Presence Of Adipocytes Research Articles

A novel DSP zebrafish model reveals training- and drug-induced modulation of arrhythmogenic cardiomyopathy phenotypes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Associazione Italiana per la Ricerca sul Cancro [AIRC grant IG-2017-19928], Italian Ministry of University and Research [grant PRIN 20173ZWACS] Introduction Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). Methods We generated the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease. Results Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, edema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed "pale", disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Conclusion Our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.

Unlocking the paracrine crosstalk: adipocyte-derived factors affect carbonic anhydrase IX expression in colon and breast cancer cells.

Obesity is a major public health concern because it increases the risk of several diseases, including cancer. Crosstalk between obesity and cancer seems to be very complex, and the interaction between adipocytes and cancer cells leads to changes in adipocytes' function and their paracrine signaling, promoting a microenvironment that supports tumor growth. Carbonic anhydrase IX (CA IX) is a tumor-associated enzyme that not only participates in pH regulation but also facilitates metabolic reprogramming and supports the migration, invasion, and metastasis of cancer cells. In addition, CA IX expression, predominantly regulated via hypoxia-inducible factor (HIF-1), serves as a surrogate marker of hypoxia. In this study, we investigated the impact of adipocytes and adipocyte-derived factors on the expression of CA IX in colon and breast cancer cells. We observed increased expression of CA9 mRNA as well as CA IX protein in the presence of adipocytes and adipocyte-derived conditioned medium. Moreover, we confirmed that adipocytes affect the hypoxia signaling pathway and that the increased CA IX expression results from adipocyte-mediated induction of HIF-1α. Furthermore, we demonstrated that adipocyte-mediated upregulation of CA IX leads to increased migration and decreased adhesion of colon cancer cells. Finally, we brought experimental evidence that adipocytes, and more specifically leptin, upregulate CA IX expression in cancer cells and consequently promote tumor progression.

Morphological criteria for sporadic multiple parathyroid gland disease

Background. There are no specific morphological signs for sporadic multiglandular disease (MGD) in primary hyperparathyroidism (PHPT). The aim of the study. To study the structure of the morphological substrate of primary, secondary and tertiary hyperparathyroidism and to assess the effectiveness of morphological criteria in the diagnosis of sporadic multiglandular disease in primary hyperparathyroidism. Methods. The study included 69 patients; 18 patients with PHPT and sporadic multiglandular disease (npreparation = 31) formed the main group, 51 patients (npreparations = 104) – the comparison group. The comparison group was divided into 3 subgroups: 1) patients with PHPT and solitary parathyroid gland (PTG) lesions – 26 patients (npreparations = 26); 2) patients with secondary hyperparathyroidism (SHPT) – 15 patients (npreparations = 48); 3) patients with tertiary hyperparathyroidism (TGPT) – 10 patients (npreparations = 30). Results. The morphological structure of the comparison groups is homogeneous: group 1 is represented by parathyroid adenoma (26 (100 %)), groups 2 and 3 – by hyperplasia (48 (100 %) and 30 (100 %), respectively). Most of the PTG specimens of the main group are represented by hyperplasia (25 (80 %)), and in 1/5 cases – by adenomas (6 (19.4 %)). Sporadic multiglandular disease in PHPT was characterized by a predominant frequency of detecting the absence of a capsule and a rim of unchanged tissue, as well as the presence of adipocytes (pχ2 < 0.01). Components of the PTG morphological structure make it possible to identify changes specific to the sporadic multiglandular disease in PHPT, with a diagnostic efficiency of 76.5–90.3 %. Conclusion. Sporadic multiglandular disease in any clinical variant of hyperparathyroidism is characterized by a high prevalence of hyperplasia – 80 % in PHPT and 100 % in SHPT and TGPT. The following morphological criteria for sporadic multiglandular disease in PHPT have been established: the presence of adipocytes in the PTG parenchyma (diagnostic efficiency (DE) – 90 %)); absence of a capsule (DE = 78 %) and a rim of unchanged gland tissue (DE = 76 %).

