Publications by authors named "Fredrik Karpe"

192 Publications

Distinct opposing associations of upper and lower body fat depots with metabolic and cardiovascular disease risk markers.

Int J Obes (Lond) 2021 Jul 30. Epub 2021 Jul 30.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

Background: To examine the associations of total and regional adiposity with metabolic and cardiovascular disease (CVD) risk markers.

Methods: This cross-sectional study included 1080 (53.8% men, aged 39-44 years) individuals from South India. Anthropometry (height, weight, waist and hip circumference), body composition assessment using dual-energy X-ray absorptiometry (DXA), blood pressure (BP), and plasma glucose, insulin and lipids were measured. Regression analysis was used to examine associations of standardized fat measurements with type 2 diabetes (T2D), insulin resistance (IR), hypertension and hypertriglyceridemia and continuous measurements of BP, glucose, insulin, HOMA-IR and lipids. Contour plots were constructed to visualize the differential effect of upper and lower fat depots.

Results: DXA-measured fat depots were positively associated with metabolic and CVD risk markers. After adjusting for fat mass index, upper body fat remained positively, while lower body fat was negatively associated with risk markers. A one standard deviation (SD) increase in android fat showed higher odds ratios (ORs) for T2D (6.59; 95% CI 3.17, 13.70), IR (4.68; 95% CI 2.31, 9.50), hypertension (2.57; 95% CI 1.56, 4.25) and hypertriglyceridemia (6.39; 95% CI 3.46, 11.90) in men. A 1 SD increase in leg fat showed a protective effect with ORs for T2D (0.42; 95% CI 0.24, 0.74), IR (0.31; 95% CI 0.17, 0.57) and hypertriglyceridemia (0.61; 95% CI 0.38, 0.98). The magnitude of the effect was greater with DXA-measured fat compared with anthropometry.

Conclusion: At any level of total body fat, upper and lower body fat depots demonstrate opposite risk associations with metabolic and CVD risk markers in Asian Indians.
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http://dx.doi.org/10.1038/s41366-021-00923-1DOI Listing
July 2021

The Relation Between Adult Weight Gain, Adipocyte Volume And The Metabolic Profile At Middle Age.

J Clin Endocrinol Metab 2021 Jun 28. Epub 2021 Jun 28.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume.

Methods: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n=6 347, discovery) and Oxford Biobank (n=6 317, replication). Adult weight gain was calculated as the absolute difference between BMI at middle age and recalled BMI at age 20. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n=114) to estimate adipocyte volume.

Results: Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins and total intermediate-density lipoprotein. One SD weight gain was associated with 386 μm3 (95% CI 143 - 629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain.

Main Conclusions: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.
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http://dx.doi.org/10.1210/clinem/dgab477DOI Listing
June 2021

Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance.

Front Endocrinol (Lausanne) 2021 8;12:684182. Epub 2021 Jun 8.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, United Kingdom.

Background: Familial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma () gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce.

Case Presentation: We present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARG variant. After six months of metreleptin treatment, HbA1c decreased from 10 to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl.

Conclusions: This case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.
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http://dx.doi.org/10.3389/fendo.2021.684182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217860PMC
June 2021

Triglyceride-lowering LPL alleles combined with LDL-C-lowering alleles are associated with an additively improved lipoprotein profile.

Atherosclerosis 2021 07 9;328:144-152. Epub 2021 May 9.

Dept. Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Dept. Internal Medicine, Div. Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Background And Aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles.

Methods: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference.

Results: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower.

Conclusions: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.015DOI Listing
July 2021

A haemagglutination test for rapid detection of antibodies to SARS-CoV-2.

Nat Commun 2021 03 29;12(1):1951. Epub 2021 Mar 29.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.
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http://dx.doi.org/10.1038/s41467-021-22045-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007702PMC
March 2021

Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese.

