Metabolic remodeling of visceral and subcutaneous white adipose tissue during reacclimation of rats after cold.

Deciphering lipid metabolism in white adipose tissue (WAT) depots during weight gain is important to understand the heterogeneity of WAT and its roles in obesity. Here, we examined the expression of key enzymes of lipid metabolism and changes in the morphology of representative visceral (epididymal) and subcutaneous (inguinal) WAT (eWAT and iWAT, respectively)-in adult male rats acclimated to cold (4 ± 1 °C) for 45 days and reacclimated to room temperature (RT, 22 ± 1 °C) for 1, 3, 7, 12, 21, or 45 days. The relative mass of both depots decreased to a similar extent after cold acclimation. However, fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), and medium-chain acyl-CoA dehydrogenase (ACADM) protein level increased only in eWAT, whereas adipose triglyceride lipase (ATGL) expression increased only in iWAT. During reacclimation, the relative mass of eWAT reached control values on day 12 and that of iWAT on day 45 of reacclimation. The faster recovery of eWAT mass is associated with higher expression of FAS, acetyl-CoA carboxylase (ACC), G6PDH, and ACADM during reacclimation and a delayed increase in ATGL. The absence of an increase in proliferating cell nuclear antigen suggests that the observed depot-specific mass increase is predominantly due to metabolic adjustments. In summary, this study shows a differential rate of visceral and subcutaneous adipose tissue weight regain during post-cold reacclimation of rats at RT. Faster recovery of the visceral WAT as compared to subcutaneous WAT during reacclimation at RT could be attributed to observed differences in the expression patterns of lipid metabolic enzymes.

Breast Cancer: Mitochondria-Centered Metabolic Alterations in Tumor and Associated Adipose Tissue.

The close cooperation between breast cancer and cancer-associated adipose tissue (CAAT) shapes the malignant phenotype, but the role of mitochondrial metabolic reprogramming and obesity in breast cancer remains undecided, especially in premenopausal women. Here, we examined mitochondrial metabolic dynamics in paired biopsies of malignant versus benign breast tumor tissue and CAAT in normal-weight and overweight/obese premenopausal women. Lower protein level of pyruvate dehydrogenase and citrate synthase in malignant tumor tissue indicated decreased carbon flux from glucose into the Krebs cycle, whereas the trend was just the opposite in malignant CAAT. Simultaneously, stimulated lipolysis in CAAT of obese women was followed by upregulated ß-oxidation, as well as fatty acid synthesis enzymes in both tumor tissue and CAAT of women with malignant tumors, corroborating their physical association. Further, protein level of electron transport chain complexes was generally increased in tumor tissue and CAAT from women with malignant tumors, respective to obesity. Preserved mitochondrial structure in malignant tumor tissue was also observed. However, mitochondrial DNA copy number and protein levels of PGC-1α were dependent on both malignancy and obesity in tumor tissue and CAAT. In conclusion, metabolic cooperation between breast cancer and CAAT in premenopausal women involves obesity-related, synchronized changes in mitochondrial metabolism.

Integrated Redox-Metabolic Orchestration Sustains Life in Hibernating Ground Squirrels.

Significance: The ultimate manifestations of life, birth, survival under various environmental pressures and death are based on bioenergetics. Hibernation is a unique survival strategy for many small mammals that is characterised by severe metabolic depression and transition from euthermia to hypothermia (torpor) at body temperatures close to 0°C. These manifestations of life were made possible by the remarkable "social" behavior of biomolecules during billions of years of evolution: the evolution of life with oxygen. Oxygen was necessary for energy production and the evolutionary explosion of aerobic organisms. Recent Advances: Nevertheless, reactive oxygen species, formed through oxidative metabolism, are dangerous-they can kill a cell and, on the other hand, play a plethora of fundamentally valuable roles. Therefore, the evolution of life depended on energy metabolism and redox-metabolic adaptations. The more extreme the conditions for survival are, the more sophisticated the adaptive responses of organisms become. Hibernation is a beautiful illustration of this principle. Hibernating animals use evolutionarily conserved molecular mechanisms to survive adverse environmental conditions, including reducing body temperature to ambient levels (often to ∼0°C) and severe metabolic depression. This long-built secret of life lies at the intersection of oxygen, metabolism, and bioenergetics, and hibernating organisms have learned to exploit all the underlying capacities of molecular pathways to survive. Critical Issues: Despite such drastic changes in phenotype, tissues and organs of hibernators sustain no metabolic or histological damage during hibernation or upon awakening from hibernation. This was made possible by the fascinating integration of redox-metabolic regulatory networks whose molecular mechanisms remain undisclosed to this day. Future Directions: Discovering these molecular mechanisms is not warranted only to understand hibernation in itself but to help explain complex medical conditions (hypoxia/reoxygenation, organ transplantation, diabetes, and cancer) and to even help overcome limitations associated with space travel. This is a review of integrated redox-metabolic orchestration in hibernation. Antioxid. Redox Signal. 40, 345-368.

