Bickerton AST, Roberts R, Fielding BA, Tornqvist H, Blaak EE, Wagenmakers AJM, Gilbert M, Humphreys SM, Karpe F, Frayn KN (2008)Adipose tissue fatty acid metabolism in insulin-resistant men, In: DIABETOLOGIA51(8)pp. 1466-1474
Fielding Barbara A, Griffin Bruce A, Hall Wendy, Hodson Leanne, Antoni Rona, Umpleby A. Margot, Robertson Tracey, Preston Tom, Brook Matthew, Pinnick Katherine (2020)Report of a member-led meeting: how stable isotope techniques can enhance human nutrition research, In: Proceedings of the Nutrition Society79(3)pp. 373-379
Cambridge University Press
A Nutrition Society member-led meeting was held on 9 January 2020 at The University of Surrey, UK. Sixty people registered for the event, and all were invited to participate, either through chairing a session, presenting a ‘3 min lightning talk’ or by presenting a poster. The meeting consisted of an introduction to the topic by Dr Barbara Fielding, with presentations from eight invited speakers. There were also eight lightning talks and a poster session. The meeting aimed to highlight recent research that has used stable isotope tracer techniques to understand human metabolism. Such studies have irrefutably shaped our current understanding of metabolism and yet remain a mystery to many. The meeting aimed to de-mystify their use in nutrition research.
Mills Charlotte , Harding Scott , Bapir Mariam, Mandalari Giuseppina, Salt Louise, Gray Robert, FIELDING BARBARA ANN, Wilde Peter, Hall Wendy, Berry Sarah Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared to a MUFA-rich oil: A randomized controlled trial, In: American Journal of Clinical Nutrition
American Society for Nutrition
Background: Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism.
Objective: To test the impact of a commonly consumed IE versus a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil (rapeseed oil; RO).
Design: A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n=20) aged 45-75 years. Postprandial plasma triacylglycerol (TG) and lipoprotein responses (including stable isotope tracing) to a test meal (50g fat) were evaluated over 8 hours. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM).
Results: Plasma TG 8h incremental area under the curves were lower following non-IE versus RO (-1.7 mmol/L.h (95% confidence interval -3.3, -0.0)), but there were no differences between IE and RO nor IE and non-IE. Low density lipoprotein (LDL) particles were smaller following IE and non-IE versus RO (P=0.005). Extra, extra large (XXL)-, extra large (XL)- and large (L)- VLDL particle concentrations were higher following IE and non-IE versus RO at 6-8 h (P <0.05). No differences in the appearance of [13C]palmitic acid in plasma TG was observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of saturated fatty acids (SFA) versus RO.
Conclusions: Interesterification did not modify fat digestion, postprandial lipemia or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA rich fats, increased pro-atherogenic large TG-rich lipoprotein remnant and small LDL particles following the SFA rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFA to cardiovascular disease risk.
Background: Cardiovascular disease (CVD) remains a significant cause of mortality globally, with a reduction in free sugars consumption a public health target for decreasing disease burden. Fructose raises post-prandial triacylglycerol (TAG) concentrations (risk factor for CVD), relative to glucose or sucrose, possibly due disrupted intestinal TAG metabolism. Aims: Determine whether effects of high-fructose consumption on plasma TAG concentration are explained by intestinal and/or hepatic TAG lipoprotein kinetics, as well as de novo lipogenesis (DNL), in humans and an in vitro model. Methods: Five overweight males consumed drinks containing 30% energy as fructose or complex carbohydrate hourly for 11h on two separate occasions, in a randomised cross-over design (4 week washout). Stable isotopes were given to measure DNL, chylomicron (CM)-TAG and VLDL-TAG kinetics. CM and VLDL were separated according to their apolipoprotein B (apoB) content (Sf>20 fraction). Caco-2 cells were treated (96h) with different fructose and glucose concentrations, or a mixture of sugars (“Mix”), and stable isotopes tracers ([13C6]-fructose; [13C6]-glucose). TAG enrichments were measured by gas chromatography-mass spectrometry. Results: Fructose consumption in comparison to the complex CHO had no effect on either intestinal or hepatic DNL. Intestinal and hepatic DNL were correlated in the fasted (P<0.0001) and fed state (P≤0.004). Plasma TAG (P<0.005) and VLDL-TAG (P=0.003) were greater, and CM-TAG production rate (PR, P=0.046) and fractional catabolic rate (FCR, P=0.073) lower, when fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (P=0.005) and apoB48 (P=0.039), apoB100 (P=0.013) and plasma NEFA (P=0.013) higher in response to fructose. Caco-2 cells utilised fructose and glucose for TAG-palmitate and TAG-glycerol synthesis dose-dependently, with more palmitate derived from glucose after “Mix” treatment (P<0.05). Conclusions: Fructose increased post-prandial TAG concentrations, possibly due to less insulin-mediated lipoprotein metabolism. DNL was unaffected by fructose consumption. This study supports public strategies to restrict dietary free sugars.
Fish skin, a by-product of filleting could be upgraded to value-added products for human consumption, thereby preventing waste and pollution. The aims were to prepare gelatin from skin of Nile or black tilapia (Oreochromis nilotica); characterize its physical-chemical, rheological and thermal properties and those of fish gelatin-whey protein mixtures; prepare hydrolysates and assess their foaming properties in the presence and absence of whey protein and green tea. Gelatin extracted successfully from tilapia skins, gave a 19-26% yield and comprised high protein (90.2 + 0.68 %) and low fat (0.62 + 0.03 %), moisture (5.2 + 0.62 %) and ash content (0.08 + 0.05 %). Amino acid profile included mainly glycine (33.94%), alanine (26.1%) and glutamic acid, proline, arginine, aspartic acid and imino acids. The Bloom strength of 6.67% (w/v) tilapia gelatin in distilled water was higher (301 + 11.6 g) than commercial tilapia (207 + 5.6 g), bovine (~ 225 g), and porcine (~ 300 g) gelatins. The rheological properties of 3,5 and 10% (w/v) tilapia gelatin indicated G’ (elastic modulus) values 1,135 and 720 Pa, respectively, and gelling points of 16.2°C, 5% 17.2°C and 19.8°C respectively whereas melting temperatures were 14.9°C, 14.9°C and 15.0°C respectively. The gels were highly stable over a frequency range of 0-100 rad/sec. DSC results indicated high melting temperatures (Tm) 22oC, compared to bovine (26.2°C) and porcine (30.7°C) gelatin. Cold water fish gelatin did not gel. However, bovine and porcine gelatins had lower enthalpy change (∆H) values 0.58 J/g and 0.45 J/g respectively, compared with tilapia gelatin (2.51 J/g), probably due to protein denaturation of collagen. In tilapia gelatin-whey protein mixed gels, whey proteins were dominant. Gelling temperatures of 10% WPI with 5% gelatin (88.9°C) or 10% gelatin (87.4°C) mixtures were higher than for WPI (80.3°C) or gelatin at 3% (16.2°C), 5% (17.2°C) and 10% (19.8°C). Whey protein (10%) was unstable but formed a good stable gel network with gelatin at 5 % (597 Pa) and 10% (26974 Pa). Whey (10 %) and gelatin (10%) also gave a strong gel by large deformation analysis. Tm and ∆H for 10% whey protein and 5 or 10% gelatin/ mixtures were higher (67.2°C, 68.8°C and 68.2°C respectively) than for gelatin or whey protein alone. The ∆H values of gelatins increased when combined with the WPI. Three % gelatin (0.03 J/g), 10% WPI + 3% gelatin (0.44 J/g), 5 % gelatin (0.18 J/g), 10% WPI + 5% gelatin (0.56), 10% gelatin (1.3 J/g) and 10% WPI + 10% gelatin (0.59). Phase contrast microscopy of gelatin showed a fine uniform and homogeneous network with small particles whereas the whey protein structure had larger aggregates. The gelatin-whey mixtures formed a compatible network. Gelatin produced the highest volume of foam FE (933%), followed by gelatin + whey protein (853%), gelatin hydrolysate + whey protein (767%); these were not significantly different (p>0.05). This was followed by a mixture of gelatin + whey protein + green tea (575%) that was significantly lower (p< 0.05). Foaming stability of mixtures of gelatin + whey protein + green tea was significantly higher at 47%, than gelatin + whey protein (34%) and gelatin + green tea (25%) (p<0.05). Tilapia gelatin was significantly higher than that of whey protein alone (p<0.05) but the combination of whey protein with gelatin resulted in a significant increase (P<0.05) compared to WP or TG alone. Whey protein at FS of 8% was not as stable as the gelatin (18%) or green tea (21%). Gelatin hydrolysate prepared with alcalase had poor FE and FS which improved with added green tea and whey protein due to protein-polyphenol interactions. Tilapia skin gelatin displayed very good nutritional and rheological properties and can be used as an alternative to mammalian gelatins if food products.