Int J Obes (Lond) 2021 07 23;45(7):1618-1622. Epub 2021 Mar 23.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

It has been suggested that metabolic dysfunction in obesity is at least in part driven by adipose tissue (AT) hypoxia. However, studies on AT hypoxia in humans have shown conflicting data. Therefore we aimed to investigate if markers of AT hypoxia were present in the subcutaneous AT of severly obese individuals (class III obesity) with and without hypoventilation syndrome (OHS) in comparison to moderately obese (class I obesity) and lean controls. To provide a proof-of-concept study, we quantified AT hypoxia by hypoxia inducible factor 1 A (HIF1A) protein abundance in human participants ranging from lean to severly obese (class III obesity). On top of that nightly arterial O saturation in individuals with obesity OHS was assessed. Subjects with class III obesity (BMI > 40 kg/m) and OHS exhibited significantly higher adipose HIF1A protein levels versus those with class I obesity (BMI 30-34.9 kg/m) and lean controls whereas those with class III obesity without OHS showed an intermediate response. HIF1A gene expression was not well correlated with protein abundance. Although these data demonstrate genuine AT hypoxia in the expected pathophysiological context of OHS, we did not observe a hypoxia signal in lesser degrees of obesity suggesting that adipose dysfunction may not be driven by hypoxia in moderate obesity.
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http://dx.doi.org/10.1038/s41366-021-00793-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236405PMC
July 2021

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BMC Med 2021 03 18;19(1):69. Epub 2021 Mar 18.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.

Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
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http://dx.doi.org/10.1186/s12916-021-01939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971964PMC
March 2021

Pregnancy-related interventions in mothers at risk for gestational diabetes in Asian India and low and middle-income countries (PRIMORDIAL study): protocol for a randomised controlled trial.

BMJ Open 2021 02 17;11(2):e042069. Epub 2021 Feb 17.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, Oxfordshire, UK

Introduction: Lifestyle modification is the mainstay of gestational diabetes mellitus (GDM) prevention. However, clinical trials evaluating the safety and efficacy of diet or physical activity (PA) in low-income and middle-income settings such as Africa and India are lacking. This trial aims to evaluate the efficacy of yoghurt consumption and increased PA (daily walking) in reducing GDM incidence in high-risk pregnant women.

Methods And Analysis: The study is a 2×2 factorial, open-labelled, multicentre randomised controlled trial to be conducted in Vellore, South India and The Gambia, West Africa. 'High-risk' pregnant women (n=1856) aged ≥18 years and ≤16 weeks of gestational age, with at least one risk factor for developing GDM, will be randomised to either (1) yoghurt (2) PA (3) yoghurt +PA or (4) standard antenatal care. Participants will be followed until 32 weeks of gestation with total active intervention lasting for a minimum of 16 weeks. The primary endpoint is GDM incidence at 26-28 weeks diagnosed using International Association of the Diabetes and Pregnancy Study Groups criteria or elevated fasting glucose (≥5.1 mmol/L) at 32 weeks. Secondary endpoints include absolute values of fasting plasma glucose concentration at 32 weeks gestation, maternal blood pressure, gestational weight gain, intrapartum and neonatal outcomes. Analysis will be both by intention to treat and per-protocol. Continuous outcome measurements will be analysed using multiple linear regression and binary variables by logistic regression.

Ethics And Dissemination: The study is approved by Oxford Tropical Research Ethics Committee (44-18), ethics committees of the Christian Medical College, Vellore (IRB 11367) and MRCG Scientific Coordinating Committee (SCC 1645) and The Gambia Government/MRCG joint ethics committee (L2020.E15). Findings of the study will be published in peer-reviewed scientific journals and presented in conferences.

Trial Registration Number: ISRCTN18467720.
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http://dx.doi.org/10.1136/bmjopen-2020-042069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893661PMC
February 2021

A prospective study of the relationships between change in body composition and cardiovascular risk factors across the menopause.

Menopause 2021 02 1;28(4):400-406. Epub 2021 Feb 1.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

Objective: Menopause increases the risk of cardiovascular disease (CVD) which in part has been attributed to the rise in cholesterol and blood pressure (BP). This study examined the hypothesis that menopausal changes in body composition and regional fat depots relate to the change in CVD risk factors.

Methods: A prospective recall study was designed to capture premenopausal women to be re-examined soon after menopause. A total of 97 women from the Oxford Biobank underwent dual x-ray absorptiometry, blood biochemistry, and BP readings pre- and postmenopause.

