Prevalence of clinical characteristics of lipodystrophy in the US adult population in a healthcare claims database.

BACKGROUND: Lipodystrophy is characterized by progressive loss of adipose tissue and consequential metabolic abnormalities. With new treatments emerging for lipodystrophy, there is a growing need to understand the prevalence of specific comorbidities that may be commonly associated with lipodystrophy to contextualize the natural history of lipodystrophy without any disease modifying therapy. OBJECTIVE: To examine the risk of specific clinical characteristics in people living with lipodystrophy (LD) in 2018-2019 compared with the general US population, among the commercially insured US population. METHODS: A retrospective cohort study was conducted using the 2018-2019 Clinformatics® Data Mart database. An adult LD cohort (age ≥ 18 years) with at least ≥ 1 inpatient or ≥ 2 outpatient LD diagnoses was created. The LD cohort included non-HIV-associated LD (non-HIV-LD) and HIV-associated LD (HIV-LD) subgroups and compared against age- and sex-matched control groups with a 1:4 ratio from the general population with neither an LD or an HIV diagnosis using odds ratios (ORs) with 95% confidence intervals. RESULTS: We identified 546 individuals with non-HIV-LD (mean age, 60.3 ± 14.9 years; female, 67.6%) and 334 individuals with HIV-LD (mean age, 59.2 ± 8.3 years; female, 15.0%) in 2018-2019. Compared with the general population, individuals with non-HIV-LD had higher risks (odds ratio [95% confidence interval]) for hyperlipidemia (3.32 [2.71-4.09]), hypertension (3.58 [2.89-4.44]), diabetes mellitus (4.72 [3.85-5.79]), kidney disease (2.78 [2.19-3.53]), liver fibrosis or cirrhosis (4.06 [1.66-9.95]), cancer (2.20 [1.59-3.01]), and serious infections resulting in hospitalization (3.00 [2.19-4.10]). Compared with individuals with HIV, those with HIV-LD have higher odds of hypertension (1.47 [1.13-1.92]), hyperlipidemia (2.46 [1.86-3.28]), and diabetes (1.37 [1.04-1.79]). CONCLUSIONS: LD imposes a substantial burden on affected individuals due to a high prevalence of metabolic comorbidities and other complications as compared with the general non-LD population. Future longitudinal follow-up studies investigating the causality between LD and observed comorbidities are warranted.

Bioconcentration of polycyclic aromatic hydrocarbons in the adipose tissue of women with pelvic endometriosis and idiopathic infertility: A case-control study.

PURPOSE: Polycyclic aromatic hydrocarbons (PAHs), present in air and food, generated during energy production and waste incineration, are known for health toxicity. PAHs may activate the aryl hydrocarbon receptor, which could in turn modify estrogen-dependent inflammatory pathways in endometriosis. The possible role of PAHs in the pathogenesis of endometriosis remains unclear. The study aimed to evaluate the potential link between exposure to PAHs and the occurrence of peritoneal and ovarian endometriosis. METHODS: A prospective case-control tertiary-center study included 46 women aged 22-45 undergoing laparoscopy due to pelvic endometriosis (n â€‹= â€‹32; arm 1) and idiopathic infertility (n â€‹= â€‹14; arm 2). A sample of the greater omentum was collected intraoperatively for detection of 16 standard PAHs by gas chromatography-isotope dilution mass spectrometry method. PAHs concentrations were compared in both study arms. The associations between PAHs concentrations and selected variables were investigated. RESULTS: There were no significant differences between both arms in terms of reference PAHs concentrations, nor correlations between PAHs concentrations and the stage of endometriosis. However, notable differences were observed in specific PAHs concentrations related to certain conditions. The concentrations of acenaphthene (p â€‹= â€‹0.016) and fluorene (p â€‹= â€‹0.013) were significantly lower in women with peritoneal adhesions, while the concentrations of benz[a]anthracene, benzo[k]fluoranthene and indeno[1,2,3-cd]pyrene [ng/g] were higher in cigarette smokers. CONCLUSIONS: The study showed no differences in exposure to PAHs between women with and without pelvic endometriosis. Determining the toxicity of PAHs in endometriosis requires further research.

Estrogen deficiency reduces maximal running capacity and affects serotonin levels differently in the hippocampus and nucleus accumbens in response to acute exercise.