Eating rate (ER) is part of the microstructure of meal ingestion and has been of increasing scientific interest due to manipulations being implicated in energy intake, appetite control and mindfulness. The current thesis aims to develop and test the slow eating rate (SER) protocol for use in overweight-free living adults and to investigate the protocol’s effects on body weight, hormones, metabolites and mindfulness.
The developmental part spanned over 5 studies. Studies A and B the SER was refined and finalised through volunteer feedback and in Study C successfully transformed into a 2-minute, online-friendly video which was then incorporated into an online (website and application) weight loss tool. In Study D software (AlexNet) which could identify chewing rate through ER video play back was developed. In Study E, the Mindful Eating Questionnaire -under development (MEQ-UD) was not found as a valid proxy for measuring ER.
The final study was a 10-week parallel, open label randomised controlled trial (control group: n = 7 intervention: n = 8) testing the SER protocol in a 6-week community intervention. Significant changes in body composition were seen in the intervention group, with reductions in weight (p= 0.006), BMI (p=0.006), body fat % (p= 0.026) and visceral fat (p= 0.007) and a trend towards a reduced energy intake (p=0.086) as compared to stable anthropometrics in the control group (n=7).The SER protocol resulted in significantly increased mindful eating in the intervention group. The online monitoring (web and app) proved effective, with duration of intervention (days), total online session duration (minutes) and average online session duration/visit (mins) shown to be the most influential parameters correlated with BMI change. Combined, these data provide novel insights into the effects of a SER protocol in controlled environments and the community. Replication and evaluation in larger and diverse population groups is warranted.
Lord Simon R., Collins Jennifer M., Cheng Wei-Chen, Haider Syed, Wigfield Simon, Gaude Edoardo, Fielding Barbara, Pinnick Katherine E., Harjes Ulrike, Segaran Ashvina, Jha Pooja, Hoefler Gerald, Pollak Michael N., Thompson Alastair M., Roy Pankaj G., English Ruth., Karpe Fredrik, Adams Rosie F., Frezza Christian, Buffa Francesca M., Harris Adrian L. (2020)Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin, In: British Journal of Cancer122(2)pp. 258-265
Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy.
Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment.
Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation.
We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.
Clinical Trial Registration NCT01266486.
Costet P, Ehrenborg E, Fisher R, Fielding B, Groen A, Kardassis D, Malle E, Mulder M, Niemeier A, Norata GD, Hansen AT, Eckardstein AV (2012)European Lipoprotein Club: Report of the 35th ELC Annual Conference (Tutzing, 10th-13th September 2012), In: Atherosclerosis Fielding BA, Frayn KN (2004)Lipid metabolism, In: CURRENT OPINION IN LIPIDOLOGY15(4)pp. 483-485
LIPPINCOTT WILLIAMS & WILKINS
Purpose of review: There is considerable political and public awareness of new recommendations to reduce sugars and sugar-sweetened beverages in our diets. It is therefore timely to review the most recent changes in guidelines, with a focus on evidence for metabolic health, recent research in the area and gaps in our knowledge. Recent findings: Sufficient evidence links a high intake of sugar to dental caries and obesity, and high intakes of sugar-sweetened beverages in particular to increased risk of type 2 diabetes. This has led to the updating of dietary recommendations related to added sugars in the diet. The effects of specific sugars at usual intakes as part of an isoenergetic diet are less clear. The glycaemic response to food is complex and mediated by many factors, but sugar intake is not necessarily the major component. Summary: There are many challenges faced by healthcare professionals and government bodies in order to improve the health of individuals and nations through evidence-based diets. Sufficiently powered long-term mechanistic studies are still required to provide evidence for the effects of reducing dietary sugars on metabolic health. However, there are many challenges for research scientists in the implementation of these studies.
Bucci M, Karmi AC, Iozzo P, Fielding BA, Viljanen A, Badeau RM, Borra R, Saunavaara V, Pham T, Hannukainen JC, Parkkola R, Kalliokoski K, Haaparanta-Solin M, Viljanen T, Frayn KN, Nuutila P (2015)Enhanced fatty acid uptake in visceral adipose tissue is not reversed by weight loss in obese individuals with the metabolic syndrome, In: DIABETOLOGIA58(1)pp. 158-164
A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 hours. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (P<0.005) and VLDL-TAG (P=0.003) were greater, and CM-TAG production rate (PR, P=0.046) and CM-TAG fractional catabolic rate (FCR, P=0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (P=0.005) and apoB48 (P=0.039), apoB100 (P=0.013) and NEFA (P=0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (P=0.043) and low-fructose (P=0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase.
Abstract: Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level, which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL), emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed, including de novo lipogenesis, apolipoprotein B48 and CM-TG production, based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted, including the accurate separation of CM and VLDL. Although the available evidence to date is limited, disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption.
Ahmad A, Stolinski M, Lovegrove JA, Johnsen Sigurd, Mendis Agampodi, Wright John, Wilinska ME, Hovorka R, Bell JD, Thomas EL, Frost GS, Griffin Bruce, Umpleby Margot, Shojaee-Moradie F, Fielding Barbara, Isherwood Cheryl, Li X, Marino A, Alsini N, Jackson N (2017)Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets, In: Clinical Science131(21)pp. 2561-2573
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. This 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.
The menopause is accompanied by increased risk of obesity, altered body fat distribution and decreased skeletal muscle mass. The resulting decrease in RMR should be accompanied by a compensatory change in energy balance to avoid weight gain. We aimed to investigate habitual energy intake and expenditure in pre- and postmenopausal women matched for abdominal obesity. We recruited fifty-one healthy Caucasian women, BMI > 18·5 and <35 kg/m(2), aged 35-45 years (premenopausal, n 26) and 55-65 years (postmenopausal, n 25). Energy intake was measured using 3 d diet diaries and dietary fat quality assessed using adipose tissue fatty acid biomarkers. RMR was measured using indirect calorimetry, and total energy expenditure (TEE) and activity energy expenditure using a combined accelerometer and heart rate monitor. Postmenopausal women had lower RMR and TEE and spent significantly less time undertaking moderate exercise than premenopausal women. Postmenopausal women had a tendency for a lower energy intake, and a similar macronutrient intake but a significantly lower adipose tissue n-6:n-3 ratio (24·6 (se 1·6) v. 37·7 (se 3·1); P < 0·001). The main lifestyle determinant of bone mineral density (which was significantly lower in postmenopausal women) was TEE for premenopausal women, and dietary n-6:n-3 ratio for postmenopausal women. The present results suggest that weight maintenance is achieved in the post- compared with premenopausal status through a combination of reduced energy intake and reduced TEE in a regimen that compromises micronutrient intake and has a negative impact on lean tissue mass. However, lower n-6:n-3 fatty acid intake in postmenopausal women is associated with greater bone mineral density.
