Targeting the immunoproteasome in hypothalamic neurons as a novel therapeutic strategy for high-fat diet-induced obesity and metabolic dysregulation.

OBJECTIVE: Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity's deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases. METHODS: The levels of the immunoproteasome ß5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome ß5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of ß5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay. RESULTS: Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the ß5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA. CONCLUSIONS: Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.

Small intestine strangulating obstruction by mesenteric pedunculated lipoma in a criollo mare

Background: The abdominal lipomas are benign tumors of hyperplastic growth that originate from mesenteric adiposetissue, most commonly in the small intestine. Pedunculated lipoma strangulation occurs when the pedicle wraps aroundan intestinal loop and its mesentery, obstructing the intestinal lumen and blood supply of the affected segment. The aim ofthe present study is to report a case of a Criollo mare presenting a strangulating obstruction of the jejunum and ileum bya pedunculated lipoma, focusing the discussion in the causes and epidemiology of this alteration.Case: A 24-year-old Criollo mare with a body condition score 8 out of 9 was referred to the Veterinary Clinical Hospitalof the Federal University of Pelotas (HCV-UFPel) presenting acute abdominal pain. At the hospital, the mare was presenting mild signs of abdominal discomfort. At the initial clinical exam, the mare had an increased heart and respiratory rates,normal body temperature, hyperemic mucous membranes, capillary refil time of 3 s and absent gut sounds in all fourquadrants during auscultation. Mild dehydration was present, increased fibrinogen and serum lactate. Rectal palpationrevealed distention of the small intestine by gas, during abdominal ultrassonography the small intestinal wall thicknesswas increased Peritoneal lactate was 11 mmol/L and protein was 6 mg/dL. Due to the clinical findings during the exam, anexploratory celiotomy was performed. Necrosis of the final third of jejunum and the entire extension of ileum was found.Examining the compromised intestinal portion, it was observed a linear structure strangulating two segments of the smallintestine. Taking into account the extensive area of irreversible necrosis and the advanced age of the patient, euthanasiawas performed. The mare was then referred for necropsy and findings confirmed...(AU)

Small intestine strangulating obstruction by mesenteric pedunculated lipoma in a criollo mare

Background: The abdominal lipomas are benign tumors of hyperplastic growth that originate from mesenteric adiposetissue, most commonly in the small intestine. Pedunculated lipoma strangulation occurs when the pedicle wraps aroundan intestinal loop and its mesentery, obstructing the intestinal lumen and blood supply of the affected segment. The aim ofthe present study is to report a case of a Criollo mare presenting a strangulating obstruction of the jejunum and ileum bya pedunculated lipoma, focusing the discussion in the causes and epidemiology of this alteration.Case: A 24-year-old Criollo mare with a body condition score 8 out of 9 was referred to the Veterinary Clinical Hospitalof the Federal University of Pelotas (HCV-UFPel) presenting acute abdominal pain. At the hospital, the mare was presenting mild signs of abdominal discomfort. At the initial clinical exam, the mare had an increased heart and respiratory rates,normal body temperature, hyperemic mucous membranes, capillary refil time of 3 s and absent gut sounds in all fourquadrants during auscultation. Mild dehydration was present, increased fibrinogen and serum lactate. Rectal palpationrevealed distention of the small intestine by gas, during abdominal ultrassonography the small intestinal wall thicknesswas increased Peritoneal lactate was 11 mmol/L and protein was 6 mg/dL. Due to the clinical findings during the exam, anexploratory celiotomy was performed. Necrosis of the final third of jejunum and the entire extension of ileum was found.Examining the compromised intestinal portion, it was observed a linear structure strangulating two segments of the smallintestine. Taking into account the extensive area of irreversible necrosis and the advanced age of the patient, euthanasiawas performed. The mare was then referred for necropsy and findings confirmed...

Melatonin profiles during the third trimester of pregnancy and health status in the offspring among day and night workers: A case series.