A novel DSP zebrafish model reveals training- and drug-induced modulation of arrhythmogenic cardiomyopathy phenotypes

Arrhythmogenic cardiomyopathy (AC) is an inherited disorder characterized by progressive loss of the ventricular myocardium causing life-threatening ventricular arrhythmias, syncope and sudden cardiac death in young and athletes. About 40% of AC cases carry one or more mutations in genes encoding for desmosomal proteins, including Desmoplakin (Dsp). We present here the first stable Dsp knock-out (KO) zebrafish line able to model cardiac alterations and cell signalling dysregulation, characteristic of the AC disease, on which environmental factors and candidate drugs can be tested. Our stable Dsp knock-out (KO) zebrafish line was characterized by cardiac alterations, oedema and bradycardia at larval stages. Histological analysis of mutated adult hearts showed reduced contractile structures and abnormal shape of the ventricle, with thinning of the myocardial layer, vessels dilation and presence of adipocytes within the myocardium. Moreover, TEM analysis revealed “pale”, disorganized and delocalized desmosomes. Intensive physical training protocol caused a global worsening of the cardiac phenotype, accelerating the progression of the disease. Of note, we detected a decrease of Wnt/β-catenin signalling, recently associated with AC pathogenesis, as well as Hippo/YAP-TAZ and TGF-β pathway dysregulation. Pharmacological treatment of mutated larvae with SB216763, a Wnt/β-catenin agonist, rescued pathway expression and cardiac abnormalities, stabilizing the heart rhythm. Overall, our Dsp KO zebrafish line recapitulates many AC features observed in human patients, pointing at zebrafish as a suitable system for in vivo analysis of environmental modulators, such as the physical exercise, and the screening of pathway-targeted drugs, especially related to the Wnt/β-catenin signalling cascade.

Deferoxamine promotes recovery of bone marrow hematopoietic function in mice exposed to a sublethal dose of X-ray irradiation

To evaluate the effect of deferoxamine (DFO) on bone marrow hematopoietic function in C57 mice exposed to a sublethal dose of X-ray irradiation. C57 mice exposed to a sublethal dose (5.4 Gy, 1.0 Gy/min) of total body X-ray irradiation (TBI) were treated with subcutaneous injection of 100 mg/kg DFO, with normal saline as the control, on a daily basis for 10 and 20 consecutive days. Body weight changes of the mice were monitored every 3 days. Five mice were selected from each group at 10 and 20 days for examination of blood cell counts, bone marrow nucleated cell counts, percentage of bone marrow CD34+ cells, bone marrow pathology, and expressions of cleaved PARP-1, cleaved caspase-3, VEGF, GPX4, and SLC7A11 in the nucleated cells. The body weight of the mice decreased significantly on day 3 in TBI and DFO groups (P<0.05), and to the lowest on day 6 in TBI group (P<0.01). Blood cell counts and bone marrow nucleated cell counts of the mice were significantly decreased at 10 and 20 days following TBI (P<0.01). On day 10 following TBI, the mice showed significantly decreased nucleated cells and the presence of adipocytes in the bone marrow, where increased expressions of cleaved PARP-1 and cleaved caspase-3 and lowered expressions of GPX4 and SLC7A11 were detected in the nucleated cells (P<0.05). In the mice exposed to TBI, treatment with DFO significantly increased CD34+ cell percentage (P<0.001), decreased the expressions of cleaved PARP-1 and cleaved caspase-3, and increased the expressions of GPX4, SLC7A11 and VEGF in the bone marrow nucleated cells (P<0.05). DFO treatment significantly increased blood cell counts and bone marrow nucleated cells in mice at 20 days following TBI (P<0.05). DFO improves bone marrow hematopoiesis in mice with sublethal-dose TBI by inhibiting apoptosis and ferroptosis of bone marrow nucleated cells and promoting VEGF expression and CD34+ cell proliferation.