Riserus U, Sprecher D, Johnson T, Olson E, Hirschberg S, Liu A, Fang Z, Hegde P, Richards D, Sarov-Blat L, Strum JC, Basu S, Cheeseman J, Fielding BA, Humphreys SM, Danoff T, Sutton P, Moore NR, Murgatroyd P, O'Rahilly S, Willson T, Hassall D, Frayn KN, Karpe F (2008)Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatly acid oxidation in moderately obese men, In: DIABETES57(2)pp. 332-339
AMER DIABETES ASSOC
Polyunsaturated fatty acids (PUFAs) are important for immune function. Limited evidence indicates that immune cell activation involves endogenous PUFA synthesis, but this has not been characterised. To address this, we measured metabolism of 18:3n-3 in quiescent and activated peripheral blood mononuclear cells (PBMCs), and in Jurkat T cell leukaemia. PBMCs from men and women (n = 34) were incubated with [1-13C]18:3n-3 with or without Concanavalin A (Con. A). 18:3n-3 conversion was undetectable in unstimulated PBMCs, but up-regulated when stimulated. The main products were 20:3n-3 and 20:4n-3, while 18:4n-3 was undetectable, suggesting initial elongation and 8 desaturation. PUFA synthesis was 17.4-fold greater in Jurkat cells than PBMCs. The major products of 18:3n-3 conversion in Jurkat cells were 20:4n-3, 20:5n-3 and 22:5n-3. 13C Enrichment of 18:4n-3 and 20:3n-3 suggests parallel initial elongation and Δ6 desaturation. The FADS2 inhibitor SC26196 reduced PBMC, but not Jurkat cell, proliferation suggesting PUFA synthesis is involved in regulating mitosis in PBMCs. Con. A stimulation increased FADS2, FADS1, ELOVL5 and ELOVL4 mRNA expression in PBMCs. A single transcript corresponding to the major isoform of FADS2, FADS20001, was detected in PBMCs and Jurkat cells. PBMC activation induced hypermethylation of a 470bp region in the FADS2 5’-regulatory sequence. This region was hypomethylated in Jurkat cells compared to quiescent PBMCs. These findings show that PUFA synthesis involving initial elongation and 8 desaturation is involved in regulating PBMC proliferation and is regulated via transcription possibly by altered DNA methylation. These processes were dysregulated in Jurkat cells. This has implications for understanding the regulation of mitosis in normal and transformed lymphocytes.
Westerbacka J, Kotronen A, Fielding BA, Wahren J, Hodson L, Perttila J, Seppanen-Laakso T, Suortti T, Arola J, Hultcrantz R, Castillo S, Olkkonen VM, Frayn KN, Oresic M, Yki-Jarvinen H (2010)Splanchnic Balance of Free Fatty Acids, Endocannabinoids, and Lipids in Subjects With Nonalcoholic Fatty Liver Disease, In: GASTROENTEROLOGY139(6)pp. 1961-U232
W B SAUNDERS CO-ELSEVIER INC
Iozzo P, Bucci M, Roivainen A, Nagren K, Jaervisalo MJ, Kiss J, Guiducci L, Fielding B, Naum AG, Borra R, Virtanen K, Savunen T, Salvadori PA, Ferrannini E, Knuuti J, Nuutila P (2010)Fatty Acid Metabolism in the Liver, Measured by Positron Emission Tomography, Is Increased in Obese Individuals, In: GASTROENTEROLOGY139(3)pp. 846-U203
W B SAUNDERS CO-ELSEVIER INC
The purpose of this study was to determine whether or not partial acylglycerols, resulting from triacylglycerol hydrolysis, accumulate during the process of fat deposition in vivo. We measured mono-, di- and triacylglycerol levels in arterialized and adipose tissue venous plasma in normal subjects before and after a test meal. The mean concentrations of partial acylglycerols were consistently low in all plasma samples, accounting for less than 2% of the total acylglycerol measurement. The absence of monoacylglycerol accumulation in the adipose tissue venous plasma samples indicates that the disposal of monoacylglycerol by the adipose tissue was not rate limiting for complete hydrolysis of triacylglycerol in vivo. After heparin was injected intravenously 300 min after the high-fat meal, the mean concentration of monoacylglycerol in arterialized plasma increased from 1.6 ± 0.6 μmol/l to 106 ± 19 μmol/l (P = 0.01), whereas the mean concentration of diacylglycerol did not change (13.0 ± 2.3 μmol/l before, 17.4 ± 4.2 μmol/l after).
Harjes U, Bridges E, Gharpure KM, Roxanis I, Sheldon H, Miranda F, Mangala LS, Pradeep S, Lopez-Berestein G, Fielding BA, Ahmed A, Sood AK, Harris A (2017)Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4, In: Oncogene36(7)pp. 912-921
Nature Publishing Group
Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that endothelial FABP4 is induced by the NOTCH1 signalling pathway, which is involved in mechanisms of resistance to anti-angiogenic tumour therapy1. Here, we investigated the role of FABP4 in endothelial fatty acid metabolism and tumour angiogenesis. We analysed the effect of transient FABP4 knockdown in human umbilical vein endothelial cells on fatty acid metabolism, viability, and angiogenesis. Through therapeutic delivery of siRNA targeting murine FABP4, we investigated the effect of stromal FABP4 knockdown on tumour growth and blood vessel formation. In vitro, siRNA-mediated FABP4 knockdown in endothelial cells led to a marked increase of endothelial fatty acid oxidation, an increase of reactive oxygen species (ROS), and decreased angiogenesis. In vivo, we found that increased NOTCH1 signalling in tumour xenografts led to increased expression of endothelial FABP4 that decreased when NOTCH1 and VEGFA inhibitors were used in combination. Angiogenesis, growth, and metastasis in ovarian tumour xenografts were markedly inhibited by therapeutic siRNA delivery targeting mouse FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has anti-angiogenic and anti-tumour effects with minimal toxicity and should be investigated further.
The menopause is accompanied by increased risk of obesity, altered body fat distribution, and decreased skeletal muscle mass. The resulting decrease in RMR should be accompanied by a compensatory change in energy balance to avoid weight gain. We aimed to investigate habitual energy intake and expenditure in pre- and post-menopausal women matched for abdominal obesity. We recruited fifty-one healthy Caucasian women, BMI >18.5 and < 35, aged 35 - 45 years (pre-menopausal, n=26) and 55-65 years (post-menopausal, n=25). Energy intake was measured using 3-day diet diaries and dietary fat quality assessed using adipose tissue fatty acid biomarkers. RMR was measured using indirect calorimetry, and total (TEE) and activity energy expenditure using a combined accelerometer and heart rate monitor. Post-menopausal women had lower RMR and TEE and spent significantly less time undertaking moderate exercise than pre-menopausal women. Post-menopausal women had a tendency for a lower calorie intake, and a similar macronutrient intake but a significantly lower adipose tissue n-6/n-3 index (24.6 (1.6) v 37.7 (3.1), P<0.001). The main lifestyle determinant of bone mineral density, (which was significantly lower in post-menopausal women), was TEE for pre-menopausal women, and dietary n-6/n-3 index for post-menopausal women. Our results suggest that weight maintenance is achieved in the post- compared with pre-menopausal status through a combination of reduced energy intake and reduced TEE in a regime that compromises micronutrient intake and negatively impacts on lean tissue mass. However, lower n-6/n-3 fatty acid intake in post-menopausal women is associated with greater bone mineral density.