Successful pregnancy requires adaptation in maternal physiology. During intrauterine life the mother's circadian timing system supports successful birth and postnatal development. Maternal melatonin is important to transmit circadian timing and day length to the fetus. This study aims to describe the third trimester of pregnancy among day (n = 5) and night (n = 3) workers by assessing their melatonin levels in a natural environment. Additionally, we describe the worker's metabolic profiles and compare the health status of the newborns between groups of day and night working mothers. Our results indicate an occurrence of assisted delivery (cesarean and forceps) among night workers. Moreover, the newborns of night workers showed lower Apgar index and breastfeeding difficulty indicating a worse condition to deal with the immediate outside the womb environment. Additionally, there was lower night-time melatonin production among pregnant night workers compared to day workers. These findings may be related to light-induced suppression of melatonin that occurs during night work. We conclude that night work and consequent exposure to light at unconventional times might compromise the success of pregnancy and the health of the newborn. Further studies need to be carried out to monitor pregnancy and newborn health in pregnant night workers.

Could semiquantitative analysis of real-time ultrasound elastography distinguish more liver parenchyma alterations of nonalcoholic fatty liver disease in patients with polycystic ovary syndrome?

ABSTRACT Objective: Nonalcoholic fatty liver disease is the commonest diffuse liver disease, of which women with polycystic ovary syndrome are at an increased risk. The aim of the present study was to assess the diagnostic value of the semiquantitative strain parameters of real-time ultrasound elastography for nonalcoholic fatty liver disease in patients with polycystic ovary syndrome. Subjects and methods: Thirty-five polycystic ovary syndrome patients with nonalcoholic fatty liver disease, 70 polycystic ovary syndrome patients without nonalcoholic fatty liver disease, and 70 healthy female controls of reproductive age were included. All participants underwent ultrasonic examination and semiquantitative analysis of real-time ultrasound elastography of the liver. Results: Main semi quantitative strain parameters, such as average strain value, differed significantly among groups polycystic ovary syndrome with nonalcoholic fatty liver disease, polycystic ovary syndrome without nonalcoholic fatty liver disease, and control (87.02 ± 10.16 vs. 96.31 ± 11.44 vs. 104.49 ± 7.28, p < 0.001). Clinical and laboratory parameters differed significantly between the two subgroups with low or high average strain value. For diagnostic value of average strain value for elevated aminotransferase, the area under the curve was 0.808 (range 0.721-0.895). In multiple linear regression analysis, polycystic ovary syndrome, waist circumference, and metabolic syndrome were stand-alone independent factors associated with average strain value among subjects without nonalcoholic fatty liver disease. Conclusion: Semiquantitative real-time ultrasound elastography analysis could distinguish liver parenchyma alterations in patients with polycystic ovary syndrome more sensitively. The diagnostic value of the proposed method for nonalcoholic fatty liver disease need further research.

Brown adipose tissue remodelling induced by corticosterone in male Wistar rats.

NEW FINDINGS: What is the central question of this study? Does glucocorticoid excess disrupt brown adipose tissue (BAT) phenotype and function? What is the main finding and its importance? Glucocorticoid excess induced an extensive remodelling of interscapular BAT, resulting in a white-like phenotype in association with metabolic disturbances. Glucocorticoids might be an important modulator of BAT physiology and BAT may have a role in pathophysiology of metabolic disturbances induced by glucocorticoid excess. ABSTRACT: In mammals, brown adipose tissue (BAT) is centrally involved in energy metabolism. To test the hypothesis that glucocorticoid excess disrupts BAT phenotype and function, male Wistar rats were treated with corticosterone in drinking water for 21 days. To confirm induction of glucocorticoid excess and metabolic disturbances, adrenal weight, corticotrophin releasing hormone mRNA levels and corticosterone serum levels were measured and a glucose tolerance test and serum triacylglycerol analyses were performed. Adipose tissue deposits were excised, weighed and evaluated by a set of biochemical, histological and molecular procedures, including thin-layer chromatography, histochemistry, immunohistochemistry, quantitative real-time polymerase chain reaction, high-resolution oxygraphy, ATP synthesis and enzymatic activity measurements. The approach was successful in induction of glucocorticoid excess and metabolic disturbances. Lower body weight and increased adiposity were observed in corticosterone-treated rats. Interscapular brown adipose tissue (iBAT) showed higher sensitivity to glucocorticoids than other fat deposits. The treatment induced lipid accumulation, unilocular rearrangement, increased collagen content and decreased innervation in iBAT. Furthermore, expression of Prdm16 (P < 0.05), Ucp1 (P <0.05) and Slc7a10 (P <0.05) mRNA decreased, while expression of Fasn (P <0.05) and Lep (P <0.05) mRNA increased in brown adipose tissue. Also, the levels of UCP1 diminished (P <0.001, 2.5-fold). Finally, lower oxygen consumption (P <0.05), ATP synthesis (P <0.05) and mitochondrial content (P <0.05) were observed in iBAT of glucocorticoid-treated rats. Glucocorticoid excess induced an extensive remodelling of interscapular brown adipose tissue, resulting in a white-like phenotype in association with metabolic disturbances.