UNCOUPLING PROTEIN UCP1 EXPRESSION DYNAMICS IN ADIPOSE TISSUES OF THE OUTBRED ICR MICE IN POSTNATAL ONTOGENESIS

Uncoupling protein (UCP1) uncouples mitochondrial respiration from ATP synthesis, resulting in heat production in brown and beige adipocytes. The presence of adipocytes with UCP1 expression in fat depots has been shown to promote metabolic health and provide protection against metabolic disorders. It stimulates interest in studying the age dynamics of UCP1 expression. There are few data available, mainly obtained on the C57Bl/6J mouse line predisposed to obesity and cover either early or late ontogenesis. In our study, for the first time, the expression of the UCP1 protein in the adipose tissues of male ICR mice was studied from the weaning to old age. Interscapular brown adipose tissue (BAT), inguinal and perigonadal white adipose tissue (IWAT and GWAT) of 20-day, 1.5, 6, 18 months mice were collected. UCP1 levels were detected by western-blotting. IWAT UCP1 expression decreased by 2 times between 20 days and 1.5 months. No UCP1 bands on blots from mice older than 1.5 months were observed. In gonadal depot UCP1 was detected only in 30% of the samples from 1.5- and 6‑months old mice, and UCP1 expression level was ten times lower in compare to inguinal depot. No statistically significant changes in UCP1 protein expression were detected in brown adipose tissue. The physiological role of UCP1-expressing cells in GWAT is discussed, as well as a possible relationship between the timing and rate of UCP1 expression decrease during the growth and maturation of reproductive function with the activation of lipogenesis in inguinal adipose tissue.

Comparative Analysis of Selected Tissues of Brown Trout from the Fish Pond and River Pliva, Bosnia and Herzegovina

Abstract Brown trout is a common type of fish grown for consumption in open and flowing fish ponds on the rivers of Bosnia and Herzegovina. We conducted this study during three seasons (spring, summer and autumn) to obtain a complete picture of the morphological and histological characteristics of selected trout tissues. The physicochemical characteristics of the water from the Pliva River near Pljeva and the fish pond where intensive breeding of trout is carried out were analyzed. These analyses have shown that there are no major deviations in water quality and that the water in the pond is of excellent quality. A total of 90 trout were harvested during all three seasons and their morphometric characteristics were determined by analyzing ten parameters. After the dissection of all individuals, histological and stereological analysis was performed to compare the tissues of the liver, stomach, gills and muscles. These analyses showed significant differences in the histoarchitecture of selected trout tissues from the pond compared to the river. Liver tissue had altered hepatocyte shape and presence of adipocytes; stomach tissue had stronger mucosa and weaker muscle layer; gill tissue had lower respiratory lamellae; while muscle tissue had a significant presence of adipose tissue in brown trout living in the fish pond compared to those in the river. All these changes are due to the quality of commercial feed and the inability to move freely.

A huge retroperitoneal ganglioneuroma in a middle-aged patient: Report of a diagnostically challenging case with review of the literature.

Ganglioneuromas (GNs) are benign, slow-growing tumors of neural crest cell origin. On rare occasions, adipose cells have been detected in these tumors. The present study reported a case of a huge retroperitoneal GN misdiagnosed and mismanaged as a liposarcoma. A 54-year-old male patient presented with gradually progressing dull back pain with abdominal discomfort for the past 6 months. The patient had abdominal distention and mild right abdominal tenderness. Ultrasound of the abdomen and pelvis revealed a large right-sided retroperitoneal mass. Contrast-enhanced computed tomography findings were consistent with sarcoma. Cytologic examination was suggestive of liposarcoma. A decision was made to start neoadjuvant radiochemotherapy, which proved ineffective. Complete surgical excision of the mass was performed via a midline laparotomy. Histopathology of the mass confirmed the diagnosis of GN. At two years post-operation, the patient developed a recurrence in the subhepatic area with the same diagnosis and the recurrent mass was surgically removed. Initially, the imaging findings were not sufficiently specific to establish the diagnosis. Rarely, cytologic techniques have detected adipose cells in these tumors, resulting in misdiagnosis. Hence, histopathology is the gold standard for definitive diagnosis. Preoperative diagnosis of GN is difficult due to the lack of specific clinical manifestations, radiological confusion with other tumors and the presence of adipocytes in rare cases, leading to misdiagnosis and mismanagement.

E2F1 transcription factor mediates a link between fat and islets to promote β cell proliferation in response to acute insulin resistance.