McQuaid SE, Hodson L, Neville MJ, Dennis AL, Cheeseman J, Humphreys SM, Ruge T, Gilbert M, Fielding BA, Frayn KN, Karpe F (2011)Downregulation of Adipose Tissue Fatty Acid Trafficking in Obesity A Driver for Ectopic Fat Deposition?, In: DIABETES60(1)pp. 47-55
AMER DIABETES ASSOC
Hultcrantz R, Castillo S, Frayn KN, Oresic M, Yki-Jarvinen H, Kotronen A, Westerbacka J, Fielding BA, Wahren J, Hodson L, Seppanen-Laakso T, Suortti T, Arola J (2010)Splanchnic balance of free fatty acids, endocannabinoids and lipids in subjects with NAFLD, In: DIABETOLOGIA53pp. S104-S104 Tran C, Jacot-Descombes D, Lecoultre V, Fielding BA, Carrel G, Le K-A, Schneiter P, Bortolotti M, Frayn KN, Tappy L (2010)Sex differences in lipid and glucose kinetics after ingestion of an acute oral fructose load, In: BRITISH JOURNAL OF NUTRITION104(8)pp. 1139-1147
CAMBRIDGE UNIV PRESS
Frost GS, Griffin B, Umpleby M, Shojaee-Moradie F, Jackson N, Fielding B, Li X, Isherwood C, Wilinska G, Hovorka R, Wright J, Bell J, Thomas EL (2015)A DIET LOW IN SUGAR REDUCES THE PRODUCTION OF ATHEROGENIC LIPOPROTEINS IN MEN WITH HIGH LIVER FAT, In: ATHEROSCLEROSIS241(1)pp. E46-E46
mpaired regulation of immune function characterised by chronic inflammation together with a declining protective immune response is a major challenge to healthy ageing. It is therefore important to understand the mechanisms that regulate immune function and the impact of ageing upon such processes. Appropriate induction and resolution of the immune response requires adequate availability of polyunsaturated fatty acids (PUFAs) for incorporation into cell membranes. However, humans are unable to synthesise PUFAs de novo and are dependent upon dietary intake for pre-formed PUFAs or synthesis by the liver from the essential fatty acids, linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (aLNA, 18:3n-3). We have shown that activation of peripheral blood mononuclear cells (PBMCs) 37 increases PUFA biosynthesis from essential fatty acids via a mechanism that involves altered epigenetic regulation of a key gene in the pathway. Moreover, induction of PUFA synthesis is directly involved in the regulation of lymphocyte activation and proliferation. The aim of the BBSRC responsive mode award ‘How does polyunsaturated fatty acid biosynthesis regulate T lymphocyte function?’ is to determine how PUFA biosynthesis regulates T cell function and the effect of ageing on this process. The project will identify points of regulation in the biosynthetic pathway and how these might influence the capacity for up-regulation of PUFA synthesis in older individuals. We will use stable isotope tracers of LA and aLNA to determine whether newly synthesised PUFAs are preferential substrates for synthesis of lipid mediators and whether they are involved in formation of membrane microdomains that mediate cell signalling.
Background Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. Material and methods The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modeling in 60 women with wide-ranging body mass index (19.5-32.9kg/m2). Results Plasma apoC-II and apoC-III concentrations were positively associated with the concentration of plasma triglycerides, VLDL1- and VLDL2- apoB-100 and triglyceride (all P<0.05). ApoC-II production rate (PR) was positively associated with VLDL1-apoB-100 concentration, VLDL1-triglyceride concentration and VLDL1-triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1-triglyceride FCR (all P<0.05). No significant associations were observed between apoC-II and VLDL2 apoB-100 or triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1-triglyceride, and VLDL2- apoB-100 and triglyceride concentrations (all P<0.05). No significant associations were observed between apoC-III and VLDL- apoB-100 and triglyceride kinetic. In multivariable analysis, including homeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 apoB-100 and -triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1- and VLDL2- apoB-100 and triglyceride concentrations and FCR. Conclusions In women, plasma apoC-II and apoC-III concentrations are regulated by their respective production rates and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.
Bernini F, Costet P, Ehrenborg E, Fisher R, Fielding B, Freeman D, Groen A, Malle E, Mulder M, Niemeier A, Hansen AT, von Eckardstein A (2012)European Lipoprotein Club: Report of the 34th ELC annual conference, Tutzing, 5-8 September 2011, In: Atherosclerosis221(1)pp. 287-293 Tan GD, Savage DB, Fielding BA, Collins J, Hodson L, Humphreys SM, O'Rahilly S, Chatterjee K, Frayn KN, Karpe F (2008)Fatty Acid Metabolism in Patients with PPAR gamma Mutations, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM93(11)pp. 4462-4470
Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, Oikonen V, Kemppainen J, Viljanen T, Guiducci L, Haaparanta-Solin M, Nagren K, Solin O, Nuutila P (2010)Increased Brain Fatty Acid Uptake in Metabolic Syndrome, In: DIABETES59(9)pp. 2171-2177
AMER DIABETES ASSOC
There is net outward flow of fatty acids from adipose tissue in the fasted state but net inward flow and storage in the postprandial state. We investigated how this is regulated. Arteriovenous differences were measured across a subcutaneous adipose depot in six normal subjects before and for 5 h after a meal containing 80 g fat and 80 g carbohydrate. In five further experiments, insulin was infused at 40 mU · m -2 · min -1 from 30 min after the meal, clamping the plasma glucose. Net transcapillary fatty acid flow changed from negative (outward flow from tissue to capillaries) in the postabsorptive state to consistently positive (net inward flow, implying fat storage) after the meal despite continued net efflux of fatty acids into venous blood. In the 'clamped' experiments (with additional insulin), net fatty acid efflux in the venous blood was suppressed and positive transcapillary flux (storage) was more marked. Regulation of fatty acid flow appeared to depend on coordinated changes in hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action and fatty acid esterification. Additional insulin caused no further suppression of HSL or activation of LPL but markedly stimulated fatty acid retention (presumed to represent esterification). In the absence of additional insulin, a high proportion of the fatty acids liberated by LPL are released into the venous plasma in both postabsorptive and postprandial states. We hypothesize that this 'loss' of fatty acids is necessary to give precise control to the pathway of fat storage.
Objectives: To comprehensively survey the sugar and nutrient contents of yogurt products available in UK supermarkets, in particular those marketed to children. Design: A cross-sectional survey of yogurt products available in the UK’s supermarkets in November 2016. Methods: Data were collected from five major online UK supermarkets and a process flow strategy was used to place yogurts into eight categories: children’s, dairy alternatives, dessert, drinks, fruit, flavoured, natural/Greek style and organic. A comprehensive database of product information for 921 unique products was created and analysed. Results: The total sugar, fat, protein, calcium and energy contents were highly variable across categories, and the ranges were extremely broad. Although lower than the dessert category, the medians (range) of the total sugar content of children’s (10.8 g/100 g (4.8–14.5)), fruit (11.9 g/100 g (4.6–21.3)), flavoured (12.0 g/100 g (0.1–18.8)) and organic (13.1 g/100 g (3.8–16.9)) yogurt products were all well above 10 g/100 g, and represented >45% of total energy. Only two out of 101 children’s yogurt and fromage frais products surveyed qualified as low sugar (≤5 g/100 g). Natural/Greek yogurts had dramatically lower sugar contents (5.0 g/100 g (1.6, 9.5), largely lactose) than all other categories. While low-fat (<3 g/100 g) products had less sugar and energy than higher fat yogurts, nonetheless 55% (285 of 518 low-fat yogurts) contained between 10 and 20 g sugar/100 g. Within the children’s category, fromage frais had higher protein (5.3 g/100 g (3.3, 8.6) vs 3.2 (2.8, 7.1); p<0.0001) and calcium contents (150 mg/100 g (90, 240) vs 130.5 mg/100 g (114, 258); p=0.0015) than yogurts. Conclusions: While there is good evidence that yogurt can be beneficial to health, products on the market vary widely in total sugars. Fewer than 9%, and only 2% of the children’s, products surveyed were low enough in sugar to earn ‘green’ in UK front of the pack labelling. Reformulation for the reduction of free sugars in yogurts is warranted.
