The main drivers of COVID-19 disease severity and the impact of COVID-19 on long-term health after recovery are yet to be fully understood. Medical imaging studies investigating COVID-19 to date have ...mostly been limited to small datasets and post-hoc analyses of severe cases. The UK Biobank recruited recovered SARS-CoV-2 positive individuals (n = 967) and matched controls (n = 913) who were extensively imaged prior to the pandemic and underwent follow-up scanning. In this study, we investigated longitudinal changes in body composition, as well as the associations of pre-pandemic image-derived phenotypes with COVID-19 severity. Our longitudinal analysis, in a population of mostly mild cases, associated a decrease in lung volume with SARS-CoV-2 positivity. We also observed that increased visceral adipose tissue and liver fat, and reduced muscle volume, prior to COVID-19, were associated with COVID-19 disease severity. Finally, we trained a machine classifier with demographic, anthropometric and imaging traits, and showed that visceral fat, liver fat and muscle volume have prognostic value for COVID-19 disease severity beyond the standard demographic and anthropometric measurements. This combination of image-derived phenotypes from abdominal MRI scans and ensemble learning to predict risk may have future clinical utility in identifying populations at-risk for a severe COVID-19 outcome.
The fatty liver index (FLI) is frequently used as a non-invasive clinical marker for research, prognostic and diagnostic purposes. It is also used to stratify individuals with hepatic steatosis such ...as non-alcoholic fatty liver disease (NAFLD), and to detect the presence of type 2 diabetes or cardiovascular disease. The FLI is calculated using a combination of anthropometric and blood biochemical variables; however, it reportedly excludes 8.5-16.7% of individuals with NAFLD. Moreover, the FLI cannot quantitatively predict liver fat, which might otherwise render an improved diagnosis and assessment of fatty liver, particularly in longitudinal studies. We propose FLI+ using predictive regression modelling, an improved index reflecting liver fat content that integrates 12 routinely-measured variables, including the original FLI.
We evaluated FLI+ on a dataset from the UK Biobank containing 28,796 individual estimates of proton density fat fraction derived from magnetic resonance imaging across normal to severe levels and interpolated to align with the original FLI range. The results obtained for FLI+ outperform the original FLI by delivering a lower mean absolute error by approximately 47%, a lower standard deviation by approximately 20%, and an increased adjusted R2 statistic by approximately 49%, reflecting a more accurate representation of liver fat content.
Our proposed model predicting FLI+ has the potential to improve diagnosis and provide a more accurate stratification than FLI between absent, mild, moderate and severe levels of hepatic steatosis.
Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization ...(MR) study to examine causality of such associations.
We used genetic variants associated (P < 5 × 10-8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n = 32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects.
Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio per 1 SD higher exposure 2.16 2.02, 2.31 and 2.11 1.96, 2.27, respectively). Pancreatic fat was associated with type 2 diabetes (1.42 1.34, 1.51) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 0.36, 0.48) and type 2 diabetes (0.73 0.68, 0.78). MR analysis provided evidence only for a causal role of liver fat and pancreas volume in risk of type 2 diabetes (1.27 1.08, 1.49 or 27% increased risk and 0.76 0.62, 0.94 or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes.
Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and type 2 diabetes.
Hepatic steatosis affects 20% to 30% of the general adult population in the western world. Currently, the technique of choice for determining hepatic fat deposition and the stage of fibrosis is liver ...biopsy. However, it is an invasive procedure and its use is limited, particularly in children. It may also be subject to sampling error. Non-invasive techniques such as ultrasound, computerised tomography （CT）, magnetic resonance imaging （MRI） and proton magnetic resonance spectroscopy （^1H MRS） can detect hepatic steatosis, but currently cannot distinguish between simple steatosis and steatohepatitis, or stage the degree of fibrosis accurately. Ultrasound is widely used to detect hepatic steatosis, but its sensitivity is reduced in the morbidly obese and also in those with small amounts of fatty infiltration. It has been used to grade hepatic fat content, but this is subjective. CT can detect hepatic steatosis, but exposes subjects to ionising radiation, thus limiting its use in longitudinal studies and in children. Recently, magnetic resonance （MR） techniques using chemical shift imaging have provided a quantitative assessment of the degree of hepatic fatty infiltration, which correlates well with liver biopsy results in the same patients. Similarly, in vivo ^1H MRS is a fast, safe, non-invasive method for the quantification of intrahepatocellular lipid （IHCL） levels. Both techniques will be useful tools in future longitudinal clinical studies, either in examining the natural history of conditions causing hepatic steatosis （e.g. non-alcoholic fatty liver disease）, or in testing new treatments for these conditions.
Abstract Objective Dietary supplementation with fermentable carbohydrate protects against body weight gain. Fermentation by the resident gut microbiota produces short-chain fatty acids, which act at ...free fatty acid receptor 2 (FFAR2). Our aim was to test the hypothesis that FFAR2 is important in regulating the beneficial effects of fermentable carbohydrate on body weight and to understand the role of gut hormones PYY and GLP-1. Methods Wild-type or Ffar2 −/− mice were fed an inulin supplemented or control diet. Mice were metabolically characterized and gut hormone concentrations, enteroendocrine cell density measurements were carried out. Intestinal organoids and colonic cultures were utilized to substantiate the in vivo findings. Results We provide new mechanistic insight into how fermentable carbohydrate regulates metabolism. Using mice that lack FFAR2, we demonstrate that the fermentable carbohydrate inulin acts via this receptor to drive an 87% increase in the density of cells that produce the appetite-suppressing hormone peptide YY (PYY), reduce food intake, and prevent diet-induced obesity. Conclusion Our results demonstrate that FFAR2 is predominantly involved in regulating the effects of fermentable carbohydrate on metabolism and does so, in part, by enhancing PYY cell density and release. This highlights the potential for targeting enteroendocrine cell differentiation to treat obesity.
