Publications
346 results found
Fiamoncini J, Rundle M, Gibbons H, et al., 2018, Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements, FASEB Journal, Vol: 32, Pages: 5447-5458, ISSN: 0892-6638
Health has been defined as the capability of the organism to adapt to challenges. In this study, we tested to what extent comprehensively phenotyped individuals reveal differences in metabolic responses to a standardized mixed meal tolerance test (MMTT) and how these responses change when individuals experience moderate weight loss. Metabolome analysis was used in 70 healthy individuals. with profiling of ∼300 plasma metabolites during an MMTT over 8 h. Multivariate analysis of plasma markers of fatty acid catabolism identified 2 distinct metabotype clusters (A and B). Individuals from metabotype B showed slower glucose clearance, had increased intra-abdominal adipose tissue mass and higher hepatic lipid levels when compared with individuals from metabotype A. An NMR-based urine analysis revealed that these individuals also to have a less healthy dietary pattern. After a weight loss of ∼5.6 kg over 12 wk, only the subjects from metabotype B showed positive changes in the glycemic response during the MMTT and in markers of metabolic diseases. Our study in healthy individuals demonstrates that more comprehensive phenotyping can reveal discrete metabotypes with different outcomes in a dietary intervention and that markers of lipid catabolism in plasma could allow early detection of the metabolic syndrome.—Fiamoncini, J., Rundle, M., Gibbons, H., Thomas, E. L., Geillinger-Kästle, K., Bunzel, D., Trezzi, J.-P., Kiselova-Kaneva, Y., Wopereis, S., Wahrheit, J., Kulling, S. E., Hiller, K., Sonntag, D., Ivanova, D., van Ommen, B., Frost, G., Brennan, L., Bell, J. Daniel, H. Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss–mediated metabolic improvements.One of the key features of human metabolism is its plasticity and capacity to regain homeostasis upon a disturbance such as acute stress, starvation, or food intake (1). In this regard it has been proposed that heal
YAGHOOTKAR H, JI Y, YIORKAS AM, et al., 2018, Genome-Wide and Abdominal Imaging Data Characterizes Common Alleles Associated with Higher BMI and Subcutaneous Fat but Less Liver Fat and Lower Risk of Type 2 Diabetes, Diabetes, Vol: 67, ISSN: 0012-1797
<jats:p>Genetic studies have identified “favourable adiposity” variants - where the allele associated with higher adiposity is associated with lower risk of type 2 diabetes. We took a novel approach to find more of these alleles and find the underlying mechanisms.</jats:p> <jats:p>We first performed a genome wide association study (GWAS) of body fat percentage using 451000 individuals from UK Biobank. Second, we used published genetic data in a multivariate test to find alleles associated with higher adiposity but a “favourable” metabolic phenotype: higher HDL-C, adiponectin, sex hormone binding globulin, but lower triglycerides, fasting insulin and alanine transaminase. Third, we used abdominal imaging data from 4 studies to define the adiposity phenotype in more detail.</jats:p> <jats:p>We identified 620 variants associated with body fat percentage (p&lt;5x10-8). Fourteen alleles had a “favourable adiposity” phenotype, including 7 previously known variants (in/near PPARG, LYPLAL1, GRB14, IRS1, PEPD, FAM13A and ANKRD55), 5 known to be associated with a relevant trait (TRIB1, KLF14/MKLN1, DNAH10, VEGFA/C6orf223 and AEBP2/PDE3A) and 2 novel variants (MAFF and CITED2). Carrying 10 additional "favourable adiposity" allele was associated with higher BMI (0.63 kg/m2, p = 4x10-45) but lower risk of type 2 diabetes (odds ratio: 0.60, p = 4x10-44, 14371 cases), lower risk of heart disease (0.82, p = 3x10-14, 37741 cases) and lower risk of hypertension (0.82, p = 1x10-33, 241691 cases). Using MRI/CT scans of abdominal fat from UK Biobank (N = 5000), NEO (2236), TÜF (900), and a published GWAS (10557), carrying more “favourable adiposity” alleles was associated with higher subcutaneous fat (p = 1x10-12) but lower liver fat (p = 1x10-7). These effects were similar when we removed the 7 known “favourable adiposity” variants.</jats:p>