Introduction: Estrogen deficiency is associated with unfavorable changes in body composition and metabolic health. While physical activity ameliorates several of the negative effects, loss of ovarian function is associated with decreased physical activity levels. It has been proposed that the changes in brain neurochemical levels and /or impaired skeletal muscle function may underlie this phenomenon. Methods: We studied the effect of estrogen deficiency induced via ovariectomy (OVX) in female Wistar rats (n = 64). Rats underwent either sham or OVX surgery and were allocated thereafter into four groups matched for body mass and maximal running capacity: sham/control, sham/max, OVX/control, and OVX/max, of which the max groups had maximal running test before euthanasia to induce acute response to exercise. Metabolism, spontaneous activity, and maximal running capacity were measured before (PRE) and after (POST) the surgeries. Three months following the surgery, rats were euthanized, and blood and tissue samples harvested. Proteins were analyzed from gastrocnemius muscle and retroperitoneal adipose tissue via Western blot. Brain neurochemical markers were measured from nucleus accumbens (NA) and hippocampus (HC) using ultra-high performance liquid chromatography. Results: OVX had lower basal energy expenditure and higher body mass and retroperitoneal adipose tissue mass compared with sham group (p ≤ 0.005). OVX reduced maximal running capacity by 17% (p = 0.005) with no changes in muscle mass or phosphorylated form of regulatory light chain (pRLC) in gastrocnemius muscle. OVX was associated with lower serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level in the NA compared with sham (p = 0.007). In response to acute exercise, OVX was associated with low serotonin level in the HC and high level in the NA (p ≤ 0.024). Discussion: Our results highlight that OVX reduces maximal running capacity and affects the response of brain neurochemical levels to acute exercise in a brain region-specific manner. These results may offer mechanistic insight into why OVX reduces willingness to exercise.

Growth hormone improves insulin resistance in visceral adipose tissue after duodenal-jejunal bypass by regulating adiponectin secretion.

BACKGROUND: The mechanism of improvement of type 2 diabetes after duodenal-jejunal bypass (DJB) surgery is not clear. AIM: To study the morphological and functional changes in adipose tissue after DJB and explore the potential mechanisms contributing to postoperative insulin sensitivity improvement of adipose tissue in a diabetic male rat model. METHODS: DJB and sham surgery was performed in a-high-fat-diet/streptozotocin-induced diabetic rat model. All adipose tissue was weighed and observed under microscope. Use inguinal fat to represent subcutaneous adipose tissue (SAT) and mesangial fat to represent visceral adipose tissue. RNA-sequencing was utilized to evaluate gene expression alterations adipocytes. The hematoxylin and eosin staining, reverse transcription-quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay were used to study the changes. Insulin resistance was evaluated by immunofluorescence. RESULTS: After DJB, whole body blood glucose metabolism and insulin sensitivity in adipose tissue improved. Fat cell volume in both visceral adipose tissue (VAT) and SAT increased. Compared to SAT, VAT showed more significantly functional alterations after DJB and KEGG analysis indicated growth hormone (GH) pathway and downstream adiponectin secretion were involved in metabolic regulation. The circulating GH and adiponectin levels and GH receptor and adiponectin levels in VAT increased. Cytological experiment showed that GH stimulated adiponectin secretion and improve insulin sensitivity. CONCLUSION: GH improves insulin resistance in VAT in male diabetic rats after receiving DJB, possibly by increasing adiponectin secretion.

Adipose Tissue Sex Steroids in Postmenopausal Women with and without Menopausal Hormone Therapy.