Acyl-ghrelin administration increases food intake, body weight, and blood glucose. In contrast, mice lacking ghrelin or ghrelin receptors (GHSRs) exhibit life-threatening hypoglycemia during ...starvation-like conditions, but do not consistently exhibit overt metabolic phenotypes when given ad libitum food access. These results, and findings of ghrelin resistance in obese states, imply nutritional state dependence of ghrelin's metabolic actions. Here, we hypothesized that liver-enriched antimicrobial peptide-2 (LEAP2), a recently characterized endogenous GHSR antagonist, blunts ghrelin action during obese states and postprandially. To test this hypothesis, we determined changes in plasma LEAP2 and acyl-ghrelin due to fasting, eating, obesity, Roux-en-Y gastric bypass (RYGB), vertical sleeve gastrectomy (VSG), oral glucose administration, and type 1 diabetes mellitus (T1DM) using humans and/or mice. Our results suggest that plasma LEAP2 is regulated by metabolic status: its levels increased with body mass and blood glucose and decreased with fasting, RYGB, and in postprandial states following VSG. These changes were mostly opposite of those of acyl-ghrelin. Furthermore, using electrophysiology, we showed that LEAP2 both hyperpolarizes and prevents acyl-ghrelin from activating arcuate NPY neurons. We predict that the plasma LEAP2/acyl-ghrelin molar ratio may be a key determinant modulating acyl-ghrelin activity in response to body mass, feeding status, and blood glucose.
Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics ...via physiological changes secondary to distinct gut anatomy manipulations.
We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity.
Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients.
The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut-brain axis in the control of reward-based eating behaviour.
Cannabidiol (CBD) and Δ(9)-tetrahydrocannabivarin (THCV) are nonpsychoactive phytocannabinoids affecting lipid and glucose metabolism in animal models. This study set out to examine the effects of ...these compounds in patients with type 2 diabetes.
In this randomized, double-blind, placebo-controlled study, 62 subjects with noninsulin-treated type 2 diabetes were randomized to five treatment arms: CBD (100 mg twice daily), THCV (5 mg twice daily), 1:1 ratio of CBD and THCV (5 mg/5 mg, twice daily), 20:1 ratio of CBD and THCV (100 mg/5 mg, twice daily), or matched placebo for 13 weeks. The primary end point was a change in HDL-cholesterol concentrations from baseline. Secondary/tertiary end points included changes in glycemic control, lipid profile, insulin sensitivity, body weight, liver triglyceride content, adipose tissue distribution, appetite, markers of inflammation, markers of vascular function, gut hormones, circulating endocannabinoids, and adipokine concentrations. Safety and tolerability end points were also evaluated.
Compared with placebo, THCV significantly decreased fasting plasma glucose (estimated treatment difference ETD = -1.2 mmol/L; P < 0.05) and improved pancreatic β-cell function (HOMA2 β-cell function ETD = -44.51 points; P < 0.01), adiponectin (ETD = -5.9 × 10(6) pg/mL; P < 0.01), and apolipoprotein A (ETD = -6.02 μmol/L; P < 0.05), although plasma HDL was unaffected. Compared with baseline (but not placebo), CBD decreased resistin (-898 pg/ml; P < 0.05) and increased glucose-dependent insulinotropic peptide (21.9 pg/ml; P < 0.05). None of the combination treatments had a significant impact on end points. CBD and THCV were well tolerated.
THCV could represent a new therapeutic agent in glycemic control in subjects with type 2 diabetes.
MRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to ...understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases.
First, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures.
We identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10-8). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective.
The association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals.
We estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.
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•Variants in metal ion transporter and NAFLD genes are associated with liver MRI-derived cT1, a steatohepatitis and fibrosis proxy.•cT1 is highly heritable, and is correlated with BMI, NAFLD and VLDL, and inversely correlated with HDL.•Insulin resistance, NAFLD and higher BMI are genetically linked to higher liver cT1, whilst favourable adiposity is linked to lower cT1.
Exosomes and microvesicles (EMV) are lipid bilayer-enclosed structures, released by cells and involved in intercellular communication through transfer of proteins and genetic material. EMV release is ...also associated with various pathologies, including cancer, where increased EMV release is amongst other associated with chemo-resistance and active transfer of pro-oncogenic factors. Recent studies show that EMV-inhibiting agents can sensitize cancer cells to chemotherapeutic agents and reduce cancer growth
. Cannabidiol (CBD), a phytocannabinoid derived from
, has anti-inflammatory and anti-oxidant properties, and displays anti-proliferative activity. Here we report a novel role for CBD as a potent inhibitor of EMV release from three cancer cell lines: prostate cancer (PC3), hepatocellular carcinoma (HEPG2) and breast adenocarcinoma (MDA-MB-231). CBD significantly reduced exosome release in all three cancer cell lines, and also significantly, albeit more variably, inhibited microvesicle release. The EMV modulating effects of CBD were found to be dose dependent (1 and 5 μM) and cancer cell type specific. Moreover, we provide evidence that this may be associated with changes in mitochondrial function, including modulation of STAT3 and prohibitin expression, and that CBD can be used to sensitize cancer cells to chemotherapy. We suggest that the known anti-cancer effects of CBD may partly be due to the regulatory effects on EMV biogenesis, and thus CBD poses as a novel and safe modulator of EMV-mediated pathological events.
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