Redox and metabolic reprogramming in breast cancer and cancer-associated adipose tissue.

Redox and metabolic processes are tightly coupled in both physiological and pathological conditions. In cancer, their integration occurs at multiple levels and is characterized by synchronized reprogramming both in the tumor tissue and its specific but heterogeneous microenvironment. In breast cancer, the principal microenvironment is the cancer-associated adipose tissue (CAAT). Understanding how the redox-metabolic reprogramming becomes coordinated in human breast cancer is imperative both for cancer prevention and for the establishment of new therapeutic approaches. This review aims to provide an overview of the current knowledge of the redox profiles and regulation of intermediary metabolism in breast cancer while considering the tumor and CAAT of breast cancer as a unique Warburg's pseudo-organ. As cancer is now recognized as a systemic metabolic disease, we have paid particular attention to the cell-specific redox-metabolic reprogramming and the roles of estrogen receptors and circadian rhythms, as well as their crosstalk in the development, growth, progression, and prognosis of breast cancer.

CT and 18FDG-PET/CT findings in progressive mediastinal idiopathic fibrosis as a benign mimicker of esophageal carcinoma: a case report.

Idiopathic mediastinal fibrosis, also called sclerosing or fibrosing mediastinitis, is a very rare and aggressive fibroinflammatory process characterized by fibrous tissue proliferation in the mediastinal region. Herein, we present a rare case of idiopathic mediastinal fibrosis presenting with esophageal obstruction, most likely associated with immunoglobulin G (IgG4)-related disease, affecting the posterior mediastinum with intrapulmonary infiltration. Computed tomography revealed a narrowed lumen and thickened wall of the distal esophagus surrounded by a necrotic mass with infiltration into the nearby structures, suggesting a locally advanced malignant process. Positron emission tomography revealed intense accumulation of 18F-fluorodeoxyglucose, indicating an active inflammatory component, which complicates further differential diagnosis of mediastinal masses. Thoracoscopic biopsy and immunohistochemical analysis confirmed a fibroinflammatory process with perivascular lymphoid cell infiltration that was cluster of differentiation (CD)3 (++) and CD20 (++), with massive numbers of IgG4-immunoreactive plasma cells. Although a benign condition, sclerosing mediastinitis is a close mimicker of esophageal carcinoma, which cannot be differentiated by computed tomography or positron emission tomography and must be considered in a differential diagnosis.

Possibility of Using Conventional Computed Tomography Features and Histogram Texture Analysis Parameters as Imaging Biomarkers for Preoperative Prediction of High-Risk Gastrointestinal Stromal Tumors of the Stomach.

BACKGROUND: The objective of this study is to determine the morphological computed tomography features of the tumor and texture analysis parameters, which may be a useful diagnostic tool for the preoperative prediction of high-risk gastrointestinal stromal tumors (HR GISTs). METHODS: This is a prospective cohort study that was carried out in the period from 2019 to 2022. The study included 79 patients who underwent CT examination, texture analysis, surgical resection of a lesion that was suspicious for GIST as well as pathohistological and immunohistochemical analysis. RESULTS: Textural analysis pointed out min norm (p = 0.032) as a histogram parameter that significantly differed between HR and LR GISTs, while min norm (p = 0.007), skewness (p = 0.035) and kurtosis (p = 0.003) showed significant differences between high-grade and low-grade tumors. Univariate regression analysis identified tumor diameter, margin appearance, growth pattern, lesion shape, structure, mucosal continuity, enlarged peri- and intra-tumoral feeding or draining vessel (EFDV) and max norm as significant predictive factors for HR GISTs. Interrupted mucosa (p < 0.001) and presence of EFDV (p < 0.001) were obtained by multivariate regression analysis as independent predictive factors of high-risk GISTs with an AUC of 0.878 (CI: 0.797-0.959), sensitivity of 94%, specificity of 77% and accuracy of 88%. CONCLUSION: This result shows that morphological CT features of GIST are of great importance in the prediction of non-invasive preoperative metastatic risk. The incorporation of texture analysis into basic imaging protocols may further improve the preoperative assessment of risk stratification.

