Increased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes.

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions.

Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver. METHODS: To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals' subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis. FINDINGS: We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels. INTERPRETATION: Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease. FUNDING: The work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research.

Application of MRI-Based Radiomics in Preoperative Prediction of NF2 Alteration in Intracranial Meningiomas.

Purpose: This study aimed to investigate the feasibility of predicting NF2 mutation status based on the MR radiomic analysis in patients with intracranial meningioma. Methods: This retrospective study included 105 patients with meningiomas, including 60 NF2-mutant samples and 45 wild-type samples. Radiomic features were extracted from magnetic resonance imaging scans, including T1-weighted, T2-weighted, and contrast T1-weighted images. Student's t-test and LASSO regression were performed to select the radiomic features. All patients were randomly divided into training and validation cohorts in a 7:3 ratio. Five linear models (RF, SVM, LR, KNN, and xgboost) were trained to predict the NF2 mutational status. Receiver operating characteristic curve and precision-recall analyses were used to evaluate the model performance. Student's t-tests were then used to compare the posterior probabilities of NF2 mut/loss prediction for patients with different NF2 statuses. Results: Nine features had nonzero coefficients in the LASSO regression model. No significant differences was observed in the clinical features. Nine features showed significant differences in patients with different NF2 statuses. Among all machine learning algorithms, SVM showed the best performance. The area under curve and accuracy of the predictive model were 0.85; the F1-score of the precision-recall curve was 0.80. The model risk was assessed by plotting calibration curves. The p-value for the H-L goodness of fit test was 0.411 (p> 0.05), which indicated that the difference between the obtained model and the perfect model was statistically insignificant. The AUC of our model in external validation was 0.83. Conclusion: A combination of radiomic analysis and machine learning showed potential clinical utility in the prediction of preoperative NF2 status. These findings could aid in developing customized neurosurgery plans and meningioma management strategies before postoperative pathology.

Hsp90 induces Acsl4-dependent glioma ferroptosis via dephosphorylating Ser637 at Drp1.

Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by the iron-dependent lipid reactive oxygen species (ROS) accumulation, but its mechanism in gliomas remains elusive. Acyl-coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4), a pivotal enzyme in the regulation of lipid biosynthesis, benefits the initiation of ferroptosis, but its role in gliomas needs further clarification. Erastin, a classic inducer of ferroptosis, has recently been found to regulate lipid peroxidation by regulating Acsl4 other than glutathione peroxidase 4 (GPX4) in ferroptosis. In this study, we demonstrated that heat shock protein 90 (Hsp90) and dynamin-related protein 1 (Drp1) actively regulated and stabilized Acsl4 expression in erastin-induced ferroptosis in gliomas. Hsp90 overexpression and calcineurin (CN)-mediated Drp1 dephosphorylation at serine 637 (Ser637) promoted ferroptosis by altering mitochondrial morphology and increasing Acsl4-mediated lipid peroxidation. Importantly, promotion of the Hsp90-Acsl4 pathway augmented anticancer activity of erastin in vitro and in vivo. Our discovery reveals a novel and efficient approach to ferroptosis-mediated glioma therapy.

Integrated analysis reveals prognostic value and mesenchymal identity suppression by glycoprotein M6B in glioma.

Glioblastoma (GBM) stem cells (GSCs) possess multilineage differentiation potential, which is responsible for cancer progression. Glycoprotein M6B (GPM6B) is a pivotal enzyme in regulating intracranial cell differentiation and neuronal myelination, and is widely studied in several cancers. However, research on GPM6B in glioma is limited. In this study, we analyzed the clinical and molecular characteristics of GPM6B using RNA sequencing data of glioma samples from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets. Quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC) were performed for further validation. Moreover, a neurosphere formation assay, extreme limiting dilution assay, and bioluminescent imaging were employed to validate the therapeutic effects targeted on GPM6B in vitro and in vivo. We found lower expression of GPM6B in aggressive glioma. Receiver operating characteristic (ROC) analysis suggested that GPM6B is an indicator of mesenchymal subtype. Kaplan-Meier analysis also revealed that patients with glioma with high GPM6B expression levels had a tendency toward prolonged survival. The GPM6B expression level could predict favorable prognosis of patients independent of age, grade, IDH status, and 1p/19q status. Additionally, targeting GPM6B impaired the self-renewal and tumorgenicity of mesenchymal GSCs by inhibiting the activation of the Wnt pathway in vitro and in vivo. Our results demonstrated that GPM6B is a crucial predictor in glioma prognosis and represents an underlying therapeutic target in GSC therapy.

Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype.

Chromosomal abnormality is one of the important causes of dysplasia in children. However, due to regional and ethnic differences, the reported rates of chromosomal abnormalities in patients with dysplasia vary greatly. Moreover, the clinical manifestations in children with rare chromosomal diseases were heterogeneous. So, we retrospectively analyzed the karyotype results of 436 children with dysplasia and conducted a detailed analysis of rare chromosomal diseases. The results showed that chromosomal abnormalities were present in 181 of 436 cases. Intellectual disability, dysmorphology, congenital malformations, the disorder of sexual development, and short stature were the main five clinical symptoms in children with chromosomal abnormalities. Moreover, 136 cases of Trisomy 21 (Tri21) were detected, of which 130 were standard Tri21, 5 were robertsonian Tri21, and 1 was chimera type. In addition, 16 cases of rare abnormal karyotype, including complex Tri21, complex Turner syndrome, 4p-syndrome, 18q-syndrome, and 5p-syndrome, were also detected. In summary, chromosome abnormality is one of the important causes of dysplasia in children. Furthermore, prenatal screening and diagnosis could play a great significance in preventing dysplasia in children. In addition, the retrospective analysis of rare cases is valuable for clinical diagnosis and risk assessment of recurrence.

Loss of deubiquitylase USP2 triggers development of glioblastoma via TGF-ß signaling.

Glioblastoma (GBM) is the most aggressive primary brain tumor as one of the deadliest cancers. The TGF-ß signaling acts as an oncogenic factor in GBM, and plays vital roles in development of GBM. SMAD7 is a major inhibitor of TGF-ß signaling, while the deubiquitination of SMAD7 has been poorly studied in GBM. Here, we found USP2 as a new prominent candidate that could regulate SMAD7 stability. USP2 was lost in GBM, leading to the poor prognosis in patients. Moreover, aberrant DNA methylation mediated by DNMT3A induced the low expression of USP2 in GBM. USP2 depletion induced TGF-ß signaling and progression of GBM. In contrast, overexpressed USP2 suppressed TGF-ß signaling and GBM development. Specifically, USP2 interacted with SMAD7 and prevented SMAD7 ubiquitination. USP2 directly cleaved Lys27- and Lys48-linked poly-ubiquitin chains of SMAD7, and Lys27-linked poly-ubiquitin chains of SMAD7 K185 mediated the recruitment of SMAD7 to HERC3, which regulated Lys63-linked poly-ubiquitination of SMAD7. Moreover, we demonstrated that the DNMT3A inhibitor SGI-1027 induced USP2, suppressed TGF-ß signaling and GBM development. Thus, USP2 repressed development of GBM by inhibition TGF-ß signaling pathway via the deubiquitination of SMAD7.

Cytogenetic analysis of 2959 couples with spontaneous abortion and detailed analysis of rare karyotypes.

Chromosome abnormality is one of the important causes of spontaneous abortion. However, due to regional and ethnic differences, the reported rates of chromosomal abnormalities in patients with spontaneous abortion vary greatly. At present, there is no large sample statistics of chromosome abnormality in patients with spontaneous abortion in Yantai, Shandong province, China and hence 2959 couples (5918 individuals) with spontaneous abortion were recruited for this study. G banding was used to examine the karyotype of patients. The results showed that chromosomal abnormalities were present in 173 of 2959 couples with the rate of 5.85%. Female carriers were significantly higher than male. Chromosomal abnormality rate was positively correlated with the number of spontaneous abortions. Structural aberrations were significantly greater than numerical aberrations, with a prevalence of 92.49% and 7.51%, respectively. Balanced translocation, Robertson translocation and inversion were the most common types of chromosomal structural abnormalities. Among them, the proportion of balanced translocation was the highest (63.13%, 101/160). In addition, three cases of rare complex abnormal karyotype were detected. In summary, chromosome abnormality could be one of the important causes of spontaneous abortion in Yantai, Shandong province, China. The sex of patients with chromosomal abnormalities and the number of spontaneous abortions should be considered in genetic counselling. When one of the partners have chromosome abnormality, preimplantation genetic diagnosis and prenatal diagnosis could play a great significance for preventing the birth of children with chromosomal diseases and reducing birth defects.

Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease.

The prevalence of non-alcoholic fatty liver disease (NAFLD), now also known as metabolic dysfunction-associated fatty liver disease (MAFLD), is rapidly increasing worldwide due to the ongoing obesity epidemic. However, currently the NALFD diagnosis requires non-readily available imaging technologies or liver biopsy, which has drastically limited the sample sizes of NAFLD studies and hampered the discovery of its genetic component. Here we utilized the large UK Biobank (UKB) to accurately estimate the NAFLD status in UKB based on common serum traits and anthropometric measures. Scoring all individuals in UKB for NAFLD risk resulted in 28,396 NAFLD cases and 108,652 healthy individuals at a >90% confidence level. Using this imputed NAFLD status to perform the largest NAFLD genome-wide association study (GWAS) to date, we identified 94 independent (R2 < 0.2) NAFLD GWAS loci, of which 90 have not been identified before; built a polygenic risk score (PRS) model to predict the genetic risk of NAFLD; and used the GWAS variants of imputed NAFLD for a tissue-aware Mendelian randomization analysis that discovered a significant causal effect of NAFLD on coronary artery disease (CAD). In summary, we accurately estimated the NAFLD status in UKB using common serum traits and anthropometric measures, which empowered us to identify 90 GWAS NAFLD loci, build NAFLD PRS, and discover a significant causal effect of NAFLD on CAD.

Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) causes a high rate of mortality and disability, and its treatment is still limited. Loss of neurons in damaged area is hardly rescued by relative molecular therapies. Based on its disease characteristics, we transplanted human embryonic stem cell- (hESC-) derived cerebral organoids in the brain lesions of controlled cortical impact- (CCI-) modeled severe combined immunodeficient (SCID) mice. Grafted organoids survived and differentiated in CCI-induced lesion pools in mouse cortical tissue. Implanted cerebral organoids differentiated into various types of neuronal cells, extended long projections, and showed spontaneous action, as indicated by electromyographic activity in the grafts. Induced vascularization and reduced glial scar were also found after organoid implantation, suggesting grafting could improve local situation and promote neural repair. More importantly, the CCI mice's spatial learning and memory improved after organoid grafting. These findings suggest that cerebral organoid implanted in lesion sites differentiates into cortical neurons, forms long projections, and reverses deficits in spatial learning and memory, a potential therapeutic avenue for TBI.

Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke.

Ischemic stroke poses a significant health risk due to its high rate of disability and mortality. To address this problem, several therapeutic approaches have been proposed, including interruption targeting programmed cell death (PCD). Ferroptosis is a newly defined PCD characterized by iron-dependent accumulation of lipid peroxidation, and is becoming a promising target for treating numerous diseases. To explore the underlying mechanisms of the initiation and execution of ferroptosis in ischemic stroke, we established stroke models in vivo and in vitro simulating ischemia/reperfusion (I/R) neuronal injury. Different from previous reports on stroke, we tested ferroptosis by measuring the levels of core proteins, such as ACSL4, 15-LOX2, Ferritin and GPX4. In addition, I/R injury induces excessive degradation of ferritin via the autophagy pathway and subsequent increase of free iron in neurons. This phenomenon has recently been termed ferritinophagy and reported to be regulated by nuclear receptor coactivator 4 (NCOA4) in some cell lines. Increased NCOA4 in cytoplasm was detected in our study and then silenced by shRNA to investigate its function. Both in vivo and in vitro, NCOA4 deletion notably abrogated ferritinophagy caused by I/R injury and thus inhibited ferroptosis. Furthermore, we found that NCOA4 was upregulated by ubiquitin specific peptidase 14 (USP14) via a deubiquitination process in damaged neurons, and we found evidence of pharmacological inhibition of USP14 effectively reducing NCOA4 levels to protect neurons from ferritinophagy-mediated ferroptosis. These findings suggest a novel and effective target for treating ischemic stroke.