DAVIES AG, PRICE DA, POSTLETHWAITE RJ, ADDISON GM, BURN JL, FIELDING BA (1985)RENAL-FUNCTION IN DIABETES-MELLITUS, In: ARCHIVES OF DISEASE IN CHILDHOOD60(4)pp. 299-304
BRITISH MED JOURNAL PUBL GROUP
Morigny Pauline, Houssier Marianne, Mairal Aline, Ghilain Claire, Etienne Mouisel, Benhamed Fadila, Masri Bernard, Recazens Emeline, Denechaud Pierre-Damien, Tavernier Geneviève, Caspar-Bauguil Sylvie, Virtue Sam, Zazoun Madjid, Sramkova Veronika, Monbrun Laurent, Mazars Anne, Guilmeau Sandra, Barquissau Valentin, Beuzelin Diane, Bonnel Sophie, Marques Marie, Monge-Roffarello Boris, Astrup Arne, Lefort Corinne, Fielding Barbara, Sulpice Thierry, Payrastre Bernard, Bertrand-Michel Justine, Meugnier Emmanuelle, Ligat Laetitia, Lopez Frederic, Guillou Hervé, Saris Wim, Ling Charlotte, Holm Cecilia, Rabasa-Lhoret Remi, Stich Vladimir, Arner Peter, Ryden Mikael, Moro Cedric, Viguerie Nathalie, Harms Matthew, Postic Catherine, Hallén Stefan, Vidal-Puig Antonio, Vidal Hubert, Langin Dominique (2018)Interaction between Hormone-Sensitive Lipase and ChREBP in Fat Cells Controls Insulin Sensitivity, In: Nature Metabolism
Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency–mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL–ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.
Herring Roselle A., Shojaee-Moradie Fariba, Garesse Robert, Stevenage Mary, Jackson Nicola, Fielding Barbara, Mendis Agampodi, Johnsen Sigurd, Umpleby Margot, Davies Melanie, Russell-Jones David L. Full Title Metabolic effects of an SGLT2 inhibitor (dapagliflozin) during a period of acute insulin withdrawal and development of ketoacidosis in people with type 1 diabetes., In: Diabetes Care
American Diabetes Association
Objective: To determine the effect of SGLT2 inhibitor dapagliflozin on glucose flux, lipolysis and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. Research Design and Methods: A double-blind placebo controlled crossover study with a 4-week wash out period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the rate of glucose production (Ra), disappearance (Rd) and lipolysis. At isotopic steady state insulin was withdrawn and the study terminated after 600 minutes or earlier if blood glucose reached 18mmol/L, bicarbonate <15mmol/L, venous pH <7.35 or capillary ketones >5.0 mmol/L. Results: At baseline, glucose Ra was significantly higher with dapagliflozin than placebo. Following insulin withdrawal, plasma glucose concentrations at the end point were significantly lower with dapagliflozin than placebo and AUC0-180min glucose Rd and AUC0-180min β-hydroxybutyrate (BOHB) were significantly higher. There was a small but significantly higher AUC0-180min glycerol Ra (measure of lipolysis) with dapagliflozin. Non-esterified fatty acid concentrations were not different between treatments.When divided by BMI>27 and <27kg/m2, basal glucose Ra and BOHB, and AUC0-180min glycerol Ra were significantly higher in the low BMI group with dapaglifozin versus placebo treatment. Conclusions: During insulin withdrawal the increase in BOHB with 3 dapaglifozin may be partially due to increased lipolysis. However reduced renal excretion, reduced BOHB uptake by peripheral tissues or a metabolic switch to increase ketogenesis within the liver may also play a role.
Mycobacterium tuberculosis (Mtb) infects macrophages and macrophage-derived foam cells, a hallmark of granulomata in tuberculous lesions. We analysed the effects of lipid accumulation in human primary macrophages and quantified strong triglyceride and phospholipid remodelling which depended on the dietary fatty acid used for the assay. The enrichment of >70% in triglyceride and phospholipids can alter cell membrane properties, signalling and phagocytosis in macrophages. In conventional macrophage cultures, cells are heterogeneous, small or large macrophages. In foam cells, a third population of 30% of cells with increased granularity can be detected. We found that foam cell formation is heterogenous and that lipid accumulation and foam cell formation reduces the phagocytosis of Mtb. Under the conditions tested, cell death was highly prevalent in macrophages, whereas foam cells were largely protected from this effect. Foam cells also supported slower Mtb replication, yet this had no discernible impact on the intracellular efficacy of four different antitubercular drugs. Foam cell formation had a significant impact in the inflammatory potential of the cells. TNF-α, IL-1β and prototypical chemokines were increased. The ratio of inflammatory IL-1β, TNF-α and IL-6 versus anti-inflammatory IL-10 was significantly higher in response to Mtb versus LPS, and was increased in foam cells compared to macrophages, suggestive of increased pro-inflammatory properties. Cytokine production correlated with NF-κB activation in our models. We conclude that foam cell formation reduces the host cell avidity for, and phagocytosis of, Mtb while protecting the cells from death. This protective effect is associated with enhanced inflammatory potential of foam cells and restricted intracellular growth of Mtb.
This pilot study investigated the effects of chilling and reheating a pasta-based meal on the postprandial glycaemic response. In this single-blind crossover study, 10 healthy volunteers consumed identical pasta meals (pasta, olive oil and tomato sauce), served either freshly prepared, chilled or chilled/reheated, on three separate randomised occasions. Capillary blood samples were taken for two hours postprandially. A significant difference in glucose Incremental Area Under the Curve (IAUC) was observed (p = 0.006), with the greatest difference observed between the freshly cooked and chilled/reheated meals (p = 0.041). Significant differences in incremental peak glucose were also observed (p = 0.018). These results suggest that making simple changes to domestic food processing methods can reduce the glycaemic excursion following a pasta meal, with the potential for health benefit.
We hypothesised that probiotic supplementation (PRO) increases the absorption and oxidation of orally ingested maltodextrin during 2h endurance cycling, thereby sparing muscle glycogen for a subsequent time trial (simulating a road race). Measurements were made of lipid and carbohydrate oxidation, plasma metabolites and insulin, gastrointestinal permeability, and subjective symptoms of discomfort. Seven male cyclists were randomized to PRO (bacterial composition given in methods) or placebo (PLC) for four weeks, separated by a 14-day washout period. After each period, cyclists consumed a 10% maltodextrin solution (initial 8 mL·kg-1 bolus and 2 mL·kg-1 every 15 min) while exercising for 2h at 55% Wmax followed by a 100 kJ time trial. PRO resulted in small increases in peak oxidation rates of the ingested maltodextrin (0.84 ± 0.10 vs 0.77 ± 0.09 g·min-1, P = 0.016), and mean total carbohydrate oxidation (2.20 ± 0.25 vs 1.87 ± 0.39 g·min-1, P = 0.038), while fat oxidation was reduced (0.40 ± 0.11 vs 0.55 ± 0.10 g·min-1, P = 0.021) . During PRO small but significant increases were seen in glucose absorption, plasma glucose and insulin concentration and decreases in NEFA and glycerol. Differences between markers of GI damage and permeability and time trial performance were not significant (P > 0.05). In contrast to the hypothesis, PRO led to minimal increases in absorption and oxidation of the ingested maltodextrin and small reductions in fat oxidation, while having no effect on subsequent time trial performance.