SUMMARYPrevention or amelioration of declining β cell mass is a potential strategy to cure diabetes. Here, we report the pathways utilized by β cells to robustly replicate in response to acute insulin resistance induced by S961, a pharmacological insulin receptor antagonist. Interestingly, pathways that include CENP-A and the transcription factor E2F1 that are independent of insulin signaling and its substrates appeared to mediate S961-induced β cell multiplication. Consistently, pharmacological inhibition of E2F1 blocks β-cell proliferation in S961-injected mice. Serum from S961-treated mice recapitulates replication of β cells in mouse and human islets in an E2F1-dependent manner. Co-culture of islets with adipocytes isolated from S961-treated mice enables β cells to duplicate, while E2F1 inhibition limits their growth even in the presence of adipocytes. These data suggest insulin resistance-induced proliferative signals from adipocytes activate E2F1, a potential therapeutic target, to promote β cell compensation.

Lipid and neutrophil accumulation and active inflammasome in high BMI tumor regions of human pancreatic ductal adenocarcinoma.

e16271 Background: Obesity is an established risk factor for cancer and cancer-related mortality. Adipocytes may act as a “damage” signal resulting in the accumulation of innate immune cells, fueling an inflammatory micro-environment. Among the innate immune cells, tumor-associated neutrophils (TANs) are confirmed to accumulate inside the tumor. As obesity is a significant risk factor for a poorer prognosis in pancreatic ductal adenocarcinoma (PDAC), we hypothesize that obesity-driven adipose fuels the progression of PDAC in a TAN and inflammasome-facilitated manner. This may happen through several mechanisms, including genomic instability of aggressive PDAC clonal populations. Methods: Tissue from resected tumors of PDAC patients (n = 44) with a body-mass index (BMI) &gt; 27 (obese [n = 21]) and BMI &lt; 22 (normal [n = 23]) were incubated with anti-human CD66b antibodies and detected using standard immunofluorescent microscopy techniques. Images were acquired in a Zeiss Axioplan microscope workstation and analyzed by ZEN and Metamorph software. Results: We identified the presence of adipocytes in all tissue sections and CD66b+ neutrophils in all tissue sections of normal BMI patients and in 81% of high BMI patients. There is a significantly greater density of adipocytes in the tumor environment when compared to adjacent normal areas, suggesting that these cells are acting as a damage signal. We have also shown that there are fewer total cells per area in the tumor region, suggesting a disorganization that may allow more adipose tissue to form in these areas of high BMI patients. Our novel data also shows that high BMI results in a significantly higher neutrophil count in tumor specific tissue when compared to patients with a low BMI. These data suggest an association between BMI and inflammasome accumulation in the tumor environment. Conclusions: Our data uniquely shows that CD66b+ neutrophils tend to accumulate inside PDAC in high BMI patients and this is associated with intra-tumoral active inflammasomes. The higher concentrations of these inflammasomes in higher BMI patients may be of mechanistic relevance in understanding how inflammation induces progression of PDAC. A larger cohort of tissues from PDAC obtained from low and high BMI individuals will be needed to test our hypothesis and to begin to decipher the role of obesity on inflammation and PDAC progression.

Significant lipid and neutrophil accumulation and active inflammasome in high BMI tumor regions of human pancreatic ductal adenocarcinoma.