Borga M, West J, Bell JD, et al., 2018, Advanced body composition assessment: from body mass index to body composition profiling, JOURNAL OF INVESTIGATIVE MEDICINE, Vol: 66, Pages: 887-895, ISSN: 1081-5589
This paper gives a brief overview of common non-invasive techniques for body composition analysis and a more in-depth review of a body composition assessment method based on fat-referenced quantitative MRI. Earlier published studies of this method are summarized, and a previously unpublished validation study, based on 4753 subjects from the UK Biobank imaging cohort, comparing the quantitative MRI method with dual-energy X-ray absorptiometry (DXA) is presented. For whole-body measurements of adipose tissue (AT) or fat and lean tissue (LT), DXA and quantitative MRIs show excellent agreement with linear correlation of 0.99 and 0.97, and coefficient of variation (CV) of 4.5 and 4.6 per cent for fat (computed from AT) and LT, respectively, but the agreement was found significantly lower for visceral adipose tissue, with a CV of >20 per cent. The additional ability of MRI to also measure muscle volumes, muscle AT infiltration and ectopic fat, in combination with rapid scanning protocols and efficient image analysis tools, makes quantitative MRI a powerful tool for advanced body composition assessment.
Cobbold JFL, Atkinson S, Marchesi JR, et al., 2018, Rifaximin in non-alcoholic steatohepatitis: An open-label pilot study, HEPATOLOGY RESEARCH, Vol: 48, Pages: 69-77, ISSN: 1386-6346
AimGut microbial dysbiosis is implicated in the pathogenesis of non‐alcoholic steatohepatitis (NASH). We investigated downstream effects of gut microbiota modulation on markers of hepatic inflammation, steatosis, and hepatic and peripheral insulin sensitivity in patients with NASH using rifaximin therapy.MethodsPatients with biopsy‐proven NASH and elevated aminotransferase values were included in this open‐label pilot study, all receiving 6 weeks rifaximin 400 mg twice daily, followed by a 6‐week observation period. The primary endpoint was change in alanine aminotransferase (ALT) after 6 weeks of rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinemic–euglycemic clamp.ResultsFifteen patients (13 men and 2 women) with a median (range) age of 46 (32–63) years were included. Seven had diabetes on oral hypoglycemic medications and 8 had no diabetes. After 6 weeks of therapy, no differences were seen in ALT (55 [33–191] vs. 63 [41–218] IU/L, P = 0.41), peripheral glucose uptake (28.9 [19.4–48.3] to 25.5 [17.7–47.9] μmol/kg/min, P = 0.30), hepatic insulin sensitivity (35.2 [15.3–51.7]% vs. 30.0 [10.8–50.5]%, P = 0.47), or hepatic lipid content (21.6 [2.2–46.2]% vs. 24.8 [1.7–59.3]%, P = 0.59) before and after rifaximin treatment. After 12 weeks from baseline, serum ALT increased to 83 (30–217) IU/L, P = 0.02. There was a significant increase in the homeostasis model assessment–estimated insulin resistance index (P = 0.05). The urinary metabolic profile indicated a significant reduction in urinary hippurate with treatment, which reverted to baseline after cessation of rifaximin, although there was no consistent difference in relative abundance of fecal microbiota with treatment.ConclusionThese data do not indicate a beneficial effect of rifaximin i
Shafique M, Russell S, Murdoch S, et al., 2017, Dietary intake in people consuming a low-carbohydrate diet in the UK Biobank., J Hum Nutr Diet