Identification of TBX15 as an adipose master trans regulator of abdominal obesity genes.

BACKGROUND: Obesity predisposes individuals to multiple cardiometabolic disorders, including type 2 diabetes (T2D). As body mass index (BMI) cannot reliably differentiate fat from lean mass, the metabolically detrimental abdominal obesity has been estimated using waist-hip ratio (WHR). Waist-hip ratio adjusted for body mass index (WHRadjBMI) in turn is a well-established sex-specific marker for abdominal fat and adiposity, and a predictor of adverse metabolic outcomes, such as T2D. However, the underlying genes and regulatory mechanisms orchestrating the sex differences in obesity and body fat distribution in humans are not well understood. METHODS: We searched for genetic master regulators of WHRadjBMI by employing integrative genomics approaches on human subcutaneous adipose RNA sequencing (RNA-seq) data (n ~ 1400) and WHRadjBMI GWAS data (n ~ 700,000) from the WHRadjBMI GWAS cohorts and the UK Biobank (UKB), using co-expression network, transcriptome-wide association study (TWAS), and polygenic risk score (PRS) approaches. Finally, we functionally verified our genomic results using gene knockdown experiments in a human primary cell type that is critical for adipose tissue function. RESULTS: Here, we identified an adipose gene co-expression network that contains 35 obesity GWAS genes and explains a significant amount of polygenic risk for abdominal obesity and T2D in the UKB (n = 392,551) in a sex-dependent way. We showed that this network is preserved in the adipose tissue data from the Finnish Kuopio Obesity Study and Mexican Obesity Study. The network is controlled by a novel adipose master transcription factor (TF), TBX15, a WHRadjBMI GWAS gene that regulates the network in trans. Knockdown of TBX15 in human primary preadipocytes resulted in changes in expression of 130 network genes, including the key adipose TFs, PPARG and KLF15, which were significantly impacted (FDR < 0.05), thus functionally verifying the trans regulatory effect of TBX15 on the WHRadjBMI co-expression network. CONCLUSIONS: Our study discovers a novel key function for the TBX15 TF in trans regulating an adipose co-expression network of 347 adipose, mitochondrial, and metabolically important genes, including PPARG, KLF15, PPARA, ADIPOQ, and 35 obesity GWAS genes. Thus, based on our converging genomic, transcriptional, and functional evidence, we interpret the role of TBX15 to be a main transcriptional regulator in the adipose tissue and discover its importance in human abdominal obesity.

Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury.

Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.

Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.

Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.

Differential Mitochondrial Gene Expression in Adipose Tissue Following Weight Loss Induced by Diet or Bariatric Surgery.