Griffin BA, Fielding BA (2001)Postprandial lipid handling, In: CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE4(2)pp. 93-98
LIPPINCOTT WILLIAMS & WILKINS
Riserus U, Tan GD, Fielding BA, Neville MJ, Currie J, Savage DB, Chatterjee VK, Frayn KN, O'Rahilly S, Karpe F (2005)Rosiglitazone increases indexes of stearoyl-CoA desaturase activity in humans - Link to insulin sensitization and the role of dominant-negative mutation in peroxisome proliferator-activated receptor-gamma, In: DIABETES54(5)pp. 1379-1384
AMER DIABETES ASSOC
Background Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis and greater secretion of large very low density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre- and post-menopausal women. Methods and Results We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 (0.02-0.08) and 0.095 (0.08-0.11) respectively). Thirty women were pre-menopausal aged 35-45 and they were matched for abdominal obesity with 28 post-menopausal women aged 55-65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404±30 v 268±26 mg/kg lean mass, P<0.001) but not small VLDL (160±11 v 142±13). However, post-menopausal status had a pronounced effect on the characteristics of small VLDL particles which were considerably triglyceride (TG)-enriched (production ratio of VLDL2-TG:apolipoprotein B 30±5.3 v 19±1.6, P<0.05). In contrast to post-menopausal women, there was a tight control of hepatic fatty acid metabolism and TG production in pre-menopausal women, whereby oxidation (rs=-0.49, P=0.006), de novo lipogenesis (rs=0.55, P=0.003) and desaturation (rs=0.48, P=0.012) were closely correlated with abdominal obesity-driven large VLDL-TG secretion rate. Conclusions In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion whereas post-menopausal status was characterised by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in post-menopausal obesity.
Most postprandial studies have investigated the response of a single meal, yet the ingestion of sequential meals is more typical in a Western society. The aim of this review is to explain how natural and stable isotope tracers of fatty acids have been used to investigate the metabolism of dietary fat after single and multiple meals, with a focus on in vivo measurements of adipose tissue metabolism. When stable isotope tracers are combined with arteriovenous difference measurements, very specific measurements of metabolic flux across tissues can be made. We have found that adipose tissue is a net importer of dietary fat for 5 h following a single test meal and for most of the day during a typical three-meal eating pattern. When dietary fat is cleared from plasma, some fatty acids ‘spillover’ into the plasma and contribute up to 50 % of postprandial plasma non-esterified fatty acid concentrations. Therefore, plasma non-esterified fatty acid concentrations after a meal reflect the balance between intracellular and extracellular lipolysis in adipose tissue. This balance is altered after the acute ingestion of fructose. The enzyme lipoprotein lipase is a key modulator of fatty acid flux in adipose tissue and its rate of action is severely diminished in obese men. In conclusion, in vivo studies of human metabolism can quantify the way that fatty acid trafficking modulates plasma lipid concentrations. The magnitude of fatty acid flux from adipose tissue has implications for ectopic fat deposition in tissues such as the liver and muscle.
Specialized metabolic-sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counter regulatory responses. Hypothalamic reactive oxygen species (ROS) may act as a metabolic signal mediating responses to changes in glucose, other substrates and hormones. The role of ROS in the brain’s control of glucose homeostasis remains unclear. We hypothesized that hydrogen peroxide (H2O2), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H2O2 with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, ICV catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus (ARC). Electrophysiological recordings revealed a subset of ARC neurons expressing pro-opiomelanocortin (POMC) that were inhibited by catalase and excited by H2O2. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H2O2 represents an important metabolic cue which, through tuning the electrical activity of key neuronal populations such as POMC neurons, may have a role in the brain’s influence of glucose homeostasis and energy balance.
Fernandez C, Lindholm M, Krogh M, Lucas S, Larsson S, Osmark P, Berger K, Boren J, Fielding B, Frayn K, Holm C (2008)Disturbed cholesterol homeostasis in hormone-sensitive lipase-null mice, In: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM295(4)pp. E820-E831
AMER PHYSIOLOGICAL SOC
Context GLP-1 agonists control postprandial glucose and lipid excursion in type 2 diabetes; however the mechanism(s) are unclear. Objective To determine the mechanism(s) of postprandial lipid and glucose control with lixisenatide (GLP-1 analogue) in type 2 diabetes. Design Randomised, double-blind, cross-over study. Setting Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, UK Patients Eight obese men with type 2 diabetes (57.3±1.9yrs; BMI 30.3±1.0kg/m2, HbA1C 66.5±2.6mmol/mol, [8.2±0.3%]). Interventions Two metabolic studies, four-weeks after lixisenatide or placebo; with cross-over and repetition of studies. Main outcome measures Study one: very-low density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with iv bolus of [2H5]glycerol in a 12h study, with hourly feeding. Oral [13C]triolein, in a single meal, labelled enterally-derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable iv [6,6-2H2]glucose infusion. Results Study one: CM-TAG (but not VLDL-TAG) pool-size, was lower with lixisenatide (P=0.046). Lixisenatide reduced CM [13C]oleate AUC60-480min concentration (P=0.048) and increased CM-TAG clearance; with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P=0.0051, P˂0.05). Total glucose production rate (Ra) (P=0.015), Rameal (P=0.0098) and acetaminophen AUC0-360min (P=0.006) were lower with lixisenatide than placebo. Conclusions Lixisenatide reduced [13C]oleate concentration, derived from a single meal in CM-TAG, as well as glucose Rameal, through delayed gastric emptying. However day-long CM production, measured with repeated meal-feeding, was not reduced by lixisenatide and decreased CM-TAG concentration was due to increased CM-TAG clearance.
Riserus U, Sprecher D, Jonson T, Olson E, Hirschberg S, Fang Z, Hegde P, Richards D, Sarov-Blat L, Strum J, Cheeseman J, Fielding B, Moore N, Murgatroyd P, O'Rahilly S, Keith F, Sutton P, Willson T, Hassall D, Karpe F (2007)PPAR-delta activation reverses multiple metabolic abnormalities, reduces oxidative stress and promotes fat oxidation in obese humans, In: INTERNATIONAL JOURNAL OF OBESITY31(9)pp. 1487-1487 Gregson CL, Karpe F, Christodoulides C, Loh NY, Neville MJ, Marinou K, Hardcastle SA, Fielding BA, Duncan EL, McCarthy MI, Tobias JH (2015)LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion, In: CELL METABOLISM21(2)pp. 262-272
Sell H, Blueher M, Kloeting N, Schlich R, Willems M, Ruppe F, Knoefel WT, Dietrich A, Fielding BA, Arner P, Frayn KN, Eckel J (2013)Adipose Dipeptidyl Peptidase-4 and Obesity Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro, In: DIABETES CARE36(12)pp. 4083-4090
AMER DIABETES ASSOC
Kotronen A, Seppala-Lindroos A, Vehkavaara S, Bergholm R, Frayn KN, Fielding BA, Yki-Javinen H (2009)Liver fat and lipid oxidation in humans, In: LIVER INTERNATIONAL29(9)pp. 1439-1446
WILEY-BLACKWELL PUBLISHING, INC
Banerjee R, Rial BF, Suttie J, Lewandowski A, Robson MD, Schneider J, Hodson L, Fielding B, Collier JD, Barnes E, Neubauer S (2012)WAIST CIRCUMFERENCE GREATER THAN 90CM IS A RISK FACTOR FOR HEPATIC STEATOSIS IN OTHERWISE HEALTHY ADULTS - A 3 TESLA MAGNETIC RESONANCE SPECTROSCOPY STUDY, In: JOURNAL OF HEPATOLOGY56pp. S504-S504
Background: Observational studies often infer hepatic de novo lipogenesis (DNL) by measuring circulating fatty acid (FA) markers; however it remains to be elucidated whether these markers accurately reflect hepatic DNL.