Results: Despite minimal changes in body weight over the 5.1 ± 0.9 year follow-up period, there was an increase in total fat mass and a decline in lean mass, where the proportional change of regional fat mass was the greatest for the visceral fat depot (+22%, P < 0.01). Plasma ApoB (+12%, P < 0.01) and C-reactive protein (+45%, P < 0.01) increased as did systolic (+7%, P < 0.001) and diastolic BP (+5%, P < 0.001). Plasma nonesterified fatty acids decreased (-20%, P < 0.05) which may reflect on a change in adipose tissue function across the menopause. PCSK-9 decreased (-26%, P < 0.01) which suggests a compensation for the postmenopausal reduction in low-density lipoprotein receptor activity. Using multilinear regression analyses the changes in ApoB and diastolic BP were associated with visceral fat mass change, but this association was lost when adjusted for total fat mass change.

Conclusion: The increase in CVD risk factor burden across menopause may not be driven by changes in body composition, rather by functional changes in end organs such as adipose tissue and liver.
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http://dx.doi.org/10.1097/GME.0000000000001721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284369PMC
February 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Effects of Obesity and Insulin on Tissue-Specific Recycling Between Cortisol and Cortisone in Men.

J Clin Endocrinol Metab 2021 03;106(3):e1206-e1220

University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.

Context: 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11βHSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown.

Objective: This work aimed to determine whether 11βHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity.

Methods: A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11β-Reductase and 11β-dehydrogenase activities were measured during infusion of 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone, respectively, on 2 occasions: once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography-tandem mass spectrometry and adipose tissue transcripts by quantitative polymerase chain reaction.

Results: Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole-body 11β-HSD1 reductase activity tended to be higher in obesity (~ 10%) and was further increased by insulin. Across adipose tissue, 11β-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99 ± 9.62 vs placebo 11.68 ± 3.63 pmol/100 g/minute; P < .05). Across skeletal muscle, 11β-dehydrogenase activity was reduced by insulin in lean men only (2.55 ± 0.90 vs 4.50 ± 1.42 pmol/100 g/minute, P < .05).

Conclusions: Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11β-reductase and 11β-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.
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http://dx.doi.org/10.1210/clinem/dgaa896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947841PMC
March 2021

Distinctive Features of Orbital Adipose Tissue (OAT) in Graves' Orbitopathy.

Int J Mol Sci 2020 Nov 30;21(23). Epub 2020 Nov 30.

School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.

Depot specific expansion of orbital-adipose-tissue (OAT) in Graves' Orbitopathy (GO) is associated with lipid metabolism signaling defects. We hypothesize that the unique adipocyte biology of OAT facilitates its expansion in GO. A comprehensive comparison of OAT and white-adipose-tissue (WAT) was performed by light/electron-microscopy, lipidomic and transcriptional analysis using ex vivo WAT, healthy OAT (OAT-H) and OAT from GO (OAT-GO). OAT-H/OAT-GO have a single lipid-vacuole and low mitochondrial number. Lower lipolytic activity and smaller adipocytes of OAT-H/OAT-GO, accompanied by similar essential linoleic fatty acid (FA) and (low) FA synthesis to WAT, revealed a hyperplastic OAT expansion through external FA-uptake via abundant (FA-transporter) expression. Mitochondrial dysfunction of OAT in GO was apparent, as evidenced by the increased mRNA expression of uncoupling protein 1 () and mitofusin-2 () in OAT-GO compared to OAT-H. Transcriptional profiles of OAT-H revealed high expression of Iroquois homeobox-family (), and low expression in -family/ (essential for WAT/BAT (brown-adipose-tissue)/BRITE (BRown-in-whITE) development). We demonstrated unique features of OAT not presented in either WAT or BAT/BRITE. This study reveals that the pathologically enhanced FA-uptake driven hyperplastic expansion of OAT in GO is associated with a depot specific mechanism (the FA-transporter) and mitochondrial dysfunction. We uncovered that OAT functions as a distinctive fat depot, providing novel insights into adipocyte biology and the pathological development of OAT expansion in GO.
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http://dx.doi.org/10.3390/ijms21239145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730568PMC
November 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Prevalence, incidence and predictors of cardiovascular risk factors: longitudinal data from rural and urban South India and comparison with global data.