CONTEXT: Mitochondria are essential for cellular energy homeostasis, yet their role in subcutaneous adipose tissue (SAT) during different types of weight-loss interventions remains unknown. OBJECTIVE: To investigate how SAT mitochondria change following diet-induced and bariatric surgery-induced weight-loss interventions in 4 independent weight-loss studies. METHODS: The DiOGenes study is a European multicenter dietary intervention with an 8-week low caloric diet (LCD; 800 kcal/d; n = 261) and 6-month weight-maintenance (n = 121) period. The Kuopio Obesity Surgery study (KOBS) is a Roux-en-Y gastric bypass (RYGB) surgery study (n = 172) with a 1-year follow-up. We associated weight-loss percentage with global and 2210 mitochondria-related RNA transcripts in linear regression analysis adjusted for age and sex. We repeated these analyses in 2 studies. The Finnish CRYO study has a 6-week LCD (800-1000 kcal/d; n = 19) and a 10.5-month follow-up. The Swedish DEOSH study is a RYGB surgery study with a 2-year (n = 49) and 5-year (n = 37) follow-up. RESULTS: Diet-induced weight loss led to a significant transcriptional downregulation of oxidative phosphorylation (DiOGenes; ingenuity pathway analysis [IPA] z-scores: -8.7 following LCD, -4.4 following weight maintenance; CRYO: IPA z-score: -5.6, all P < 0.001), while upregulation followed surgery-induced weight loss (KOBS: IPA z-score: 1.8, P < 0.001; in DEOSH: IPA z-scores: 4.0 following 2 years, 0.0 following 5 years). We confirmed an upregulated oxidative phosphorylation at the proteomics level following surgery (IPA z-score: 3.2, P < 0.001). CONCLUSIONS: Differentially regulated SAT mitochondria-related gene expressions suggest qualitative alterations between weight-loss interventions, providing insights into the potential molecular mechanistic targets for weight-loss success.

Serum aromatic and branched-chain amino acids associated with NASH demonstrate divergent associations with serum lipids.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has been associated with multiple metabolic abnormalities. By applying a non-targeted metabolomics approach, we aimed at investigating whether serum metabolite profile that associates with NAFLD would differ in its association with NAFLD-related metabolic risk factors. METHODS & RESULTS: A total of 233 subjects (mean ± SD: 48.3 ± 9.3 years old; BMI: 43.1 ± 5.4 kg/m2 ; 64 male) undergoing bariatric surgery were studied. Of these participants, 164 with liver histology could be classified as normal liver (n = 79), simple steatosis (SS, n = 40) or non-alcoholic steatohepatitis (NASH, n = 45). Among the identified fasting serum metabolites with higher levels in those with NASH when compared to those with normal phenotype were the aromatic amino acids (AAAs: tryptophan, tyrosine and phenylalanine), the branched-chain amino acids (BCAAs: leucine and isoleucine), a phosphatidylcholine (PC(16:0/16:1)) and uridine (all FDRp < 0.05). Only tryptophan was significantly higher in those with NASH compared to those with SS (FDRp < 0.05). Only the AAAs tryptophan and tyrosine correlated positively with serum total and LDL cholesterol (FDRp < 0.1), and accordingly, with liver LDLR at mRNA expression level. In addition, tryptophan was the single AA associated with liver DNA methylation of CpG sites known to be differentially methylated in those with NASH. CONCLUSIONS: We found that serum levels of the NASH-related AAAs and BCAAs demonstrate divergent associations with serum lipids. The specific correlation of tryptophan with LDL-c may result from the molecular events affecting LDLR mRNA expression and NASH-associated methylation of genes in the liver.

Clinical, cytogenetic and molecular analyses of a rare case with ring chromosome 15 and review of the literature.

OBJECTIVE: Ring chromosome 15 [r (15)], accompanied by a series of clinical symptoms, is a rare genetic disease. The genotype and phenotypic diversity of patients with r (15) still needed further enrichment. In this study we present a rare case of mosaic ring chromosome 15 with facial anomalies and extremities slenderness. CASE REPORT: This case involves a 30-year-old woman, unpregnancy within 6 years. Clinical examination of the patient only revealed facial anomalies and extremities slenderness. The result of routine G-band karyotyping was 46,XX,r(15)(p12q26.3)[53]/46,XX,r(15;15)(p11.2q26.3;p11.2q11.2)[28]/45,XX, -15[10]/46,XX,r(15;15)(p11q26.3;p11q26.3)[4]. SNP array was employed to investigate the genome copy number variations (CNVs). The result revealed that there was a micro-duplication of 2.0 Mb at 15q26.3(arr[ph19]15q26.3 (100,400,214- 102,429,112)×3). The duplicated chromosomal section encompassed genes including CHSY1, ALDHIA3, LRRK1, and INS1. We further compared to the cytogenetic characteristics and clinical symptoms of the patient with those already reported by reviewing the literature. CONCLUSION: This report is especially helpful to supplement the phenotypic diversity of patients with r (15).

The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.