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Abstract Background Sinetrol® Xpur is a polyphenolic ingredient rich in citrus flavonoids that has shown weight loss effects in previous studies. The dose dependent nature, gut microbial actions of this product has not been explored previously, thus presented in this study. Methods In this open label study, we evaluated the effect of Sinetrol® Xpur supplementation on healthy but overweight/obese adults (20–50 yrs) for 16 weeks. Participants (n = 20) were randomly allocated to a high dose group (HD, 1800 mg/day) or low dose group (LD, 900 mg/day) of the product for 16 weeks. Fat composition, gut microbial composition, were evaluated using MRI and 16S rDNA sequencing respectively at week 1 and 16. Results We observed HDL, HbA1C, LDL and leptin improved significantly over 16 weeks, irrespective of the dosage. There was a trend for decrease in visceral adipose tissue (VAT), BMI over time and body weight displayed a trend for dose dependent decrease. Eubacterium xylanophilum, Ruminococcacea UCG-004 genus which increased in HD and LD respectively were negatively associated to VAT. Both doses increased butyrate producers such as Eubacterium ruminantium and Ruminococcaceae NK4A214 genus. Conclusions Overall chronic supplementation of Sinetrol® Xpur, irrespective of their dose improved HDL, HbA1c, LDL and leptin and tended to decrease visceral adipose tissue via changes in gut microbiota. Trial registration number NCT03823196.

Emerin (EMD) and barrier to autointegration factor 1 (BANF1) each bind A-type lamins (LMNA) as fundamental components of nuclear lamina structure. Mutations in LMNA, EMD and BANF1 are genetically linked to many tissue-specific disorders including Emery-Dreifuss muscular dystrophy and cardiomyopathy (LMNA, EMD), lipodystrophy, insulin resistance and type 2 diabetes (LMNA) and progeria (LMNA, BANF1). To explore human genetic variation in these genes, we analyzed EMD and BANF1 alleles in the Exome Aggregation Consortium (ExAC) cohort of 60,706 unrelated individuals. We identified 13 rare heterozygous BANF1 missense variants (p.T2S, p.H7Y, p.D9N, p.S22R, p.G25E, p.D55N, p.D57Y, p.L63P, p.N70T, p.K72R, p.R75W, p.R75Q, p.G79R), and one homozygous variant (p.D9H). Several variants are known (p.G25E) or predicted (e.g., p.D9H, p.D9N, p.L63P) to perturb BANF1 and warrant further study. Analysis of EMD revealed two previously identified variants associated with adult-onset cardiomyopathy (p.K37del, p.E35K) and one deemed ‘benign’ in an Emery-Dreifuss patient (p.D149H). Interestingly p.D149H was the most frequent emerin variant in ExAC, identified in 58 individuals (overall allele frequency 0.06645%), of whom 55 were East Asian (allele frequency 0.8297%). Furthermore, p.D149H associated with four ‘healthy’ traits: reduced triglycerides (-0.336; p = 0.0368), reduced waist circumference (-0.321; p = 0.0486), reduced cholesterol (-0.572; p = 0.000346) and reduced LDL cholesterol (-0.599; p = 0.000272). These traits are distinct from LMNA-associated metabolic disorders and provide the first insight that emerin influences metabolism. We also identified one novel in-frame deletion (p.F39del) and 62 novel emerin missense variants, many of which were relatively frequent and potentially disruptive including p.N91S and p.S143F (∼0.041% and ∼0.034% of non-Finnish Europeans, respectively), p.G156S (∼0.39% of Africans), p.R204G (∼0.18% of Latinx), p.R207P (∼0.08% of South Asians) and p.R221L (∼0.15% of Latinx). Many novel BANF1 variants are predicted to disrupt dimerization or binding to DNA, histones, emerin or A-type lamins. Many novel emerin variants are predicted to disrupt emerin filament dynamics or binding to BANF1, HDAC3, A-type lamins or other partners. These new human variants provide a foundational resource for future studies to test the molecular mechanisms of BANF1 and emerin function, and to understand the link between emerin variant p.D149H and a ‘healthy’ lipid profile.

Abstract Background The aim of this study (EPIDIAB) was to assess the relationship between epicardial adipose tissue (EAT) and the micro and macrovascular complications (MVC) of type 2 diabetes (T2D). Methods EPIDIAB is a post hoc analysis from the AngioSafe T2D study, which is a multicentric study aimed at determining the safety of antihyperglycemic drugs on retina and including patients with T2D screened for diabetic retinopathy (DR) (n = 7200) and deeply phenotyped for MVC. Patients included who had undergone cardiac CT for CAC (Coronary Artery Calcium) scoring after inclusion (n = 1253) were tested with a validated deep learning segmentation pipeline for EAT volume quantification. Results Median age of the study population was 61 [54;67], with a majority of men (57%) a median duration of the disease 11 years [5;18] and a mean HbA1c of7.8 ± 1.4%. EAT was significantly associated with all traditional CV risk factors. EAT volume significantly increased with chronic kidney disease (CKD vs no CKD: 87.8 [63.5;118.6] vs 82.7 mL [58.8;110.8], p = 0.008), coronary artery disease (CAD vs no CAD: 112.2 [82.7;133.3] vs 83.8 mL [59.4;112.1], p = 0.0004, peripheral arterial disease (PAD vs no PAD: 107 [76.2;141] vs 84.6 mL[59.2; 114], p = 0.0005 and elevated CAC score (> 100 vs