BMJ Open Diabetes Res Care 2020 10;8(1)

MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, Hampshire, UK.

Introduction: India has high mortality rates from cardiovascular disease (CVD). Understanding the trends and identifying modifiable determinants of CVD risk factors will guide preventive strategies and policy making.

Research Design And Methods: CVD risk factors (obesity, central obesity, and type 2 diabetes (T2D), hypertension, hypercholesterolemia and hypertriglyceridemia) prevalence and incidence were estimated in 962 (male 519) non-migrant adults from Vellore, South India, studied in: (1) 1998-2002 (mean age 28.2 years) and (2) 2013-2014 (mean age 41.7 years). Prevalence was compared with the Non-Communicable Disease Risk Collaboration (global) data. Incidence was compared with another Indian cohort from New Delhi Birth Cohort (NDBC). Regression analysis was used to test baseline predictors of incident CVD risk factors.

Results: The prevalence at 28 and 42 years was 17% (95% CI 14% to 19%) and 51% (95% CI 48% to 55%) for overweight/obesity, 19% (95% CI 17% to 22%) and 59% (95% CI 56% to 62%) for central obesity, 3% (95% CI 2% to 4%) and 16% (95% CI 14% to 19%) for T2D, 2% (95% CI 1% to 3%) and 19% (95% CI 17% to 22%) for hypertension and 15% (95% CI 13% to 18%) and 30% (95% CI 27% to 33%) for hypertriglyceridemia. The prevalence of T2D at baseline and follow-up and hypertension at follow-up was comparable with or exceeded that in high-income countries despite lower obesity rates. The incidence of most risk factors was lower in Vellore than in the NDBC. Waist circumference strongly predicted incident T2D, hypertension and hypertriglyceridemia.

Conclusions: A high prevalence of CVD risk factors was evident at a young age among Indians compared with high and upper middle income countries, with rural rates catching up with urban estimates. Adiposity predicted higher incident CVD risk, but the prevalence of hypertension and T2D was higher given a relatively low obesity prevalence. Preventive efforts should target both rural and urban India and should start young.
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http://dx.doi.org/10.1136/bmjdrc-2020-001782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583064PMC
October 2020

Associations between outdoor temperature and bright sunlight with metabolites in two population-based European cohorts.

Nutr Metab Cardiovasc Dis 2020 11 28;30(12):2252-2261. Epub 2020 Jul 28.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background And Aims: Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics.

Methods And Results: Cross-sectional analyses were undertaken in non-diabetic individuals from the Oxford BioBank (OBB; N = 6368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N = 5916; mean age 55.6 years, males 43%) study. Data on mean outdoor bright sunlight and temperature were collected from local weather stations in the week prior to blood sampling. Fasting serum levels of 148 metabolites, including 14 lipoprotein subclasses, were measured using NMR spectroscopy. Linear regression analyses were performed to assess the associations between mean outdoor temperature and bright sunlight duration with metabolomics adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. A higher mean outdoor temperature was associated with increased serum concentrations of lipoprotein (sub)particles (β (SE) = 0.064 (0.018) SD per 5 °C, p = 5.03e) and certain amino acids such as phenylalanine (0.066 (0.016) SD, p = 6.44e) and leucine (0.111 (0.018) SD, p = 1.25e). In contrast, longer duration of bright sunlight was specifically associated with lower concentrations of very low-density lipoprotein (sub)particles (e.g., VLDL cholesterol (-0.024 (0.005) SD per 1-h bright sunlight, p = 8.06e)). The direction of effects was generally consistent between the OBB and NEO, although effect sizes were generally larger in the OBB.

Conclusions: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.
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http://dx.doi.org/10.1016/j.numecd.2020.07.030DOI Listing
November 2020

Differential occupational risks to healthcare workers from SARS-CoV-2 observed during a prospective observational study.

Elife 2020 08 21;9. Epub 2020 Aug 21.

Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45-6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99-3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07-2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28-0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25-2.21]) and Asian (1.51 [1.28-1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34-3.15]).
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http://dx.doi.org/10.7554/eLife.60675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486122PMC
August 2020

RSPO3 impacts body fat distribution and regulates adipose cell biology in vitro.