BACKGROUND: Low-carbohydrate diets are becoming increasingly popular, although their dietary quality outside of clinical studies is unknown. A previous study analysed the dietary intake in people consuming a reduced-carbohydrate diet (<40% calories). However, it is not clear what foods people consume when carbohydrate is reduced to below 26% of total calories. METHODS: In the present cross-sectional study, the dietary and nutrient intake collected via up to five consecutive 24-h dietary recalls and a food frequency questionnaire of 444 individuals (aged 46-79 years) consuming <26% of calories from carbohydrate (LCHO) was compared with that of 131 897 individuals consuming ≥45% calories from carbohydrate (NCHO) using the UK Biobank Dataset. Absolute cut-offs to define the low-carbohydrate group (<130 g day-1 ; n = 1953 versus ≥225 g day-1 , n = 113 036) were also used. RESULTS: Both NCHO (>45% calories and ≥225 g) groups consumed significantly more high-sugar, high-fat snacks [median 6.0, interquartile range (IQR) = 2.0-11.0 and median 6.0, IQR = 3.0-11.8, respectively) compared to the LCHO (<26% calories and <130 g) groups (median 0, IQR = 0-2.8 and median 1, IQR = 0-3.8, respectively) (P < 0.0001). Both LCHO groups reported consuming significantly more red meat, oily fish, nuts and seeds but fewer fruits, vegetables and pulses compared to the NCHO groups. In general, the consumption of oily fish, nuts, seeds and pulses was low across the whole cohort and differences in intake between the LCHO and NCHO groups were small. After adjusting for socio-economic status, most differences remained. CONCLUSIONS: Carbohydrate restriction is associated with both beneficial and potentially deleterious dietary changes compared to a normal carbohydrate intake.
Umpleby AM, Shojaee-Moradie F, Fielding B, et al., 2017, Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets., Clinical Science, Vol: 131, Pages: 2561-2573, ISSN: 0143-5221
Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n = 11) and low liver fat 'controls' (n = 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling.There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high (P<0.02) and low sugar (P<0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet (P<0.01), and a higher VLDL1-TAG production rate after the low sugar diet (P<0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG (P<0.02) in the controls, but in contrast, a higher production of VLDL2-TAG (P<0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. The present study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars.
Brody LP, Sahuri-Arisoylu M, Parkinson JR, et al., 2017, Cationic lipid-based nanoparticles mediate functional delivery of acetate to tumor cells in vivo leading to significant anticancer effects, International Journal of Nanomedicine, Vol: 12, Pages: 6677-6685, ISSN: 1176-9114
Metabolic reengineering using nanoparticle delivery represents an innovative therapeutic approach to normalizing the deregulation of cellular metabolism underlying many diseases, including cancer. Here, we demonstrated a unique and novel application to the treatment of malignancy using a short-chain fatty acid (SCFA)-encapsulated lipid-based delivery system – liposome-encapsulated acetate nanoparticles for cancer applications (LITA-CAN). We assessed chronic in vivo administration of our nanoparticle in three separate murine models of colorectal cancer. We demonstrated a substantial reduction in tumor growth in the xenograft model of colorectal cancer cell lines HT-29, HCT-116 p53+/+ and HCT-116 p53-/-. Nanoparticle-induced reductions in histone deacetylase gene expression indicated a potential mechanism for these anti-proliferative effects. Together, these results indicated that LITA-CAN could be used as an effective direct or adjunct therapy to treat malignant transformation in vivo.
Hameed S, Patterson M, Dhillo W, et al., 2017, Thyroid hormone receptor beta in the ventromedial hypothalamus is essential for the physiological regulation of food intake and body weight, Cell Reports, Vol: 19, Pages: 2202-2209, ISSN: 2211-1247
The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.