438 Background: Obesity is an established risk factor for cancer and cancer-related mortality. Adipocytes may act as a “damage” signal resulting in the accumulation of innate immune cells, fueling an inflammatory micro-environment. Among the innate immune cells, tumor-associated neutrophils (TANs) are confirmed to accumulate inside the tumor. As obesity is a significant risk factor for a poorer prognosis in pancreatic ductal adenocarcinoma (PDAC), we hypothesize that obesity-driven adipose fuels the progression of PDAC in a TAN and inflammasome-facilitated manner. This may happen through several mechanisms, including genomic instability of aggressive PDAC clonal populations. Methods: Tissue from resected tumors of PDAC patients (n = 44) with a body-mass index (BMI) &gt; 27 (obese [n = 21]) and BMI &lt; 22 (normal [n = 23]) were incubated with anti-human CD66b antibodies and detected using standard immunofluorescent microscopy techniques. Images were acquired in a Zeiss Axioplan microscope workstation and analyzed by ZEN and Metamorph software. Results: We identified the presence of adipocytes in all tissue sections and CD66b+ neutrophils in all tissue sections of normal BMI patients and in 81% of high BMI patients. There is a significantly greater density of adipocytes in the tumor environment when compared to adjacent normal areas, suggesting that these cells are acting as a damage signal. Our novel data also shows that high BMI results in a significantly higher neutrophil count in tumor specific tissue when compared to patients with a low BMI. These data suggest an association between BMI and inflammasome accumulation in the tumor environment. Conclusions: Our data uniquely shows that CD66b+ neutrophils tend to accumulate inside PDAC in high BMI patients and this is associated with intra-tumoral active inflammasomes. The higher concentrations of these inflammasomes in higher BMI patients may be of mechanistic relevance in understanding how inflammation induces progression of PDAC. A larger cohort of tissues from PDAC obtained from low and high BMI individuals will be needed to test our hypothesis and to begin to decipher the role of obesity on inflammation and PDAC progression.

Presence of adipose tissue in aortic valves from aortic regurgitation patients: pathophysiological role and clinical implications

Abstract Introduction Adipose tissue is a common constituent of the heart and it is located, without great clinical relevance, frequently in the pericardium. The presence of adipose tissue in the aortic valve is rare, with unknown significance on valve structural properties and function. Aortic regurgitation (AR) is the third most prevalent valve disease, although it is uncommon to find it in isolation. Myxoid degeneration may be the cause or result of AR, although the pathophysiology remains poorly understood. Purpose To describe and characterize the presence of adipose tissue in the aortic valves from a cohort of AR patients. Methods 116 patients undergoing aortic valve replacement due to severe AR were enrolled. We classified them in two groups according to the histological results showing presence or absence of adipose tissue in the aortic valves. In the valve tissue molecular analysis were performed by RT-PCR, Western Blot and ELISA to analyze markers of adipocytes (leptin, adiponectin, resistin), inflammation (Rantes, interleukin-6, interleukin-1β), extracellular matrix remodeling (metalloproteinases-1, -2 and -9), proteoglycans (aggrecan, hyaluronan, lumican, syndecan-1, decorin) and fibrosis (collagens, fibronectin). Results Adipose tissue was found in 63% of the aortic valves analyzed. Baseline characteristics (age, hypertension, dyslipidemia, diabetes, smoking, left ventricular telediastolic diameter, left ventricular systolic function, ascending aorta) were similar in patients presenting valve adipose tissue as compared with patients without valve adipose tissue. Valves containing adipocytes exhibited a higher leptin content (p&amp;lt;0.001), fibronectin (p&amp;lt;0.01), decorin (p&amp;lt;0,0001), hyaluronan (p=0.03), aggrecan (p=0.04) and metalloproteinase 1 (p=0.03). Interestingly, the presence of adipocytes in the valve was positively correlated with valve thickness measured by echocardiogram (Pearson chi2 statistical significance = 26.3345 p&amp;lt;0.001). Conclusion To our knowledge, this is the first study that describes the presence of adipose cells in aortic valves from a cohort of AR patients. Aortic valves containing adipocytes were thicker and exhibited significant higher levels of proteoglycans, suggesting that adipocytes could contribute to the myxomatous degeneration process. Our results propose that the valve adipose tissue could play a role in the pathophysiology of AR. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Gobierno de Navarra