BackgroundType 2 diabetes (T2D) and obesity induce left ventricular (LV) dysfunction. The underlying pathophysiological mechanisms remain unclear, but myocardial triglyceride content (MTGC) could be involved.ObjectivesThis study aimed to determine which clinical and biological factors are associated with increased MTGC and to establish whether MTGC is associated with early changes in LV function.MethodsA retrospective study was conducted using five previous prospective cohorts, leading to 338 subjects studied, including 208 well-phenotyped healthy volunteers and 130 subjects living with T2D and/or obesity. All the subjects underwent proton magnetic resonance spectroscopy and feature tracking cardiac magnetic resonance imaging to measure myocardial strain.ResultsMTGC content increased with age, body mass index (BMI), waist circumference, T2D, obesity, hypertension, and dyslipidemia, but the only independent correlate found in multivariate analysis was BMI (p=0.01; R²=0.20). MTGC was correlated to LV diastolic dysfunction, notably with the global peak early diastolic circumferential strain rate (r=-0.17, p=0.003), the global peak late diastolic circumferential strain rate (r=0.40, p

Abstract Early in the COVID‐19 pandemic, type 2 diabetes (T2D) was marked as a risk factor for severe disease and mortality. Inflammation is central to the aetiology of both conditions where variations in immune responses can mitigate or aggravate disease course. Identifying at‐risk groups based on immunoinflammatory signatures is valuable in directing personalised care and developing potential targets for precision therapy. This observational study characterised immunophenotypic variation associated with COVID‐19 severity in T2D. Broad‐spectrum immunophenotyping quantified 15 leucocyte populations in peripheral circulation from a cohort of 45 hospitalised COVID‐19 patients with and without T2D. Lymphocytopenia and specific loss of cytotoxic CD8+ lymphocytes were associated with severe COVID‐19 and requirement for intensive care in both non‐diabetic and T2D patients. A morphological anomaly of increased monocyte size and monocytopenia restricted to classical CD14Hi CD16− monocytes was specifically associated with severe COVID‐19 in patients with T2D requiring intensive care. Increased expression of inflammatory markers reminiscent of the type 1 interferon pathway (IL6, IL8, CCL2, INFB1) underlaid the immunophenotype associated with T2D. These immunophenotypic and hyperinflammatory changes may contribute to increased voracity of COVID‐19 in T2D. These findings allow precise identification of T2D patients with severe COVID‐19 as well as provide evidence that the type 1 interferon pathway may be an actionable therapeutic target for future studies.

Hypothalamus (HT), this small structure often perceived through the prism of neuroimaging as morphologically and functionally homogeneous, plays a key role in the primitive act of feeding. The current paper aims at reviewing the contribution of magnetic resonance imaging (MRI) in the study of the role of the HT in food intake regulation. It focuses on the different MRI techniques that have been used to describe structurally and functionally the Human HT. The latest advances in HT parcellation as well as perspectives in this field are presented. The value of MRI in the study of eating disorders such as anorexia nervosa (AN) and obesity are also highlighted.

Background/objective: The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children’s irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors. Design: We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n = 12) or not received (n = 12) TBI. Subjects/methods: Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture. Results: Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P = 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1 (minus 39%, P = 0.01) and CIDEA (minus 36%, P = 0.004) and a clear alteration of pre-adipocyte differentiation. Conclusions: These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.

Aim: We aimed to analyze changes in retinal microvascularization with intensive reduction of glycated hemoglobin A1c (HbA1c) in patients with poorly controlled diabetes using quantitative optical coherence tomography angiography (OCT-A) metrics. Method: This was a retrospective observational study in patients with uncontrolled diabetes admitted to the hospital for glycemic control. A second set of 15 healthy volunteers was included to serve as a control group. OCT-A was performed at inclusion and at 3 months to measure foveal avascular zone area (FAZA), vessel density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP), acircularity index (AI), and fractal dimension (FD). Results: This analysis included 35 patients (35 eyes): 28 type-2 diabetics and 7 type-1 diabetics. Mean HbA1c was 13.1 ± 2.0% at inclusion and 7.0 ± 1.5% at 3 months. In the short period from inclusion to 3 months post-inclusion, patients showed significant decrease in VD–DCP (28.8% vs. 27.8%; p = 0.014), a significant increase in FAZA (0.300 mm2 vs. 0.310 mm2; p < 0.001), and a significant increase in AI (1.31 vs. 1.34; p < 0.01). Multivariate analysis found an increase in FAZA was correlated with baseline HbA1c level and age (R2 = 0.330), and a decrease in VD-DCP was correlated with HbA1c decrease and diabetes duration (R2 = 0.286). Conclusions: Rapid glycemic control in patients with uncontrolled diabetes led to possible short-term microvascular damage that correlated to both initial and decreased HbA1c.