Objective: We investigated associations between fasting hepatic DNL and proposed FA markers of DNL in subjects consuming their habitual diet.
Design: Fasting hepatic DNL was assessed using ²H2O (heavy water) in 149 non-diabetic men and women and measuring the synthesis of very low-density lipoprotein triglyceride (VLDL-TG) palmitate. FA markers of blood lipid fractions was determined by gas chromatography (GC).
Results: Neither the lipogenic index (16:0/18:2n-6) nor the SCD index (16:1n-7/16:0) in VLDL-TG were associated with isotopically assessed DNL (r=0.13, P=0.1 and r=-0.08, P=0.35, respectively). The relative abundance (mol%) of 14:0, 16:0 and 18:0 in VLDL-TG were weakly (r≤0.35) associated with DNL whereas abundance of 16:1n-7, 18:1n-7 and 18:1n-9 were not associated. When the cohort was split by median DNL, only abundance of 14:0 and 18:0 in VLDL-TG could discriminate between subjects having high (11.5%) and low (3.8%) fasting hepatic DNL. Based on a subgroup, FA markers in total plasma TG, plasma cholesteryl esters, plasma phospholipids and red blood cell phospholipids were generally not associated with DNL.
Conclusions: The usefulness of circulating FAs as markers of hepatic DNL in healthy individuals consuming their habitual diet is limited due to their inability to clearly discriminate between individuals with low and high fasting hepatic DNL.
Potatoes have been an affordable, staple part of the diet for many hundreds of years. Recently however, there has been a decline in consumption, perhaps influenced by erroneous reports of being an unhealthy food. This review provides an overview of the nutritional value of potatoes and examines the evidence for associations between potato consumption and non-communicable diseases. Potatoes are an important source of micronutrients, such as vitamin C, vitamin B6, potassium, folate, and iron and contribute a significant amount of fibre to the diet. However, nutrient content is affected by cooking method; boiling causes leaching of water-soluble nutrients, whereas frying can increase the resistant starch content of the cooked potato. Epidemiological studies have reported associations between potato intake and obesity, type 2 diabetes and cardiovascular disease. However, results are contradictory and confounded by lack of detail on cooking methods. Indeed, potatoes have been reported to be more satiating than other starchy carbohydrates, such as pasta and rice, which may aid weight maintenance. Future research should consider cooking methods in the study design in order to reduce confounding factors and further explore the health impact of this food.
Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, Peltonen M, Romeo S, Lundbom J, Lundbom N, Olkkonen VM, Yki-Jarvinen H, Gylling H, Fielding BA, Rissanen A (2012)Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans, In: AMERICAN JOURNAL OF CLINICAL NUTRITION96(4)pp. 727-734
AMER SOC NUTRITION-ASN
A sensitive method has been developed to measure specific mono-, di- and triacylglycerol concentrations in human plasma, using thin-layer chromatography and enzymatic assay. The levels of partial acylglycerols in human plasma from fasting subjects were lower than previous reports had suggested and amounted to less than 3% of the total acylglycerols. After heparin injection the plasma monoacylglycerol concentration increased markedly (P < 0.01) while the triacylglycerol concentration decreased significantly (P < 0.001). The plasma diacylglycerol concentration did not change significantly although it increased as a percentage of the total (P < 0.05); after heparin partial acylglycerols accounted for more than 10% of the total. After a high-fat meal the plasma concentrations of di- and triacylglycerol increased approximately two-fold (P < 0.005) but no significant change was observed for mono-acylglycerol. The percentage contribution of partial acylglycerols was unchanged (2.6% fasting, 2.4% postprandially).
Purpose of review In 2004, the ‘omega-3 index’ was described as the sum of eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) in red blood cells (RBCs) as an index of coronary heart disease mortality. This review outlines new evidence to support the omega-3 index as a tool to inform disease prognosis. Recent findings Recent studies have reported differential metabolism of EPA and DHA. High dose supplementation with EPA and DHA led to increased levels of RBC DHA that were associated with decreased liver fat. EPA and DHA in RBCs were associated with reduced mortality in a prospective study of patients with cardiac disease; the strongest association was with EPA. A diet containing 9.5 g alpha linolenic acid lead to an increase in EPA but not DHA status in middle aged women. Summary: Dietary intake or supplementation studies with n-3 fatty acids should include measurement of n-3 status in a standardised way. The omega-3 index, reflecting EPA and DHA status throughout the body, is convenient and may be appropriate in some cases, but since EPA and DHA assimilate differently in membranes, and have different potency, measurement of individual fatty acid composition in RBCs may be more informative
Lord Simon R., Collins Jennifer M., Cheng Wei-Chen, Haider Syed, Wigfield Simon, Gaude Edoardo, Fielding Barbara A., Pinnick Katherine E., Harjes Ulrike, Segaran Ashvina, Jha Pooja, Hoefler Gerald, Pollak Michael N., Thompson Alastair M., Roy Pankaj G., English Ruth, Adams Rosie F. Adams, Harris Adrian L., Frezza Christian, Buffa Francesca M., Karpe Fredrik (2019)Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin, In: British Journal of Cancer
Background: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy.
Methods: 36 patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment.
Results: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between 2 previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation.
Conclusions: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.
Different lipid fractions in humans have characteristic fatty acid profiles and these are maintained partly through diet and to a lesser extent through endogenous synthesis. The enzyme stearoyl-CoA desaturase (SCD; EC 220.127.116.11) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids such as palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9). These are the two most abundant monounsaturated fatty acids in human plasma lipids, membranes and adipose tissue. Although in quantitative terms, the endogenous synthesis of fatty acids in humans is not great in most circumstances, it is becoming increasingly evident that SCD plays important structural and metabolic roles. In addition, 16:1 n-7 has been purported to act as a beneficial 'lipokine' in an animal model. Research in humans has relied on indirect measurements of SCD1 activity and therefore, much of our understanding has come from work on animal models. However, results have been somewhat counterintuitive and confusing, so the purpose of this review is to try to summarise our current understanding of this fascinating enzyme.
Theytaz F, Noguchi Y, Egli L, Campos V, Buehler T, Hodson L, Patterson BW, Nishikata N, Kreis R, Mittendorfer B, Fielding B, Boesch C, Tappy L (2012)Effects of supplementation with essential amino acids on intrahepatic lipid concentrations during fructose overfeeding in humans, In: AMERICAN JOURNAL OF CLINICAL NUTRITION96(5)pp. 1008-1016
AMER SOC NUTRITION-ASN
The expansion of lower-body adipose tissue (AT) is paradoxically associated with reduced cardiovascular disease and diabetes risk. We examined whether the beneficial metabolic properties of lower-body AT are related to the production and release of the insulin-sensitizing lipokine palmitoleate (16:1n-7). Using venoarterial difference sampling, we investigated the relative release of 16:1n-7 from lower-body (gluteofemoral) and upper-body (abdominal subcutaneous) AT depots. Paired gluteofemoral and abdominal subcutaneous AT samples were analyzed for triglyceride fatty acid composition and mRNA expression. Finally, the triglyceride fatty acid composition of isolated human preadipocytes was determined. Relative release of 16:1n-7 was markedly higher from gluteofemoral AT compared with abdominal subcutaneous AT. Stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in endogenous 16:1n-7 production, was more highly expressed in gluteofemoral AT and was associated with greater enrichment of 16:1n-7. Furthermore, isolated human preadipocytes from gluteofemoral AT displayed a higher content of SCD1-derived fatty acids. We demonstrate that human gluteofemoral AT plays a major role in determining systemic concentrations of the lipokine palmitoleate. Moreover, this appears to be an inherent feature of gluteofemoral AT. We propose that the beneficial metabolic properties of lower-body AT may be partly explained by the intrinsically greater production and release of palmitoleate.