Nat Commun 2020 06 3;11(1):2797. Epub 2020 Jun 3.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK.

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.
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http://dx.doi.org/10.1038/s41467-020-16592-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271210PMC
June 2020

Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism.

BMJ Open Diabetes Res Care 2020 03;8(1)

University of Oxford, Oxford, Oxfordshire, UK

Objective: Increased hepatic de novo lipogenesis (DNL) is suggested to be an underlying cause in the development of nonalcoholic fatty liver disease and/or insulin resistance. It is suggested that omega-3 fatty acids (FA) lower hepatic DNL. We investigated the effects of omega-3 FA supplementation on hepatic DNL and FA oxidation using a combination of human in vivo and in vitro studies.

Research Design And Methods: Thirty-eight healthy men were randomized to take either an omega-3 supplement (4 g/day eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA) as ethyl esters) or placebo (4 g/day olive oil) and fasting measurements were made at baseline and 8 weeks. The metabolic effects of omega-3 FAs on intrahepatocellular triacylglycerol (IHTAG) content, hepatic DNL and FA oxidation were investigated using metabolic substrates labeled with stable-isotope tracers. In vitro studies, using a human liver cell-line was undertaken to gain insight into the intrahepatocellular effects of omega-3 FAs.

Results: Fasting plasma TAG concentrations significantly decreased in the omega-3 group and remained unchanged in the placebo group. Eight weeks of omega-3 supplementation significantly decreased IHTAG, fasting and postprandial hepatic DNL while significantly increasing dietary FA oxidation and fasting and postprandial plasma glucose concentrations. In vitro studies supported the in vivo findings of omega-3 FAs (EPA+DHA) decreasing intracellular TAG through a shift in cellular metabolism away from FA esterification toward oxidation.

Conclusions: Omega-3 supplementation had a potent effect on decreasing hepatic DNL and increasing FA oxidation and plasma glucose concentrations. Attenuation of hepatic DNL may be considered advantageous; however, consideration is required as to what the potential excess of nonlipid substrates (eg, glucose) will have on intrahepatic and extrahepatic metabolic pathways.

Trial Registration Number: NCT01936779.
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http://dx.doi.org/10.1136/bmjdrc-2019-000871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078804PMC
March 2020

Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

Br J Cancer 2020 01 10;122(2):258-265. Epub 2019 Dec 10.

Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.

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: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1038/s41416-019-0665-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986920PMC
January 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Correction to: Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis.

Int J Obes (Lond) 2019 Dec;43(12):2593

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

We erroneously published the original Article with an incorrect Copyright line. This has been updated in the XML, PDF and HTML versions of this Article.
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http://dx.doi.org/10.1038/s41366-019-0475-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608295PMC
December 2019

Hyperinsulinaemia: does it tip the balance toward intrahepatic fat accumulation?

Endocr Connect 2019 Oct;8(10):R157-R168

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, UK.

In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.
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http://dx.doi.org/10.1530/EC-19-0350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826170PMC
October 2019

Conditionally immortalized brown preadipocytes can switch between proliferative and differentiated states.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 12 26;1864(12):158511. Epub 2019 Aug 26.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, United Kingdom. Electronic address:

Brown adipose tissue (BAT) is a potential target to treat cardiometabolic disorders because of its capacity to combust glucose and fatty acids for thermoregulation. Its cellular and molecular investigation in humans is hampered by the limited availability of cell material and the heterogeneity of BAT between and within individuals. In this study, monoclonal lines of conditionally immortalized brown preadipocytes (iBPAs) of mouse and human origin were generated. Conditional immortalization was achieved by doxycycline-controlled expression of simian virus 40 large tumor antigen (LT) with a repressor-based Tet-On system. In the presence of doxycycline, both the murine and human cell lines showed long-term proliferation capacity with a population doubling time of ~28 h. After switching off LT expression by doxycycline removal and exposure to adipogenic differentiation medium, cells from both species acquired brown adipocyte properties. This was evidenced by the accumulation of multilocular lipid droplets, the upregulation of brown adipocyte markers including uncoupling protein 1 and an increase in lipolysis and oxygen consumption following adrenergic stimulation. Switching off LT expression before the onset of adipogenic differentiation was only critical for inducing adipogenesis in the human iBPAs, while their murine counterparts showed adipogenesis upon exposure to the adipogenic differentiation cocktail regardless of LT expression. When switched to proliferation medium, cultures of adipogenically differentiated human iBPAs de-differentiated and resumed cell division without losing their adipogenic capacity. We suggest that iBPAs represent an easy-to-use model for fundamental and applied research into BAT offering unique experimental opportunities due to their capacity to switch between proliferative and differentiated states.
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http://dx.doi.org/10.1016/j.bbalip.2019.08.007DOI Listing
December 2019