Tratamento de Lipoma Pós-traumático em face: relato de caso

O Lipoma é um tumor mesenquimal benigno de tecido mole que surge em locais com presença de adipócitos. São mais comuns na vida adulta, sendo encontrados em 80% dos casos no tórax e nas extremidades do corpo. Em menor freqüência, cerca de 13-20%, manifestam-se em cabeça e pescoço. O tumor exibe predileção por caucasianos do sexo masculino, entre 49 e 60 anos. Os lipomas detêm uma etiologia relacionada a doenças genéticas, distúrbios endócrinos, hereditariedade, infecção local e trauma. O tratamento de escolha é a excisão cirúrgica da lesão, sendo raros casos de recorrência. Geralmente, estes estão associados á ressecção inadequada da neoplasia, sobretudo, de lipomas intramusculares com padrão infiltrativo. Assim o objetivo deste artigo é apresentar um caso clínico de lipoma que se desenvolveu após um trauma em região de face. Foi descrito um caso de uma paciente do sexo masculino, 53 anos, feoderma, com histórico de acidente motociclistico há cerca de 3 anos. Ao exame físico observou-se aumento de volume circunscrito em região temporofrontal direita, mesma região acometida há 3 anos no acidente pregresso, com cerca de 10 cm de diâmetro, amolecida a palpação, coloração normal do tecido adjacente, sem queixas álgicas relacionadas. Foi realizada uma punção aspirativa de agulha fina (PAAF), o qual apresentou-se negativa, em seguida excisão cirúrgica da lesão. Após biopsia excisional, foi confirmado por meio de diagnóstico macroscópico, que se tratava de tecido adiposo, compatível com um lipoma. O paciente segue com dois meses de pós-operatório, sem sinais de recidiva.

Computational deconvolution of synovial tissue cellular composition: presence of adipocytes in synovial tissue decreased during arthritis pathogenesis and progression.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are the most common forms of arthritis. The synovial tissue is the major site of inflammation of OA and RA and consists of diverse cells. Synovial tissue cell composition changes during arthritis pathogenesis and progression have not been systematically characterized and may provide critical insights into disease processes. In this study we aimed at systematically examining cellular changes in synovial tissue. Publicly available synovial tissue transcriptomic data sets were used. We computationally estimated cell compositions in synovial tissue based on transcriptomic data and compared cell compositions in different diseases or at different disease stages. Synovial fibroblasts, macrophages, adipocytes, and immune cells were the major cell types in all synovial tissue. Both OA and RA patients had a significantly lower adipocyte fraction compared with healthy controls. The decrease trend was also observed during OA and RA progression. The fraction of monocytes was also increased in both OA and RA arthritis patients, consistent with the observations that inflammation involved in both OA and RA. But the monocyte fraction in RAs was much higher than the ones in healthy controls and OAs. The M2 macrophage fraction was reduced in RA compared with OA, the reduction trend continued during RA progression from the early- to the late-stage. There were consistent cell composition differences between different types or stages of arthritis. Both in RA and OA, the new discovery of changes in the adipocyte and M2 macrophage fractions has potential leading to novel therapeutic development.

Bone Marrow Adiposity: Basic and Clinical Implications.

The presence of adipocytes in mammalian bone marrow (BM) has been recognized histologically for decades, yet, until recently, these cells have received little attention from the research community. Advancements in mouse transgenics and imaging methods, particularly in the last 10 years, have permitted more detailed examinations of marrow adipocytes than ever before and yielded data that show these cells are critical regulators of the BM microenvironment and whole-body metabolism. Indeed, marrow adipocytes are anatomically and functionally separate from brown, beige, and classic white adipocytes. Thus, areas of BM space populated by adipocytes can be considered distinct fat depots and are collectively referred to as marrow adipose tissue (MAT) in this review. In the proceeding text, we focus on the developmental origin and physiologic functions of MAT. We also discuss the signals that cause the accumulation and loss of marrow adipocytes and the ability of these cells to regulate other cell lineages in the BM. Last, we consider roles for MAT in human physiology and disease.

Interstitial Adipocytes in the Beagle Dog and New Zealand White Rabbit Choroid Plexus.

The choroid plexus (CP) produces cerebrospinal fluid and has epithelial, interstitial, and vascular compartments. The CP is a potential site of toxicity, and recognizing the normal microanatomy in different animal models is important for the pathologist. In preclinical studies with beagle dog and New Zealand white rabbits, we observed variable numbers of adipocytes in the CP interstitium of control and xenobiotic-treated animals. The adipocytes were unilocular and consistent morphologically with white adipose tissue. There was a striking variability in the number of adipocytes; however, the presence of adipocytes was not associated with other microscopic findings that would suggest a pathologic process. The morphology of adipocytes was reminiscent of what is observed normally in the interstitium of other tissues like skeletal muscle, bone marrow, and the subcutis. Therefore, we propose that the interstitial adipocytes not be recorded as a finding in preclinical studies unless the adipocytes are altered spontaneously (ie, lipoma) or after xenobiotic treatment.