Kyriakidou Y, Kantorovich RC, Bell J, et al., 2017, The Potential Of Omega 3 Supplementation To Reduce Muscle-inflammation After Muscle-damaging Exercise, MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, Vol: 49, Pages: 583-583, ISSN: 0195-9131
Wilman HR, Kelly M, Garratt S, et al., 2017, Characterisation of liver fat in the UK Biobank cohort, PLOS ONE, Vol: 12, ISSN: 1932-6203
Non-alcoholicfattyliverdiseaseandtheriskof progressionto steatohepatitis,cirrhosisandhepatocellularcarcinomahavebeenidentifiedasmajorpublichealthconcerns.Wehavedemonstratedthefeasibilityandpotentialvalueof measuringliverfatcontentbymagneticresonanceimaging(MRI)in a largepopulationin thisstudyof 4,949participants(aged45–73years)in theUKBiobankimagingenhancement. Despiterequirementsforonlya single( 3min)scanof eachsubject,liverfatwasableto bemeasuredastheMRIprotondensityfatfraction(PDFF)withanoverallsuccessrateof 96.4%.Theoverallhepaticfatdistributionwascentredbetween1–2%,andwashighlyskewedtowardshigherfatcontent.ThemeanPDFFwas3.91%,andmedian2.11%.Analysisof PDFFin conjunctionwithotherdatafieldsavailablefromtheUKBiobankResourceshowedassociationsof increasedliverfatwithgreaterage,BMI,weightgain,highbloodpressureandType2 diabetes.SubjectswithBMIlessthan25kg/m2hada lowrisk(5%)of highliverfat(PDFF>5.5%),whereasin thehigherBMIpopulation(>30kg/m2) theprevalenceof highliverfatwasapproximately1 in 3. Thesedatasuggestthatpopulationscreeningto identifypeoplewithhighPDFFis possibleandcouldbecosteffective.MRIbasedPDFFis aneffectivemethodforthis.Finally,althoughcrosssectional,thisstudysuggeststheutilityof thePDFFmeasurement withinUKBiobank,particularlyforapplicationsto elucidatingriskfactorsthroughassociationswithprospec-tivelyacquireddataonclinicaloutcomesof liverdiseases,includingnon-alcoholicfattyliverdisease.
Henley AB, Yang L, Chuang K-L, et al., 2017, Withania somnifera Root Extract Enhances Chemotherapy through ‘Priming’, PLoS ONE, Vol: 12, ISSN: 1932-6203
Withania somnifera extracts are known for their anti-cancerous, anti-inflammatory and antioxidativeproperties. One of their mechanisms of actions is to modulate mitochondrial functionthrough increasing oxidative stress. Recently ‘priming’ has been suggested as apotential mechanism for enhancing cancer cell death. In this study we demonstrate that‘priming’, in HT-29 colon cells, with W. somnifera root extract increased the potency of thechemotherapeutic agent cisplatin. We have also showed the W. somnifera root extractenhanced mitochondrial dysfunction and that the underlying mechanism of ‘priming’ wasselectively through increased ROS. Moreover, we showed that this effect was not seen innon-cancerous cells.
Schofield S, Parkinson J, Henley A, et al., 2017, Metabolic dysfunction following weight cycling in male mice, International Journal of Obesity, Vol: 41, Pages: 402-411, ISSN: 0307-0565
Background: Combatting overweight or obesity can lead to large fluctuations in an individual’s body weight, often referred to as weight cycling or ‘yo-yo’ dieting. Current evidence regarding the potentially damaging effects of these changes is conflicting.Methods: Here, we assess the metabolic effects of weight cycling in a murine model, comprising three dietary switches to normal or high-fat diets at 6 week intervals; male C57BL/6 mice were fed either a control (C) or high-fat (F) diet for 6 weeks (n=140/group). C and F groups were then either maintained on their initial diet (CC and FF, respectively) or switched to a high-fat (CF) or control (FC) diet (n=35/group). For the final 6 week interval, CC and CF groups were returned to the control diet (CCC and CFC groups), while FC and FF groups were placed on a high-fat diet (FCF and FFF) (n=28/group).Results: For the majority of metabolic outcomes changes aligned with dietary switches; however, assessment of neuropeptides and receptors involved in appetite regulation and reward signalling pathways reveal variable patterns of expression. Furthermore, we demonstrate that multiple cycling events leads to a significant increase in internal fat deposition, even when compared with animals maintained on a high-fat diet (internal fat: FCF: 7.4±0.2 g vs FFF: 5.6±0.2 g; P<0.01).Conclusions: Increased internal adipose tissue is strongly linked to the development of metabolic syndrome associated conditions such as type 2 diabetes, cardiovascular disease and hypertension. Although further work will be required to elucidate the mechanisms underlying the neuronal control of energy homoeostasis, these studies provide a causative link between weight cycling and adverse health.