CONTEXT: The decrease in serum estrogens after menopause is associated with a shift from a gynoid to an android adipose tissue (AT) distribution. Menopausal hormone therapy (HT) mitigates this change and accompanying metabolic dysfunction, but its effects on AT sex steroid metabolism have not been characterized. OBJECTIVE: We studied effects of HT on subcutaneous and visceral AT estrogen and androgen concentrations and metabolism in postmenopausal women. DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: Serum and subcutaneous and visceral AT from 63 postmenopausal women with (n=50) and without (n=13) per oral HT were analyzed for estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and serum estrone sulfate using liquid chromatography-tandem mass spectrometry. Steroid sulfatase activity was measured using radiolabeled precursors. mRNA expression of genes encoding sex steroid-metabolizing enzymes and receptors was performed using real-time reverse transcription quantitative polymerase chain reaction. RESULTS: HT users had 4- to 7-fold higher concentrations of estrone and estradiol in subcutaneous and visceral AT, and 30% lower testosterone in visceral AT compared to non-users. Estrogen-to-androgen ratios were 4- to 12-fold higher in AT of users compared to non-users of HT. In visceral AT, estrogen-to-androgen ratios increased with HT estradiol dose. AT to serum ratios of estrone and estradiol remained high in HT users. CONCLUSIONS: Higher local estrogen to androgen ratios and high AT to serum ratios of estrogen concentrations in HT users suggest that HT may significantly influence intracrine sex steroid metabolism in AT, and these local changes could be involved in the preventive effect of HT on menopause-associated abdominal adiposity.

Comparison and precision of visceral adipose tissue measurement techniques in a multisite longitudinal study using MRI.

BACKGROUND: Measurement of visceral adipose tissue (VAT) using magnetic resonance imaging (MRI) is considered accurate and safe. Single slice measurements perform similar to volumetric measurements for cross-sectional observation studies but may not perform as well for longitudinal studies. This study compared the performance of single slice to volumetric VAT measurements in a prospective longitudinal study. Consistency of results across sites and over time was also evaluated. METHODS: A total of 935 healthy participants were recruited and scanned with MRI twice, approximately six months apart as part of a randomized, controlled, parallel arm, unblinded study conducted at four clinical centers in the United States. A 3D Dixon MRI sequence was used to image the abdomen, and visceral fat volumes were quantified for the abdomen, reduced coverage volumes (11 and 25 slices), and at single slices positioned at anatomical landmarks. A traveling phantom was scanned twice at all imaging sites. RESULTS: The correlation of single slice VAT measurement to full abdomen volumetric measurements ranged from 0.78 to 0.93 for cross-sectional observation measurements and 0.30 to 0.55 for longitudinal change. Reduced coverage volumetric measurement outperformed single slice measurements but still showed improved precision with more slices with cross-sectional observation and longitudinal correlations of 0.94 and 0.66 for 11 slices and 0.94 and 0.70 for 25 slices, respectively. No significant differences were observed across sites or over time with the traveling phantom and the volume measurements had a standard deviation of 14.1 mL, 2.6% of the measured volume. CONCLUSION: Single slice VAT measurements had significantly lower correlation with abdomen VAT volume for longitudinal change than for cross-sectional observation measurements and may not be suitable for longitudinal studies. Data from multiple sites, different scanners, and over time did not show significant differences.

M6A modification and T cells in adipose tissue inflammation.

Adipose tissue in the obese state can lead to low-grade chronic inflammation while inducing or exacerbating obesity-related metabolic diseases and impairing overall health.T cells, which are essential immune cells similar to macrophages, are widely distributed in adipose tissue and perform their immunomodulatory function; they also cross-talk with other cells in the vascular stromal fraction. Based on a large number of studies, it has been found that N6 methyl adenine (m6A) is one of the most representative of epigenetic modifications, which affects the crosstalk between T cells, as well as other immune cells, in several ways and plays an important role in the development of adipose tissue inflammation and related metabolic diseases. In this review, we first provide an overview of the widespread presence of T cells in adipose tissue and summarize the key role of T cells in adipose tissue inflammation. Next, we explored the effects of m6A modifications on T cells in adipose tissue from the perspective of adipose tissue inflammation. Finally, we discuss the impact of m6a-regulated crosstalk between T cells and immune cells on the prospects for improving adipose tissue inflammation research, providing additional new ideas for the treatment of obesity.

SGLT2 inhibitor canagliflozin reduces visceral adipose tissue in db/db mice by modulating AMPK/KLF4 signaling and regulating mitochondrial dynamics to induce browning.