Genome-wide analysis reveals miR-3184-5p and miR-181c-3p as a critical regulator for adipocytes-associated breast cancer.

Obesity is considered as an independent risk factor for breast cancer (BCa) and plays a major role in the breast tumor microenvironment. The etiology and mechanisms by which obesity contributes to BCa development is not yet understood. Herein, we show that in vitro coculture of BCa cells with mature adipocytes (MA-BCa) increased proliferation, migration, and invasive phenotype of BCa cells. MA-BCa coculture led to increased production of proinflammatory cytokines and chemokines. To identify microRNAs (miRNAs) in BCa cells that are modulated by the presence of adipocytes, we used small RNA sequencing analysis. Sequencing data revealed that 98 miRNAs were differentially expressed in MA-BCa. Among them, miR-3184-5p and miR-181c-3p were found to be the most upregulated and downregulated miRNAs, and direct targets are FOXP4 and PPARα, respectively. In vitro functional assays using a combination of miR-3184-5p inhibitor and miR-181c-3p mimic synergistically decreased adipocytes-induced cell proliferation and invasive capacity of BCa cells. Gene Set Enrichment analysis indicated that transcription factors were highly enriched followed by protein kinases, oncogene, and protein regulators in MA-BCa. GeneGo Metacore pathway analysis uncovered "NOTCH-induced EMT pathway" was found to be the most abundant in MA-BCa. Consistently, epithelial-mesenchymal transition-associated markers were also increased in MA-BCa. The disease enrichment analysis of the predict target genes revealed that diabetes mellitus was significantly affected disease in MA-BCa. Taken together, our data suggest that miRNA-based regulatory mechanism associated with deregulation of pathways and biological functions orchestrated by adipocytes-secreted factors might drive the BCa progression and metastasis in obese patients.

Adipocytes impair efficacy of antiretroviral therapy

Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1-infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular-fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue.

Abdominal wall extra-adrenal myelolipoma, a case report and review of the literature

Extra-adrenal myelolipomas (EAMLs) are extremely rare soft tissue tumours that constitute <15% of all myelolipomas. We present a 70-year-old patient with a midline swelling of the anterior abdominal wall. It was clinically diagnosed as an incisional hernia, though the computerized scan indicated an internal hernia. During laparoscopy a soft tissue tumour of the abdominal wall was identified and excised. Pathology confirmed an extra-adrenal myelolipoma of the anterior abdominal wall through the presence of adipocytes and trilineage haematopoetic cell lines. EAMLs are rare mesenchymal soft tissue tumours with less than a hundred cases reported in the English literature. Pathological diagnosis shows the presence of mature adipocytes as well as myeloid and erythroid cell lines. This is the first case report of an EAML of the anterior abdominal wall. This case report is made even more rare as it is present in a male patient.

Appearance of Adipocytes in Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) is a lethal vascular disease that involves localized dilation of the thoracic aorta. The detailed mechanisms of TAA development and rupture are not fully understood. Recent reports have shown that the abnormal appearance of adipocytes in the vascular wall is associated with abdominal aortic aneurysm (AAA) progression or rupture. However, the presence of adipocytes in the TAA wall remains unknown. In this study, we observed the pathology of thoracic aortae to investigate whether adipocytes abnormally appear in the TAA wall. Abnormal appearance of adipocytes was mainly observed in the adventitia in the TAA vascular walls. The adipocyte area in the vascular wall was significantly increased in the TAA wall compared to the control wall. Destruction of collagen fibers, and increase in areas positive for matrix metalloproteinase (MMP) -2, MMP-9, and Mac387+ macrophages were observed in the area around adipocytes in the vascular wall. This study demonstrated the appearance of adipocytes in the TAA wall. The accumulation of adipocytes in AAA wall reportedly facilitates the destruction of fibers surrounding adipocytes, and thereby, leads to vascular wall weakness. Therefore, adipocytes in the TAA wall can be associated with the weakening of the vascular wall as well as the AAA wall. The appropriate control of adipocytes in the vascular wall may prevent weakening of the vascular wall in TAA.