Thomas E, Fitzpatrick J, Chambers E, et al., 2017, Psoas major cross-sectional area: A potential marker of cardiorespiratory fitness, International Journal of Clinical and Experimental Physiology, Vol: 4, Pages: 15-15, ISSN: 2348-8832
Nunn AVW, Guy GW, Bell JD, 2017, The Hormesis of Thinking: A Deeper Quantum Thermodynamic Perspective?, International Journal of Neurorehabilitation, Vol: 04
Villarini B, Asaturyan H, Thomas EL, et al., 2017, A Framework for Morphological Feature Extraction of Organs from MR Images for Detection and Classification of Abnormalities, 30th IEEE International Symposium on Computer-Based Medical Systems (IEEE CBMS), Publisher: IEEE, Pages: 666-671, ISSN: 2372-9198
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Lee S, Norheim F, Langleite TM, et al., 2016, Effect of energy restriction and physical exercise intervention on phenotypic flexibility as examined by transcriptomics analyses of mRNA from adipose tissue and whole body magnetic resonance imaging., Physiological Reports, Vol: 4, ISSN: 2051-817X
Overweight and obesity lead to changes in adipose tissue such as inflammation and reduced insulin sensitivity. The aim of this study was to assess how altered energy balance by reduced food intake or enhanced physical activity affect these processes. We studied sedentary subjects with overweight/obesity in two intervention studies, each lasting 12 weeks affecting energy balance either by energy restriction (~20% reduced intake of energy from food) in one group, or by enhanced energy expenditure due to physical exercise (combined endurance- and strength-training) in the other group. We monitored mRNA expression by microarray and mRNA sequencing from adipose tissue biopsies. We also measured several plasma parameters as well as fat distribution with magnetic resonance imaging and spectroscopy. Comparison of microarray and mRNA sequencing showed strong correlations, which were also confirmed using RT-PCR In the energy restricted subjects (body weight reduced by 5% during a 12 weeks intervention), there were clear signs of enhanced lipolysis as monitored by mRNA in adipose tissue as well as plasma concentration of free-fatty acids. This increase was strongly related to increased expression of markers for M1-like macrophages in adipose tissue. In the exercising subjects (glucose infusion rate increased by 29% during a 12-week intervention), there was a marked reduction in the expression of markers of M2-like macrophages and T cells, suggesting that physical exercise was especially important for reducing inflammation in adipose tissue with insignificant reduction in total body weight. Our data indicate that energy restriction and physical exercise affect energy-related pathways as well as inflammatory processes in different ways, probably related to macrophages in adipose tissue.
Brooks L, Viardot A, Tsakmaki A, et al., 2016, Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety, Molecular Metabolism, Vol: 6, Pages: 48-60, ISSN: 2212-8778
ObjectiveDietary 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. MethodsWild-type or Ffar2-/-mice were fed an inulin supplemented or control diet. Mice were metabolically characterised and gut hormone concentrations, enteroendocrine cell density measurements were carried out. Intestinal organoids and colonic cultures were utilised to substantiate the in vivo findings.ResultsWe 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-supressing 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.