Obesity is characterized by excessive accumulation of adipose tissue (mainly visceral). The morphology and function of mitochondria are crucial for regulating adipose browning and weight loss. Research suggests that the SGLT2 inhibitor canagliflozin may induce weight loss through an unknown mechanism, particularly targeting visceral adipose tissue. While Krueppel-Like Factor 4 (KLF4) is known to be essential for energy metabolism and mitochondrial function, its specific impact on visceral adipose tissue remains unclear. We administered canagliflozin to db/db mice for 8 weeks, or exposed adipocytes to canagliflozin for 24 h. The expression levels of browning markers, mitochondrial dynamics, and KLF4 were assessed. Then we validated the function of KLF4 through overexpression in vivo and in vitro. Adenosine monophosphate-activated protein kinase (AMPK) agonists, inhibitors, and KLF4 si-RNA were employed to elucidate the relationship between AMPK and KLF4. The findings demonstrated that canagliflozin significantly decreased body weight in db/db mice and augmented cold-induced thermogenesis. Additionally, canagliflozin increased the expression of mitochondrial fusion-related factors while reducing the levels of fission markers in epididymal white adipose tissue. These consistent findings were mirrored in canagliflozin-treated adipocytes. Similarly, overexpression of KLF4 in both adipocytes and db/db mice yielded comparable results. In all, canagliflozin mitigates obesity in db/db mice by promoting the brown visceral adipocyte phenotype through enhanced mitochondrial fusion via AMPK/KLF4 signaling.

RNA editing landscape of adipose tissue in polycystic ovary syndrome provides insight into the obesity-related immune responses.

Background: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder with wide-ranging metabolic implications, including obesity. RNA editing, a post-transcriptional modification, can fine-tune protein function and introduce heterogeneity. However, the role of RNA editing and its impact on adipose tissue function in PCOS remain poorly understood. Methods: This study aimed to comprehensively analyze RNA-editing events in abdominal and subcutaneous adipose tissue of PCOS patients and healthy controls using high-throughput whole-genome sequencing (WGS) and RNA sequencing. Results: Our results revealed that PCOS patients exhibited more RNA-editing sites, with adenosine-to-inosine (A-to-I) editing being prevalent. The expression of ADAR genes, responsible for A-to-I editing, was also higher in PCOS. Aberrant RNA-editing sites in PCOS adipose tissue was enriched in immune responses, and interleukin-12 biosynthetic process. Tumor necrosis factor (TNF) signaling, nuclear factor kappa B (NF-κB) signaling, Notch signaling, terminal uridylyl transferase 4 (TUT4), hook microtubule tethering protein 3 (HOOK3), and forkhead box O1 (FOXO1) were identified to be of significant differences. Differentially expressed genes (DEGs) in PCOS adipose tissue were enriched in immune responses compared with controls, and the DEGs between subcutaneous and abdominal adipose tissue were also enriched in immune responses suggesting the important role of subcutaneous adipose tissue. Furthermore, we identified the correlations between RNA editing levels and RNA expression levels of specific genes, such as ataxia-telangiectasia mutated (ATM) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) in inflammation pathways and ATM, TUT4, and YTH N6-methyladenosine RNA-binding protein C2 (YTHDC2) in oocyte development pathway. Conclusions: These findings suggest that RNA-editing dysregulation in PCOS adipose tissue may contribute to inflammatory dysregulations. Understanding the interplay between RNA editing and adipose tissue function may unveil potential therapeutic targets for PCOS management. However, further research and validation are required to fully elucidate the molecular mechanisms underlying these associations.

Increased secretion of adipocyte-derived extracellular vesicles is associated with adipose tissue inflammation and the mobilization of excess lipid in human obesity.

BACKGROUND: Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesity's impact on EV secretion from human AT remains limited. METHODS: We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry. RESULTS: EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation. CONCLUSIONS: We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.

Generation of functionally active resident macrophages from adipose tissue by 3D cultures.

Introduction: Within adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties. Methods: Stroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate. Results: This innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow-derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages. Discussion: Our study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.

Fgf9 regulates bone marrow mesenchymal stem cell fate and bone-fat balance in osteoporosis by PI3K/AKT/Hippo and MEK/ERK signaling.