Limpet, Patella vulgata is an underutilised mollusc found on rocky shores in the United Kingdom and Asia. The objective was to analyse the physical-chemical and functional properties of limpet muscle. Patella vulgata contained protein (15.3%) and lipid (2.5%). The fatty acid profile comprised saturated (28.09%), monounsaturated (24.33%) and polyunsaturated fatty acids (47. 58%). Patella vulgata muscle indicated a water-soluble protein content of 3.07% ± 0.05 and salt-soluble proteins of 2.86% ± 0.17%. Protein characterization by SDS-polyacrylamide gel electrophoresis (SDS-Page) exhibited the major bands for myofibrillar proteins including myosin heavy chain, troponin and actin. The essential amino acid profile included lysine, threonine, valine, histidine, methionine, phenylalanine, leucine and isoleucine. Limpet muscle exhibited excellent rheological properties and denatured between 50 and 60 °C as determined by differential scanning calorimetry. The gel strength and nutritional value of limpet were improved when combined with tapioca starch (10:5) and with whey protein isolate (7.5:7.5) when compared to limpet alone. Limpet flesh showed favourable interactions with other nutrients in food model systems and was further tested in real products like soups and sausages. Spices as chilli, turmeric, ginger and garlic (0.01%) were used in four soup formulations as natural anti-oxidants, and all dried formulations were stored and were monitored for lipid oxidation for 12 weeks. The recipe with the combination of turmeric and chilli exhibited the best result for inhibiting peroxide value (PV) (49.1 meq/kg of lipid, P <0.05) and inhibiting thiobarbituric reactive species (TBARS) formation (166 mg TBARS/mg lipid, P <0.05) when compared with recipe control. All spices prevented the toughness of the soup powder during storage, resulting in a better texture compared to the control. Limpet sausages, gluten free and low in salt, were also developed with and without 2% turmeric and/or 2% ginger. The recipe containing ginger alone inhibited PV (3.3 meq/kg of lipid, P <0.05) versus the control (8.04 meq/kg of lipid), while the formulation with turmeric inhibited TBARS more effectively (0.016 mg TBARS/mg lipid, P <0.05) versus control (0.05 mg TBARS/mg lipid). The texture of cooked limpet sausages had a similar texture to commercial Quorn sausages with no significant difference in gel strength values (P <0.05) and was softer than chicken sausage. These project findings indicate that underutilised limpets can contribute to valuable protein and lipids in novel food products.
Conversion of the essential n-3 (18:3n-3) and n-6 (18:2n-6) fatty acids to longer chain polyunsaturated fatty acids (PUFA) involves sequential desaturation and elongation reactions. Previous studies have reported gender differences in n-3 PUFA synthesis, whereas the effect of age is less clear. n-3 PUFAs are reported to have important effects on immune cell function. A previous study reported long chain PUFA synthesis in mitogen stimulated but not quiescent peripheral blood mononuclear cells (PBMCs). However, the underlying mechanism is not known. PUFA synthesis was investigated in PBMCs incubated with [1-13C]18:3n-3 for 48 h. Activation with the T-lymphocyte mitogen concanavalin A (Con A) increased PUFA synthesis. 22:6n-3 synthesis was not detected. [1-13C] incorporation was greatest for 20:3n-3 suggesting initial chain elongation is an important fate for 18:3n-3. Con A increased expression of three key genes (FADS2, FADS1 and ELOVL5) involved in PUFA synthesis, suggesting upregulation of the pathway is controlled at the transcriptional level. ELOVL2 expression was negligible, possibly explaining the lack of 22:6n-3 synthesis. Con A increased methylation of 12 CpGs in the FADS2 promoter contradicting the general view that DNA methylation represses transcription. Subsequent 5’RACE analysis verified that activated PBMCs were not using an alternative promoter for FADS2 transcription. Contrary to expectation, 18:3n-3 conversion in activated PBMCs was not affected by gender or menopausal status and there was no clear age effect. PUFA synthesis was constitutive in the Jurkat T-lymphocyte leukaemic cell-line and was higher than in PBMCs. FADS2, FADS1 and ELOVL5 mRNA expression was also higher in Jurkat cells and was associated with 50% lower methylation of 17 CpGs in the FADS2 promoter, suggesting transcriptional dysregulation of PUFA synthesis in Jurkat cells involves altered DNA methylation. These findings have provided novel insights into the regulation of PUFA biosynthesis in PBMCs and upregulation of the pathway in activated PBMCs suggests that newly synthesised PUFAs may be important for cell function.
Food security can be improved by reducing post-harvest losses in sustainable food product chains. About 50% of fish is lost during filleting, including significant levels of high quality protein (10–23% (w/w)), which may be a source for biofunctional peptides. The fish processing waste protein hydrolysate can be a potential solution for minimizing the environmental issues related to marine processing products, and act as an alternative to producing value added fish processing by products. The main aim of this study was to investigate the physicochemical properties of fish processing waste streams from Atlantic Mackerel (Scomber scombrus) and mixed fish by membrane separation. Protein hydrolysates of Atlantic Mackerel (Scomber scombrus) and mixed fish from fish waste streams were prepared by enzymatic hydrolysis using pepsin and pancreatin and measured for their antioxidant and functional properties. The chemical composition (moisture, protein, total lipids and ash) of the Atlantic mackerel and Nile Perch (Lates niloticus) fish fillets (FF) compared to fish waste (FW) was also investigated. Protein fractions from the fish waste samples were separated by using the TFF cogent μscale ultrafiltration system from Millipore, and parameters including transmembrane pressure (TMP) on flux excursion, protein performance scalability, mass transfer analysis, as well as hold up volume were studied. The mechanism of antioxidant activity was studied by DPPH, FRAP, FTC and TBARS assays. It was demonstrated that fish waste water protein hydrolysate especially for Atlantic Mackerel showed good antioxidant activities by the Ferric Thiocyanate (FTC) and Thiobarbituric acid Reactive substances (TBARS) methods and compared well with other antioxidants (BHA, ascorbic acid and trolox). There was significant difference (p<0.05) between samples and negative control (no antioxidant). DPPH scavenging activity increased with the extract concentration in the range of 1.5-26 %. In FRAP assay, both sample showed that there was an increase in absorbance with an increase in concentration. Structural and thermodynamic changes in fish waste samples were also determined by FT-Raman spectroscopy, differential scanning calorimetry (DSC) and small deformation rheology respectively. The DSC thermograms from the samples indicated that fish waste samples may be comparable. Moreover in fish waste sample hydrolysates, the same trends were obtained in 10 kDa AM and MF fractions. Fish waste samples especially hydrolysed fish waste samples, showed different protein denaturation transition peaks, indicating that enzymatic hydrolysis can affect the thermodynamic and functional properties of protein samples. Similarly, the rheological properties were different for different fish samples (AM and MF) with AM showing higher G’ or elastic modulus values (p<0.05). The proteins in mackerel and mixed fish waste stream were characterised by FT-Raman spectroscopy and showed significant differences in their respective spectra and most of the assigned peaks (p<0.05).