MRI Tumor Regression Grade Combined with T2-Weighted Volumetry May Predict Histopathological Response in Locally Advanced Rectal Cancer following Neoadjuvant Chemoradiotherapy-A New Scoring System Proposal.

Modern studies focus on the discovery of innovative methods to improve the value of post-treatment magnetic resonance imaging (MRI) in the prediction of pathological responses to preoperative neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC). The aim of this study was to assess the potential benefits of combining magnetic resonance tumor regression grade (mrTRG) with T2-weighted volumetry in the prediction of pathological responses to nCRT in LARC. This was a cohort study conducted on patients with histopathologically confirmed LARC in a period from 2020 to 2022. After histopathological verification, all patients underwent initial MRI studies, while the follow-up MRI was performed after nCRT. Tumor characteristics, MRI estimated tumor regression grade (mrTRG) and tumor volumetry were evaluated both initially and at follow-up. All patients were classified into responders and non-responders according to pathological tumor regression grade (pTRG) and mrTRG. A total of 71 patients, mostly male (66.2%) were included in the study. The median tumor volume reduction rate was significantly higher in nCRT-responders compared to non-responders (79.9% vs. 63.3%) (p = 0.003). Based on ROC analysis, optimal cut-off value for tumor volume reduction rate was determined with an area under the curve (AUC) value of 0.724 (p = 0.003). Using the tumor volume reduction rate ≥75% with the addition of response to nCRT according to mrTRG, a new scoring system for prediction of pTRG to preoperative nCRT in LARC was developed. Diagnostic performance of prediction score was tested and the sensitivity, PPV, specificity, and NPV were 81.8%, 56.3%, 71.4%, and 89.7%, respectively. The combination of mrTRG and T2-weighted volumetry increases the MRI-based prediction of pTRG to preoperative nCRT in LARC. The proposed scoring system could aid in distinguishing responders to nCRT, as these patients could benefit from organ-preserving treatment and a "watch and wait" strategy.

ACOX-driven peroxisomal heterogeneity and functional compartmentalization in brown adipocytes of hypothyroid rats.

We previously demonstrated that hypothyroidism increases peroxisomal biogenesis in rat brown adipose tissue (BAT). We also showed heterogeneity in peroxisomal origin and their unique structural association with mitochondria and/or lipid bodies to carry out ß-oxidation, contributing thus to BAT thermogenesis. Distinctive heterogeneity creates structural compartmentalization within peroxisomal population, raising the question of whether it is followed by their functional compartmentalization regarding localization/colocalization of two main acyl-CoA oxidase (ACOX) isoforms, ACOX1 and ACOX3. ACOX is the first and rate-limiting enzyme of peroxisomal ß-oxidation, and, to date, their protein expression patterns in BAT have not been fully defined. Therefore, we used methimazole-induced hypothyroidism to study ACOX1 and ACOX3 protein expression and their tissue immunolocalization. Additionally, we analysed their specific peroxisomal localization and colocalization in parallel with peroxisomal structural compartmentalization in brown adipocytes. Hypothyroidism caused a linear increase in ACOX1 expression, while a temporary decrease in ACOX3 levels is only recovered to the control level at day 21. Peroxisomal ACOX1 and ACOX3 localization and colocalization patterns entirely mirrored heterogeneous peroxisomal biogenesis pathways and structural compartmentalization, e.g. associations with mitochondria and/or lipid bodies. Hence, different ACOX isoforms localization/colocalization creates distinct functional heterogeneity of peroxisomes and drives their functional compartmentalization in rat brown adipocytes.

The Role of MRI in the Diagnosis of Solid Pseudopapillary Neoplasm of the Pancreas and Its Mimickers: A Case-Based Review with Emphasis on Differential Diagnosis.