Ganho de peso e alterações metabólicas em esquizofrenia / Weight gain and metabolic disorders in schizophrenia

CONTEXTO: Após cinco décadas de síntese e disseminação de uso de drogas para o tratamento da esquizofrenia, foi possível observar a disponibilidade de drogas com diferentes perfis farmacológicos e um largo perfil de efeitos adversos que se estendem além dos originalmente descritos em área endocrinológica e neurológica, se expandindo para aumento de peso, transtornos metabólicos, transtornos cardiovasculares e morte prematura associada a doenças comuns. Estas evidências, agravadas com a relativa ausência de diretrizes e orientações para o clínico, apontam para a necessidade de se produzir orientações claras e sintéticas para uso pelo clínico, orientando para a seleção de drogas e medidas de prevenção e tratamento de transtornos de peso e metabolismo. OBJETIVO: Identificar a freqüência e o tipo de alterações de peso e metabolismo em pessoas diagnosticadas com esquizofrenia, antes e depois do uso de diferentes antipsicóticos, e sintetizar as medidas preventivas e paliativas adequadas para a redução desses desfechos desfavoráveis. MÉTODOS: Efetuada breve revisão em PubMed e Scielo nos últimos cinco anos com os descritores weight, metabolic syndrome AND schizophrenia, e a partir dos artigos encontrados, selecionados artigos com dados clínicos. RESULTADO: Foram identificados aumento de peso, dislipidemia e síndrome metabólica em pacientes portadores do diagnóstico de esquizofrenia, antes, durante e após o uso de antipsicóticos, especialmente em drogas de nova geração, com taxas perto de duas vezes maiores do que na população geral, que resultam de redução de cerca de 20 por cento na expectativa de vida desses pacientes. CONCLUSÃO: Devido a estes riscos elevados e à inexistência de critérios claros de definição de risco de ganho de peso antes da exposição a antipsicóticos (apesar do maior risco associado a uso de clozapina e olanzapina), recomenda-se seguimento ativo de pacientes em regime de drogas antipsicóticas, com troca logo que observado...

BACKGROUND: Five decades after use and dissemination of use of drugs for the treatment of schizophrenia, with different pharmacologic profiles, it has been evidenced that these drugs display a large profile of adverse events other than endocrinological and neurological, including weight gain, metabolic disorders, increased frequency of cardiovascular disorders and premature death associated to common disorders. These evidences, aggravated by the lack of synthetic and clear description of guidelines for the clinical practitioner, points to the need of comprehensive studies about weight gain and metabolic disturbances followed by clear and simple guidelines orienting drug selection and measures for prevention and treatment of weight and metabolic disturbances. OBJECTIVE: Identification of frequency and type of weight and metabolic disturbances in people diagnosed with schizophrenia, before and after the use of different antipsychotics. METHODS: A PubMed and Scielo review of the last 5 years using descriptors such as weight, metabolic syndrome AND schizophrenia, and after that, the authors selected articles with clinical data. RESULT: Increased weight, dislipidemia and metabolic syndrome in subjects with schizophrenia, before, was evidenced during and after drug use, especially new-generation drugs, with overall rates around 2 times the general population, resulting in a 20 percent reduction of life expectancy in these patients. CONCLUSION: The evidence of elevated risk for overweight and metabolic syndrome and the lack of defined criteria for risk assessment for weight gain before drug use (despite of increased pre-drug use risk with clozapine and olanzapine) it is recommended active follow-up of patients under antipsychotic drug use, with drug change when observed 5 percent or more weight gain, with maintenance of active care of nutritional, lifestyle and activity level. There is also a need of systematic reviews for controlling selection...