a skin lesion of the abdominal wall made the diagnosis of actinomycosis, avoiding a major surgical procedure. The patient was treated with a long-term course of antibiotics with favorable outcome. Liposarcoma was ruled out after the patient's full recovery with antibiotics and the misdiagnosis was credit to the overconfidence on the immunohistochemical positivity to MDM2.

Growth and weight status of Brazilian children with autism spectrum disorders: A mixed longitudinal study / Crescimento e massa corporal em crianças brasileiras com transtornos do espectro autista: um estudo longitudinal misto

ABSTRACT Objective: This study examined the growth status and physical development of Brazilian children with autism spectrum disorders from 4 to 15 years of age. Furthermore, it was examined whether variation in growth patterns and weight status was influenced by the use of psychotropic medications. Methods: One-hundred and twenty children aged 3.6-12.1 years at baseline (average = 7.2 years, SD = 2.3 years) diagnosed with autism spectrum disorders were measured on three repeated occasions across a 4-year period. Stature, body mass, and body mass index were considered. Bayesian multilevel modeling was used to describe the individual growth patterns. Results: Growth in stature was comparable to the age-specific 50th percentile for Centers for Disease Control and Prevention reference data until approximately 8 years, but a substantial decrease in growth rate was observed thereafter, reaching the age-specific 5th percentile at 15 years of age. Both body mass and body mass index values were, on average, higher than both the Brazilian and Centers for Disease Control and Prevention age-specific 95th percentile reference until 8 years, but below the 50th specific-age percentile at the age of 15 years. Conclusions: Brazilian boys with autism spectrum disorders between 4 and 15 years appear to have impaired growth in stature after 8-9 years of age, likely impacting pubertal growth. A high prevalence of overweight and obesity was observed in early childhood, although a trend of substantial decrease in body mass and body mass index was apparent when children with autism spectrum disorders entered the years of pubertal development.

RESUMO Objetivo: Este estudo examinou o estado de crescimento e o desenvolvimento físico de crianças brasileiras com transtornos do espectro autista entre 4 e 15 anos. Adicionalmente, examinamos se a variação nos padrões de crescimento e na massa corporal foi influenciada pelo uso de medicamentos psicotrópicos. Métodos: 120 crianças com idades entre 3,6 e 12,1 anos no início do estudo (média = 7,2 anos, DP = 2,3 anos) diagnosticadas com transtornos do espectro autista foram avaliadas em três ocasiões repetidas em um período de 4 anos. Foram considerados estatura, massa corporal e índice de massa corporal. O modelo multinível bayesiano foi utilizado para descrever os padrões de crescimento individual. Resultados: O crescimento em estatura foi comparável ao percentil 50 específico para a idade para os dados de referência do Centro de Controle e Prevenção de Doenças dos Estados Unidos até cerca de 8 anos. Porém, foi observada uma redução substancial na taxa de crescimento depois dos 8 anos, atingindo o percentil 5 específico para a idade aos 15 anos de idade. Tanto os valores de massa corporal quanto de índice de massa corporal foram, em média, maiores comparativamente ao percentil 95 específico para a idade até aos 8 anos da referência brasileira e do Centro de Controle e Prevenção de Doenças dos Estados Unidos, porém abaixo do percentil 50 específico para a idade aos 15 anos de idade. Conclusões: Os meninos brasileiros com transtornos do espectro autista entre 4 e 15 anos parecem ter retardo do crescimento na estatura após os 8-9 anos, provavelmente afeta o crescimento púbere. Foi observada uma alta prevalência de sobrepeso e obesidade na primeira infância, apesar de uma tendência de redução substancial na massa corporal e no índice de massa corporal ter sido aparente quando as crianças com transtornos do espectro autista entraram nos anos de desenvolvimento púbere.