Shojaee-Moradie F, Cuthbertson DJ, Barrett M, et al., 2016, Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance But Not VLDL Production in NAFLD, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 101, Pages: 4219-4228, ISSN: 0021-972X
Jadoon KA, Ratcliffe SH, Barrett DA, et al., 2016, Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study, DIABETES CARE, Vol: 39, Pages: 1777-1786, ISSN: 0149-5992
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West J, Leinhard OD, Romu T, et al., 2016, Feasibility of MR-Based Body Composition Analysis in Large Scale Population Studies, PLOS ONE, Vol: 11, ISSN: 1932-6203
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Nunn AVW, Guy GW, Bell JD, 2016, The quantum mitochondrion and optimal health, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 44, Pages: 1101-1110, ISSN: 0300-5127
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Alzoubi S, Brody L, Rahman S, et al., 2016, Synergy between histone deacetylase inhibitors and DNA-damaging agents is mediated by histone deacetylase 2 in colorectal cancer, Oncotarget, Vol: 7, Pages: 44505-44521, ISSN: 1949-2553
Previous studies have associated the overexpression of histone deacetylase 2 (HDAC2) and the presence of TP53 mutations with the progression to advanced stage drug resistant colorectal cancer (CRC). However, the mechanistic link between HDAC2 expression and the TP53 mutational status has remained unexplored. Here, we investigated the function of HDAC2 in drug resistance by assessing the synergistic effects of DNA-targeted chemotherapeutic agents and HDAC inhibitors (HDACis) on two TP53-mutated colorectal adenocarcinoma CRC cell lines (SW480 and HT-29) and on the TP53-wild type carcinoma cell line (HCT116 p53+/+) and its TP53 deficient sub-line (HCT116 p53-/-). We showed that in the untreated SW480 and HT-29 cells the steady-state level of HDAC2 was low compared to a TP53-wild type carcinoma cell line (HCT116 p53+/+). Increased expression of HDAC2 correlated with drug resistance, and depletion by shRNA sensitised the multi-drug resistance cell line HT-29 to CRC chemotherapeutic drugs such as 5-fluorouracil (5-FU) and oxaliplatin (Oxa). Combined treatment with the HDACi suberoylanilide hydroxamic acid plus 5-FU or Oxa reduced the level of HDAC2 expression, modified chromatin structure and induced mitotic cell death in HT-29 cells. Non-invasive bioluminescence imaging revealed significant reductions in xenograft tumour growth with HDAC2 expression level reduced to <50% in treated animals. Elevated levels of histone acetylation on residues H3K9, H4K12 and H4K16 were also found to be associated with resistance to VPA/Dox or SAHA/Dox treatment. Our results suggest that HDAC2 expression rather than the p53 mutation status influences the outcome of combined treatment with a HDACi and DNA-damaging agents in CRC.
Uthaya SN, Liu X, Babalis D, et al., 2016, Nutritional Evaluation and Optimisation in Neonates (NEON): a randomised double-blind controlled trial of amino-acid regimen and intravenous lipid composition in preterm parenteral nutrition, American Journal of Clinical Nutrition, Vol: 103, Pages: 1443-1452, ISSN: 1938-3207
BackgroundParenteral nutrition is central to the care of very immature infants. Current international recommendations favour higher amino-acid intakes and fish oil-containing lipid emulsions. ObjectiveThe aim of this two-by-two factorial, double-blind multicentre randomised controlled trial was to compare the effect of high (immediate Recommended Daily Intake: Imm-RDI) versus low (incremental introduction: Inc-AA) parenteral amino-acid delivery, commenced within 24 hours of birth, on body composition, and a multi-component lipid emulsion containing 30% soy bean oil, 30% medium chain triglycerides, 25% olive oil and 15% fish oil (SMOF) versus soybean oil based lipid emulsion (SO) on Intra-Hepato-Cellular Lipid (IHCL) content. ResultsWe randomised 168 infants born <31 weeks gestation. We evaluated outcomes at term in 133 infants. There were no significant differences between Imm-RDI and Inc-AA