Bone-fat balance is crucial to maintain bone homeostasis. As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal stem cells (BMSCs) are delicately balanced for their differentiation commitment. However, the exact mechanisms governing BMSC cell fate are unclear. In this study, we discovered that fibroblast growth factor 9 (Fgf9), a cytokine expressed in the bone marrow niche, controlled bone-fat balance by influencing the cell fate of BMSCs. Histomorphology and cytodifferentiation analysis showed that Fgf9 loss-of-function mutation (S99N) notably inhibited bone marrow adipose tissue (BMAT) formation and alleviated ovariectomy-induced bone loss and BMAT accumulation in adult mice. Furthermore, in vitro and in vivo investigations demonstrated that Fgf9 altered the differentiation potential of BMSCs, shifting from osteogenesis to adipogenesis at the early stages of cell commitment. Transcriptomic and gene expression analyses demonstrated that FGF9 upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. Mechanistic studies revealed that FGF9, through FGFR1, promoted adipogenic gene expression via PI3K/AKT/Hippo pathways and inhibited osteogenic gene expression via MAPK/ERK pathway. This study underscores the crucial role of Fgf9 as a cytokine regulating the bone-fat balance in adult bone, suggesting that FGF9 is a potentially therapeutic target in the treatment of osteoporosis.

Effectiveness of human adipose tissue-derived mesenchymal stem cells expressing alpha-1 antitrypsin gene in liver fibrosis: a study in mice.

Aim: The present study examined the protective potential of human adipose tissue-derived mesenchymal stem cells (hASCs) modified to overexpress alpha-1 antitrypsin (AAT), in a mouse model of the liver fibrosis. Background: For the treatment of end-stage liver diseases, cell therapy has emerged as a promising noninvasive alternative to liver transplantation. Mesenchymal stem cells (MSCs) are being evaluated due to their dual capabilities of promoting liver regeneration and modulating the pathogenic inflammation of the immune system. Methods: Liver fibrosis was induced in mice via the intraperitoneal injection of carbon tetrachloride (CCl4). MSCs were extracted from the human adipose tissue. After stemness confirmation, the cells were transduced with the lentiviruses containing the AAT gene, and then injected into the mice's tail vein. Fourteen days' post-transplantation, mice were sacrificed, and blood and tissue samples were collected for analysis. Important liver enzymes, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin, and total bilirubin (TB), were measured. Histological studies were carried out using the hematoxylin and eosin (H&E), as well as Masson's trichrome (MT) staining. Results: Compared to hASCs, treatment with AAT-hASCs resulted in greater reductions in ALT, AST, ALP, and TB, as well as normalized albumin levels. AAT-hASCs promoted enhanced liver regeneration histologically, likely attributable to anti-inflammatory and anti-proteolytic properties of AAT. Conclusion: These findings indicate AAT-engineered hASCs as a promising cell-gene therapy candidate for further study in liver cirrhosis models.

MicroRNA-21 modulates brown adipose tissue adipogenesis and thermogenesis in a mouse model of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with increased obesity, hyperandrogenism, and altered brown adipose tissue (BAT) thermogenesis. MicroRNAs play critical functions in brown adipocyte differentiation and maintenance. We aim to study the role of microRNA-21 (miR-21) in altered energy homeostasis and BAT thermogenesis in a PCOS mouse model of peripubertal androgen exposure. METHODS: Three-week-old miR-21 knockout (miR21KO) or wild-type (WT) female mice were treated with dihydrotestosterone (DHT) or vehicle for 90 days. Body composition was determined by EchoMRI. Energy expenditure (EE), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory exchange ratio (RER) were measured by indirect calorimetry. Androgen receptor (AR), and markers of adipogenesis, de novo lipogenesis, angiogenesis, extracellular matrix remodeling, and thermogenesis were quantified by RT-qPCR and/or Western-blot. RESULTS: MiR-21 ablation attenuated DHT-mediated increase in body weight while having no effect on fat or BAT mass. MiR-21 ablation attenuated DHT-mediated BAT AR upregulation. MiR-21 ablation did not alter EE; however, miR21KO DHT-treated mice have reduced VO2, VCO2, and RER. MiR-21 ablation reversed DHT-mediated decrease in food intake and increase in sleep time. MiR-21 ablation decreased some adipogenesis (Adipoq, Pparγ, and Cebpß) and extracellular matrix remodeling (Mmp-9 and Timp-1) markers expression in DHT-treated mice. MiR-21 ablation abolished DHT-mediated increases in thermogenesis markers Cpt1a and Cpt1b, while decreasing CIDE-A expression. CONCLUSIONS: Our findings suggest that BAT miR-21 may play a role in regulating DHT-mediated thermogenic dysfunction in PCOS. Modulation of BAT miR-21 levels could be a novel therapeutic approach for the treatment of PCOS-associated metabolic derangements.