Solid pseudopapillary neoplasm (SPN) is rare pancreatic tumor occurring most commonly in young females. The typical imaging appearance of SPN is of well-defined, encapsulated, and large heterogeneous tumors, consisting of solid and cystic components due to various degrees of intralesional hemorrhage and necrosis. However, atypical imaging presentation in the form of small solid tumors or uniformly cystic lesions might also be seen, which can be explained by specific pathological characteristics. Other imaging features such as a round shape, the absence of main pancreatic duct dilatation, and slow growth, in combination with vague symptoms, favor the diagnosis of SPNs. Nevertheless, the radiological findings of SPN might overlap with other solid and cystic pancreatic neoplasms, such as neuroendocrine tumors, serous and mucinous neoplasms, and even small pancreatic adenocarcinomas. In addition, a few benign non-tumorous conditions including walled-of-necrosis, and intrapancreatic accessory spleen may also pose diagnostic dilemmas simulating SPNs on imaging studies. The aim of this manuscript is to provide a comprehensive overview of the typical and atypical imaging features of SPNs and to describe useful tips for differential diagnosis with its potential mimickers.

Redox-metabolic reprogramming of skin in mice lacking functional Nrf2 under basal conditions and cold acclimation.

Adaptive responses to environmental and physiological challenges, including exposure to low environmental temperature, require extensive structural, redox, and metabolic reprogramming. Detailed molecular mechanisms of such processes in the skin are lacking, especially the role of nuclear factor erythroid 2-related factor 2 (Nrf2) and other closely related redox-sensitive transcription factors Nrf1, Nrf3, and nuclear respiratory factor (NRF1). To investigate the role of Nrf2, we examined redox and metabolic responses in the skin of wild-type (WT) mice and mice lacking functional Nrf2 (Nrf2 KO) at room (RT, 24 ± 1°C) and cold (4 ± 1°C) temperature. Our results demonstrate distinct expression profiles of major enzymes involved in antioxidant defense and key metabolic and mitochondrial pathways in the skin, depending on the functional Nrf2 and/or cold stimulus. Nrf2 KO mice at RT displayed profound alterations in redox, mitochondrial and metabolic responses, generally akin to cold-induced skin responses in WT mice. Immunohistochemical analyses of skin cell compartments (keratinocytes, fibroblasts, hair follicle, and sebaceous gland) and spatial locations (nucleus and cytoplasm) revealed synergistic interactions between members of the Nrf transcription factor family as part of redox-metabolic reprogramming in WT mice upon cold acclimation. In contrast, Nrf2 KO mice at RT showed loss of NRF1 expression and a compensatory activation of Nrf1/Nrf3, which was abolished upon cold, concomitant with blunted redox-metabolic responses. These data show for the first time a novel role for Nrf2 in skin physiology in response to low environmental temperature, with important implications in human connective tissue diseases with altered thermogenic responses.

The Utility of Conventional CT, CT Perfusion and Quantitative Diffusion-Weighted Imaging in Predicting the Risk Level of Gastrointestinal Stromal Tumors of the Stomach: A Prospective Comparison of Classical CT Features, CT Perfusion Values, Apparent Diffusion Coefficient and Intravoxel Incoherent Motion-Derived Parameters.

Background: The role of advanced functional imaging techniques in prediction of pathological risk categories of gastrointestinal stromal tumors (GIST) is still unknown. The purpose of this study was to evaluate classical CT features, CT-perfusion and magnetic-resonance-diffusion-weighted-imaging (MR-DWI)-related parameters in predicting the metastatic risk of gastric GIST. Patients and methods: Sixty-two patients with histologically proven GIST who underwent CT perfusion and MR-DWI using multiple b-values were prospectively included. Morphological CT characteristics and CT-perfusion parameters of tumor were comparatively analyzed in the high-risk (HR) and low-risk (LR) GIST groups. Apparent diffusion coefficient (ADC) and intravoxel-incoherent-motion (IVIM)-related parameters were also analyzed in 45 and 34 patients, respectively. Results: Binary logistic regression analysis revealed that greater tumor diameter (p < 0.001), cystic structure (p < 0.001), irregular margins (p = 0.007), irregular shape (p < 0.001), disrupted mucosa (p < 0.001) and visible EFDV (p < 0.001), as well as less ADC value (p = 0.001) and shorter time-to-peak (p = 0.006), were significant predictors of HR GIST. Multivariate analysis extracted irregular shape (p = 0.006) and enlarged feeding or draining vessels (EFDV) (p = 0.017) as independent predictors of HR GIST (area under curve (AUC) of predicting model 0.869). Conclusion: Although certain classical CT imaging features remain most valuable, some functional imaging parameters may add the diagnostic value in preoperative prediction of HR gastric GIST.

l-Arginine Induces White Adipose Tissue Browning-A New Pharmaceutical Alternative to Cold.