groups for non-adipose mass (adjusted mean difference (95% CI): 1.0g (-108, 111) p=0.98) or between SMOF and SO groups for IHCL (adjusted mean ratio SMOF:SO (95% CI): 1.1 (0.8, 1.6) p=0.58). SMOF does not affect IHCL content. There was a significant interaction (p=0.05) between the two interventions for non-adipose mass. There were no significant interactions between group differences for either primary outcome measure after adjusting for additional confounders. Imm-RDI infants were more likely than Inc-AA infants to have blood urea nitrogen levels greater than 7mmol/l or 10mmol/l respectively (75% vs 49%; p<0.01 and 49% vs 18%; p<0.01). Head circumference at term was smaller in the Imm-RDI group (mean difference (95% CI): -0.8cm (-1.5, -0.1) p= 0.02). There were no significant differences in any pre-specified secondary outcomes including adiposity, liver function tests, incidence of conjugated hyperbilirubinaemia, weight, length, mortality and brain volumes. ConclusionsImmediate delivery of Recommended Daily Intake of parenteral amino-acids does not benefit body compo
Uthaya S, Liu X, Babalis D, et al., 2016, Nutritional Evaluation and Optimisation in Neonates (NEON) trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition: a randomised double-blind controlled trial, Efficacy and Mechanism Evaluation, Vol: 3, ISSN: 2050-4365
BackgroundParenteral nutrition (PN) is central to the care of very immature infants. Early intakes of higher amounts of amino acids and the use of lipid emulsions containing fish oils are recommended by current international recommendations.ObjectiveTo confirm the safety and demonstrate efficacy of the immediate introduction of the recommended daily intake of amino acids (Imm-RDI) and soya bean oil, medium-chain triglycerides, olive oil and fish oil lipid in PN to increase non-adipose (lean) body mass and decrease intrahepatocellular lipid (IHCL) content.DesignMulticentre, double-blind, 2 × 2 factorial and randomised controlled trial (RCT).SettingNeonatal units in London and south-east England, UK.ParticipantsExtremely preterm infants born before 31 weeks of gestation without major congenital or life-threatening abnormalities who could to be randomised to receive PN within 24 hours of birth.InterventionsInfants were randomised within 24 hours of birth to receive PN containing either high [RDI of amino acids (Imm-RDI)] or low [incremental amino acids (Inc-AA) control] levels of amino acids. In addition, infants were randomised to receive either 20% SMOFlipid® (Fresenius Kabi AG, Richmond Hill, ON, Canada) or 20% Intralipid® (Fresenius Kabi AG, Richmond Hill, ON, Canada) (control). This resulted in four groups: (1) Inc-AA/Intralipid, (2) Inc-AA/SMOFlipid, (3) Imm-RDI/Intralipid and (4) Imm-RDI/SMOFlipid. The intervention was continued until infants were receiving 150 ml/kg/day of enteral feeds for 24 hours.Primary outcome measureFor the amino acid intervention, this was non-adipose or lean body mass measured by magnetic resonance imaging. For the lipid composition intervention, this was IHCL content as measured by hepatic magnetic resonance spectroscopy. Primary outcomes were measured at term age equivalent, between 37 and 44 weeks postmenstrual age.ResultsWe randomised 168 infants born before 31 weeks of gestation. We evaluated outc
Meienberg F, Yee M, Johnston D, et al., 2016, Liver fat in adults with GH deficiency: comparison to matched controls and the effect of GH replacement, Clinical Endocrinology, Vol: 85, Pages: 76-84, ISSN: 1365-2265
Sahuri-Arisoylu M, Brody LP, Parkinson JR, et al., 2016, Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate, International Journal of Obesity, Vol: 40, Pages: 955-963, ISSN: 1476-5497
Background/Objectives: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible.Subjects/Methods: C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated.Results: In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity.Conclusions: This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including ‘browning’ and enhancement of hepatic mitochondrial function.