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the “cytokine storm” and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.

The epicardial adipose tissue (EAT) is the visceral fat depot of the heart which is highly plastic and in direct contact with myocardium and coronary arteries. Because of its singular proximity with the myocardium, the adipokines and pro-inflammatory molecules secreted by this tissue may directly affect the metabolism of the heart and coronary arteries. Its accumulation, measured by recent new non-invasive imaging modalities, has been prospectively associated with the onset and progression of coronary artery disease (CAD) and atrial fibrillation in humans. Recent studies have shown that EAT exhibits beige fat-like features, and express uncoupling protein 1 (UCP-1) at both mRNA and protein levels. However, this thermogenic potential could be lost with age, obesity and CAD. Here we provide an overview of the physiological and pathophysiological relevance of EAT and further discuss whether its thermogenic properties may serve as a target for obesity therapeutic management with a specific focus on the role of immune cells in this beiging phenomenon.

Background: To develop a deep-learning (DL) pipeline that allowed an automated segmentation of epicardial adipose tissue (EAT) from low-dose computed tomography (LDCT) and investigate the link between EAT and COVID-19 clinical outcomes. Methods: This monocentric retrospective study included 353 patients: 95 for training, 20 for testing, and 238 for prognosis evaluation. EAT segmentation was obtained after thresholding on a manually segmented pericardial volume. The model was evaluated with Dice coefficient (DSC), inter-and intraobserver reproducibility, and clinical measures. Uni-and multi-variate analyzes were conducted to assess the prognosis value of the EAT volume, EAT extent, and lung lesion extent on clinical outcomes, including hospitalization, oxygen therapy, intensive care unit admission and death. Results: The mean DSC for EAT volumes was 0.85 ± 0.05. For EAT volume, the mean absolute error was 11.7 ± 8.1 cm3 with a non-significant bias of −4.0 ± 13.9 cm3 and a correlation of 0.963 with the manual measures (p < 0.01). The multivariate model providing the higher AUC to predict adverse outcome include both EAT extent and lung lesion extent (AUC = 0.805). Conclusions: A DL algorithm was developed and evaluated to obtain reproducible and precise EAT segmentation on LDCT. EAT extent in association with lung lesion extent was associated with adverse clinical outcomes with an AUC = 0.805.

In magnetic resonance imaging (MRI), epicardial adipose tissue (EAT) overload remains often overlooked due to tedious manual contouring in images. Automated four-chamber EAT area quantification was proposed, leveraging deep-learning segmentation using multi-frame fully convolutional networks (FCN). The investigation involved 100 subjects—comprising healthy, obese, and diabetic patients—who underwent 3T cardiac cine MRI, optimized U-Net and FCN (noted FCNB) were trained on three consecutive cine frames for segmentation of central frame using dice loss. Networks were trained using 4-fold cross-validation (n = 80) and evaluated on an independent dataset (n = 20). Segmentation performances were compared to inter-intra observer bias with dice (DSC) and relative surface error (RSE). Both systole and diastole four-chamber area were correlated with total EAT volume (r = 0.77 and 0.74 respectively). Networks’ performances were equivalent to inter-observers’ bias (EAT: DSCInter = 0.76, DSCU-Net = 0.77, DSCFCNB = 0.76). U-net outperformed (p < 0.0001) FCNB on all metrics. Eventually, proposed multi-frame U-Net provided automated EAT area quantification with a 14.2% precision for the clinically relevant upper three quarters of EAT area range, scaling patients’ risk of EAT overload with 70% accuracy. Exploiting multi-frame U-Net in standard cine provided automated EAT quantification over a wide range of EAT quantities. The method is made available to the community through a FSLeyes plugin.

This study details the clinical and cellular phenotypes associated with two missense heterozygous mutations in LMNA, c.1745G>T p.(Arg582Leu), and c.1892G>A p.(Gly631Asp), in two patients with early onset of diabetes mellitus, hypertriglyceridemia and non-alcoholic fatty liver disease. In these two patients, subcutaneous adipose tissue was persistent, at least on the abdomen, and the serum leptin level remained in the normal range. Cellular studies showed elevated nuclear anomalies, an accelerated senescence rate and a decrease of replication capacity in patient cells. In cellular models, the overexpression of mutated prelamin A phenocopied misshapen nuclei, while the partial reduction of lamin A expression in patient cells significantly improved nuclear morphology. Altogether, these results suggest a link between lamin A mutant expression and senescence associated phenotypes. Transcriptome analysis of the whole subcutaneous adipose tissue from the two patients and three controls, paired for age and sex using RNA sequencing, showed the up regulation of genes implicated in immunity and the down regulation of genes involved in development and cell differentiation in patient adipose tissue. Therefore, our results suggest that some mutations in LMNA are associated with severe metabolic phenotypes without subcutaneous lipoatrophy, and are associated with nuclear misshaping.

ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.