The beneficial effects of l-arginine supplementation in obesity and type II diabetes involve white adipose tissue (WAT) reduction and increased substrate oxidation. We aimed to test the potential of l-arginine to induce WAT browning. Therefore, the molecular basis of browning was investigated in retroperitoneal WAT (rpWAT) of rats exposed to cold or treated with 2.25% l-arginine for 1, 3, and 7 days. Compared to untreated control, levels of inducible nitric oxide (NO) synthase protein expression and NO signaling increased in both cold-exposed and l-arginine-treated groups. These increases coincided with the appearance of multilocular adipocytes and increased expression levels of uncoupling protein 1 (UCP1), thermogenic and beige adipocyte-specific genes (Cidea, Cd137, and Tmem26), mitochondriogenesis markers (peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α, mitochondrial DNA copy number), nuclear respiratory factor 1, PPARα and their respective downstream lipid oxidation enzymes after l-arginine treatment. Such browning phenotype in the l-arginine-treated group was concordant with end-course decreases in leptinaemia, rpWAT mass, and body weight. In conclusion, l-arginine mimics cold-mediated increases in NO signaling in rpWAT and induces molecular and structural fingerprints of rpWAT browning. The results endorse l-arginine as a pharmaceutical alternative to cold exposure, which could be of great interest in obesity and associated metabolic diseases.

Hepatocellular Carcinoma Presenting Simultaneously with Echinococcal Cyst Mimicking a Single Liver Lesion in a Non-Cirrhotic Patient: A Case Report and Review of the Literature.

A coexistance of liver cystic echinococcosis (CE) and hepatocellular carcinoma (HCC) is very rare. HCC is the leading cause of cancer-related mortality worldwide, while CE is a globally endemic zoonosis caused by the cestode tapeworm Echinococcus granulosus. The association between these two diseases is still not well-defined. A preoperative diagnosis may be challenging, especially if HCC and CE present as a single lesion and if atypical imaging features are present. Herein, we present a case of the patient that was initially diagnosed as an extensive necrotic tumor in the left liver lobe and highly suspicious of being HCC associated with peritumoral hematoma. Left hemihepatectomy was performed, and the histopathological findings showed the collision of two lesions: a hydatid cyst and HCC.

Fatal gastrointestinal bleeding associated with acute pancreatitis as a complication of Covid-19: a case report.

Clinical manifestations of Covid-19 vary widely among patients. Recent studies suggest that up to 15% of patients with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections develop gastrointestinal symptoms. The location of virus-host cell receptors angiotensin-converting enzyme 2 and transmembrane serine protease 2 has an important role in the pathophysiology and presentation of disease. They are expressed in the respiratory tract, as well as other organs and tissues including exocrine and endocrine pancreatic cells. These cells are therefore a possible target for the virus, which could explain the relationship between SARS-CoV-2 infection and pancreatic injury. We report a disastrous collateral effect of the Covid-19 pandemic on a 33-year-old man with chronic renal insufficiency and asymptomatic SARS-CoV-2 infection, who developed acute pancreatitis. Inflammation progressed rapidly toward necrosis and the development of a peripancreatic pseudoaneurysm which subsequently ruptured, causing death.

Total Pancreatectomy for Multicentric Cystic Neuroendocrine Tumor of the Pancreas: A Case Report.

Pancreatic neuroendocrine tumors (PNETs) are uncommon pancreatic neoplasms with malignant potential, heterogeneous clinical behavior, as well as imaging appearance. These tumors represent less than 3% of all pancreatic neoplasms with typical CT presentation as solid, well-circumscribed, hypervascular lesions. Cystic PNET is a rare pancreatic tumor which is nowadays more often detected due to the widespread use of high-resolution cross-sectional imaging. They are mainly solitary lesions most commonly localized in the body and the tail of the pancreas. Due to cystic presentation these lesions often present a diagnostic challenge to both experienced radiologists and pathologists. Herein, we present a rare case of synchronous, multiple cystic and solid pancreatic neuroendocrine tumors, which due to their extensiveness required total dudenopancreatectomy with splenectomy. Histopathological findings confirmed microscopic and macroscopic cystic components as well as typical solid variants of neuroendocrine tumors along the entire pancreas.

Endovascular treatment of a pseudoaneurysm of the posterior inferior pancreaticoduodenal artery as a complication of chronic pancreatitis: a case report.

A pancreatic pseudoaneurysm is a rare but life-threatening clinical entity. Prompt diagnosis and appropriate treatment are of great clinical importance. We herein present an unusual case of a pseudoaneurysm of the posterior inferior pancreaticoduodenal artery that developed as a complication of chronic pancreatitis. It was detected in a timely manner and successfully treated with minimally invasive endovascular therapy.