Cuthbertson DJ, Shojaee-Moradie F, Sprung VS, et al., 2015, Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease, Clinical Science, Vol: 130, Pages: 93-104, ISSN: 1470-8736
Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision (n=38) or counselling (n=31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset (n=12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m2 (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Δ mean change 4.7% (0.01, 9.4); P<0.05], which correlated with the change in cardiorespiratory fitness (r=–0.34, P=0.0173). With exercise, peripheral insulin sensitivity significantly increased (following high-dose insulin) despite no significant change in hepatic glucose production (HGP; following low-dose insulin); no changes were observed in the control group. Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the reduction in liver fat was insufficient to improve hepatic IR.
Borga M, Thomas EL, Romu T, et al., 2015, Validation of a fast method for quantification of intra-abdominal and subcutaneous adipose tissue for large-scale human studies, NMR IN BIOMEDICINE, Vol: 28, Pages: 1747-1753, ISSN: 0952-3480
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Goldstone AP, Miras AD, Scholtz S, et al., 2015, Link between increased satiety gut hormones and reduced food reward following gastric bypass surgery for obesity, Journal of Clinical Endocrinology & Metabolism, Vol: 101, Pages: 599-609, ISSN: 1945-7197
Context: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weightloss maintenance, reducing appetite, and also food reward, via unclear mechanisms.Objective: To investigate the role of elevated satiety gut hormones after RYGB, we examined foodhedonic-reward responses following their acute post-prandial suppression.Design: Randomised placebo-controlled double-blind cross-over experimental medicine studies.Patients: Two groups, over 5 months after RYGB for obesity (n7–11), compared with non-obesecontrols (n10), or patients after gastric banding (BAND) surgery (n9).Intervention: Studies were performed after acute administration of the somatostatin analogueOctreotide or saline. In one study, patients after RYGB, and non-obese controls, performed abehavioral progressive ratio task (PRT) for chocolate sweets. In another study, patients after RYGB,and controls after BAND surgery, performed a functional magnetic resonance imaging (fMRI) foodpicture evaluation task.Main outcome measures: Octreotide increased both appetitive food reward (breakpoint) in thePRT (n9), and food appeal (n9) and reward system blood oxygen level dependent (BOLD) signal(n7) in the fMRI task, in the RYGB group, but not in control groups.ISSN
Guess ND, Dornhorst A, Oliver N, et al., 2015, A randomized controlled trial: the effect of inulin on weight management and ectopic fat in subjects with prediabetes, Nutrition & Metabolism, Vol: 12, ISSN: 1743-7075
BackgroundFat infiltration of the liver, muscle and pancreas is associated with insulin resistance and risk of diabetes. Weight loss reduces ectopic fat deposition and risk of diabetes, but is difficult to sustain to due to compensatory increases in appetite. Fermentable carbohydrates have been shown to decrease appetite and food intake, and promote weight loss in overweight subjects. In animal studies, fermentable carbohydrate reduces ectopic fat independent of weight loss. We aimed to investigate the effect of the fermentable carbohydrate inulin on weight maintenance, appetite and ectopic fat in subjects with prediabetes.MethodsForty-four subjects with prediabetes were randomized to 18 weeks’ inulin or cellulose supplementation. During weeks 1–9 (weight loss phase) all subjects had four visits with a dietitian to guide them towards a 5 % weight loss. During weeks 10–18 (weight maintenance phase) subjects continued taking their assigned supplementation and were asked to maintain the weight they had lost but were offered no further support. All subjects attended study sessions at baseline, 9 and 18 weeks for measurement of weight; assessment of adipose tissue and ectopic fat content by magnetic resonance imaging and magnetic resonance spectroscopy; glucose, insulin and GLP-1 levels following a meal tolerance test; and appetite by ad libitum meal test and visual analogue scales.ResultsBoth groups lost approximately 5 % of their body weight by week nine (−5.3 ± 0.1 % vs −4.3 ± 0.4 %, p = 0.13, but the inulin group lost significantly more weight between 9 and 18 weeks (−2.3 ± 0.5 % vs −0.6 ± 0.4 %, p = 0.012). Subjects taking inulin had lower hepatic (p = 0.02) and soleus muscle (p < 0.05) fat content at 18 weeks compared to control even after controlling for weight loss and consumed les
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