Polycystic ovary syndrome (PCOS) is a common hormone disorder in premenopausal women, often linked to obesity and abnormal brown fat tissue activity. Women with PCOS have elevated male hormones, which are responsible for many metabolic problems. Our study focuses on understanding the role of microRNA-21 (miR-21) in the energy balance and brown fat tissue activity in a PCOS mouse model. We studied female mice with and without miR-21, treating them with a male hormone. We measured body composition and energy expenditure. We also analyzed the levels of specific genes and proteins related to fat tissue and energy production. Our findings showed that mice lacking miR-21 had less weight gain in response to male hormones, without fat or brown fat tissue mass changes. They also had reduced energy production, changed eating habits, and altered expression of genes related to fat tissue and energy production. In conclusion, our study suggests that miR-21 in brown fat tissue may regulate the energy imbalance caused by male hormones in PCOS. Adjusting miR-21 levels in brown fat tissue could be a new way to address the metabolic issues associated with PCOS.

Optimization and validation of a fat-on-a-chip model for non-invasive therapeutic drug discovery.

Obesity is a significant public health concern that is closely associated with various comorbidities such as heart disease, stroke, type II diabetes (T2D), and certain cancers. Due to the central role of adipose tissue in many disease etiologies and the pervasive nature in the body, engineered adipose tissue models are essential for drug discovery and studying disease progression. This study validates a fat-on-a-chip (FOAC) model derived from primary mature adipocytes. Our FOAC model uses a Micronit perfusion device and introduces a novel approach for collecting continuous data by using two non-invasive readout techniques, resazurin and glucose uptake. The Micronit platform proved to be a reproducible model that can effectively maintain adipocyte viability, metabolic activity, and basic functionality, and is capable of mimicking physiologically relevant responses such as adipocyte hypertrophy and insulin-mediated glucose uptake. Importantly, we demonstrate that adipocyte size is highly dependent on extracellular matrix properties, as adipocytes derived from different patients with variable starting lipid areas equilibrate to the same size in the hyaluronic acid hydrogel. This model can be used to study T2D and monitor adipocyte responses to insulin for longitudinally tracking therapeutic efficacy of novel drugs or drug combinations.

Outcomes of combined mitochondria and mesenchymal stem cells-derived exosome therapy in rat acute respiratory distress syndrome and sepsis.

BACKGROUND: The treatment of acute respiratory distress syndrome (ARDS) complicated by sepsis syndrome (SS) remains challenging. AIM: To investigate whether combined adipose-derived mesenchymal-stem-cells (ADMSCs)-derived exosome (EXAD) and exogenous mitochondria (mitoEx) protect the lung from ARDS complicated by SS. METHODS: In vitro study, including L2 cells treated with lipopolysaccharide (LPS) and in vivo study including male-adult-SD rats categorized into groups 1 (sham-operated-control), 2 (ARDS-SS), 3 (ARDS-SS + EXAD), 4 (ARDS-SS + mitoEx), and 5 (ARDS-SS + EXAD + mitoEx), were included in the present study. RESULTS: In vitro study showed an abundance of mitoEx found in recipient-L2 cells, resulting in significantly higher mitochondrial-cytochrome-C, adenosine triphosphate and relative mitochondrial DNA levels (P < 0.001). The protein levels of inflammation [interleukin (IL)-1ß/tumor necrosis factor (TNF)-α/nuclear factor-κB/toll-like receptor (TLR)-4/matrix-metalloproteinase (MMP)-9/oxidative-stress (NOX-1/NOX-2)/apoptosis (cleaved-caspase3/cleaved-poly (ADP-ribose) polymerase)] were significantly attenuated in lipopolysaccharide (LPS)-treated L2 cells with EXAD treatment than without EXAD treatment, whereas the protein expressions of cellular junctions [occluding/ß-catenin/zonula occludens (ZO)-1/E-cadherin] exhibited an opposite pattern of inflammation (all P < 0.001). Animals were euthanized by 72 h post-48 h-ARDS induction, and lung tissues were harvested. By 72 h, flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflammatory cells (Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+) and albumin were lowest in group 1, highest in group 2, and significantly higher in groups 3 and 4 than in group 5 (all P < 0.0001), whereas arterial oxygen-saturation (SaO2%) displayed an opposite pattern of albumin among the groups. Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers (CD68+/γ-H2AX) displayed an identical pattern of SaO2% among the groups (all P < 0.0001). The protein expressions of inflammatory (TLR-4/MMP-9/IL-1ß/TNF-α)/oxidative stress (NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged (cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic (beclin-1/Atg-5/ratio of LC3B-II/LC3B-I) biomarkers exhibited a similar manner, whereas antioxidants [nuclear respiratory factor (Nrf)-1/Nrf-2]/cellular junctions (ZO-1/E-cadherin)/mitochondrial electron transport chain (complex I-V) exhibited an opposite manner of albumin among the groups (all P < 0.0001). CONCLUSION: Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.