Imaging Spectrum of Intrahepatic Mass-Forming Cholangiocarcinoma and Its Mimickers: How to Differentiate Them Using MRI.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, with mass-forming growth pattern being the most common. The typical imaging appearance of mass-forming ICC (mICC) consists of irregular ring enhancement in the arterial phase followed by the progressive central enhancement on portal venous and delayed phases. However, atypical imaging presentation in the form of hypervascular mICC might also be seen, which can be attributed to distinct pathological characteristics. Ancillary imaging features such as lobular shape, capsular retraction, segmental biliary dilatation, and vascular encasement favor the diagnosis of mICC. Nevertheless, these radiological findings may also be present in certain benign conditions such as focal confluent fibrosis, sclerosing hemangioma, organizing hepatic abscess, or the pseudosolid form of hydatid disease. In addition, a few malignant lesions including primary liver lymphoma, hemangioendothelioma, solitary hypovascular liver metastases, and atypical forms of hepatocellular carcinoma (HCC), such as scirrhous HCC, infiltrative HCC, and poorly differentiated HCC, may also pose a diagnostic dilemma by simulating mICC in imaging studies. Diffusion-weighted imaging and the use of hepatobiliary contrast agents might be helpful for differential diagnosis in certain cases. The aim of this manuscript is to provide a comprehensive overview of mICC imaging features and to describe useful tips for differential diagnosis with its potential mimickers.

Effects of Remote Ischaemic Preconditioning on the Internal Thoracic Artery Nitric Oxide Synthase Isoforms in Patients Undergoing Coronary Artery Bypass Grafting.

Remote ischaemic preconditioning (RIPC) is a medical procedure that consists of repeated brief periods of transient ischaemia and reperfusion of distant organs (limbs) with the ability to provide internal organ protection from ischaemia. Even though RIPC has been successfully applied in patients with myocardial infarction during coronary revascularization (surgery/percutaneous angioplasty), the underlying molecular mechanisms are yet to be clarified. Thus, our study aimed to determine the role of nitric oxide synthase (NOS) isoforms in RIPC-induced protection (3 × 5 min of forearm ischaemia with 5 min of reperfusion) of arterial graft in patients undergoing urgent coronary artery bypass grafting (CABG). We examined RIPC effects on specific expression and immunolocalization of three NOS isoforms - endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) in patients' internal thoracic artery (ITA) used as a graft. We found that the application of RIPC protocol leads to an increased protein expression of eNOS, which was further confirmed with strong eNOS immunopositivity, especially in the endothelium and smooth muscle cells of ITA. The same analysis of two other NOS isoforms, iNOS and nNOS, showed no significant differences between patients undergoing CABG with or without RIPC. Our results demonstrate RIPC-induced upregulation of eNOS in human ITA, pointing to its significance in achieving protective phenotype on a systemic level with important implications for graft patency.

Hypothyroidism Intensifies Both Canonic and the De Novo Pathway of Peroxisomal Biogenesis in Rat Brown Adipocytes in a Time-Dependent Manner.

Despite peroxisomes being important partners of mitochondria by carrying out fatty acid oxidation in brown adipocytes, no clear evidence concerning peroxisome origin and way(s) of biogenesis exists. Herein we used methimazole-induced hypothyroidism for 7, 15, and 21 days to study peroxisomal remodeling and origin in rat brown adipocytes. We found that peroxisomes originated via both canonic, and de novo pathways. Each pathway operates in euthyroid control and over the course of hypothyroidism, in a time-dependent manner. Hypothyroidism increased the peroxisomal number by 1.8-, 3.6- and 5.8-fold on days 7, 15, and 21. Peroxisomal presence, their distribution, and their degree of maturation were heterogeneous in brown adipocytes in a Harlequin-like manner, reflecting differences in their origin. The canonic pathway, through numerous dumbbell-like and "pearls on strings" structures, supported by high levels of Pex11ß and Drp1, prevailed on day 7. The de novo pathway of peroxisomal biogenesis started on day 15 and became dominant by day 21. The transition of peroxisomal biogenesis from canonic to the de novo pathway was driven by increased levels of Pex19, PMP70, Pex5S, and Pex26 and characterized by numerous tubular structures. Furthermore, specific peroxisomal origin from mitochondria, regardless of thyroid status, indicates their mutual regulation in rat brown adipocytes.