Regional adiposity and insulin sensitivity - interactions with menopause and HIV in middle-aged Black African women.

OBJECTIVE: To explore depot-specific functional aspects of adipose tissue, examining the putative role for menopause and HIV status on insulin sensitivity (SI) and beta-cell function in Black South African women. METHODS: Women (n = 92) from the Middle-Aged Soweto Cohort, including premenopausal HIV-negative (n = 21); premenopausal women living with HIV (WLWH; n = 11); postmenopausal HIV-negative (n = 42); postmenopausal WLWH (n = 18) underwent the following tests: body composition (dual energy x-ray absorptiometry); fasting bloods for sex hormones, inflammation and adipokines; frequently sampled intravenous glucose tolerance test for SI and beta-cell function (disposition index, DI); abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) biopsies for cell size and mRNA expression of adipokines, inflammation, and estrogen receptors [ER]. RESULTS: Depot-specific associations between gene expression and insulin parameters did not differ by HIV or menopause status. Pooled analysis showed significant models for SI (P = 0.002) and DI (P = 0.003). Higher SI was associated with lower leptin and CD11c expression in aSAT and higher adiponectin in gSAT. Higher DI was associated with higher aSAT and gSAT expression of adiponectin, LPL, ERα, and PPARγ, and lower leptin in aSAT. WLWH had higher expression of adiponectin and lower expression of leptin in both aSAT (P = 0.002 and P = 0.005) and gSAT (P = 0.004 and P = 0.002), respectively, and a larger proportion of smaller cells in aSAT (P < 0.001). CONCLUSION: Insulin sensitivity and beta cell function were distinctively associated with aSAT and gSAT. While menopause did not influence these relationships, HIV had a significant effect on adipose tissue, characterised by variations in cell size distribution and transcript levels within the depots.

A Rare Case of Sublingual Lipoma.

Lipomas are benign soft tissue tumors that are ubiquitous in nature. Available literature suggests that benign tumors are harmless unless they increase in size, resulting in compression of vital structures. This case report discusses the case of a 52-year-old man who presented to the clinic with a painless, growing lump on the right side of his mouth. The patient's symptoms included difficulty swallowing and speaking, which led the doctors to recommend surgical excision of the mass. There were no issues during the mass removal surgery, and the incision healed without compromising the lingual or hypoglossal nerves or Wharton's duct, as observed during follow-up visits. Patient history, symptoms, preoperative examination, treatment strategy, and surgical technique are all included in this case study, which focuses on the extremely unusual development of lipomas in the oral cavity, particularly on the floor of the mouth.

Hibernoma in the renal sinus: A case mimicking malignancy.

Introduction: Hibernomas are benign tumors of brown adipose tissue. Hibernoma in the renal sinus is extremely rare. Herein, we present the third known case of renal hibernoma. Case presentation: A 71-year-old man reported to our department with a left kidney tumor with an average growth rate of 5 mm/year and a progressive contrast effect on computed tomography. It was diagnosed as a hibernoma following a laparoscopic radical nephrectomy. Conclusion: We encountered a rare case of a hibernoma in the renal sinus. Development of new and accurate diagnostic methods for hibernoma, without resorting to nephrectomy, is essential.

Excessive accumulation of epicardial adipose tissue promotes microvascular obstruction formation after myocardial ischemia/reperfusion through modulating macrophages polarization.

BACKGROUND: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship. METHODS: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation. RESULTS: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation. CONCLUSIONS: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.