Bone morphogenetic protein 2 is a depot-specific regulator of human adipogenesis.

Int J Obes (Lond) 2019 12 19;43(12):2458-2468. Epub 2019 Jul 19.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

Background: Bone morphogenetic proteins (BMPs) regulate adipogenesis but it is not clear whether they influence regional adipose tissue (AT) development in humans.

Objective: To characterise BMP2 expression, BMP2-SMAD1/5/8 signalling, and BMP2's potential effect on proliferation and adipogenesis in human subcutaneous abdominal and gluteal AT and its constituent preadipocytes.

Methods: BMP2 expression was measured in whole AT and immortalised preadipocytes via qPCR and Western blot; secreted/circulating BMP2 was measured by ELISA. The effect of BMP2 on preadipocyte proliferation was evaluated using a fluorescent assay. BMP2's effect on adipogenesis in immortalised preadipocytes was determined via qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation. BMP2-SMAD1/5/8 signalling was assessed in immortalised preadipocytes via Western blot and qPCR of ID1 expression.

Results: BMP2 was expressed and released by abdominal and gluteal AT and preadipocytes. Exogenous BMP2 dose dependently promoted adipogenesis in abdominal preadipocytes only; 50 ng/ml BMP2 increased PPARG2 expression (10-fold compared to vehicle, p < 0.001) and TAG accumulation (3-fold compared to vehicle; p < 0.001). BMP2 stimulated SMAD1/5/8 phosphorylation and ID1 expression in abdominal and gluteal preadipocytes but this was blocked by 500 nM K02288, a type 1 BMP receptor inhibitor (p < 0.001). Co-administration of 500 nM K02288 also inhibited the pro-adipogenic effect of 50 ng/ml BMP2 in abdominal cells; >90% inhibition of TAG accumulation (p < 0.001) and ~50% inhibition of PPARG2 expression (p < 0.001). The endogenous iron regulator erythroferrone reduced BMP2-SMAD1/5/8 signalling by ~30% specifically in subcutaneous abdominal preadipocytes (p < 0.01), suggesting it plays a role in restricting the expansion of the body's largest AT depot during energy deficiency. Additionally, a waist-hip ratio-increasing common polymorphism near BMP2 is an eQTL associated with ~15% lower BMP2 expression in abdominal and gluteal AT (p < 0.05) as well as altered adipocyte size in male abdominal AT (p < 0.05).

Conclusions: These data implicate BMP2-SMAD1/5/8 signalling in depot-specific preadipocyte development and abdominal AT expansion in humans.
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http://dx.doi.org/10.1038/s41366-019-0421-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892741PMC
December 2019

The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study.

Diabetologia 2019 11 15;62(11):2079-2087. Epub 2019 Jul 15.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.

Aims/hypothesis: Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans.

Methods: Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME.

Results: A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses.

Conclusions/interpretation: Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.
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http://dx.doi.org/10.1007/s00125-019-4947-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805813PMC
November 2019

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

Cardiovasc Diabetol 2019 06 4;18(1):71. Epub 2019 Jun 4.

Unidad de Prevención Cardiometabólica Cardiocob. Servicio de Cardiología Hospital el Pino Santiago de Chile, Sociedad Inter Americana de Cardiología SIAC Chairman Cardiovascular Prevention Comite, Santiago de Chile, Chile.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.
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http://dx.doi.org/10.1186/s12933-019-0864-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549355PMC
June 2019

MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition.

EBioMedicine 2019 Jun 28;44:467-475. Epub 2019 May 28.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK; NIHR Oxford Biomedical Research Centre, OUH Trust, Oxford OX3 7LE, UK. Electronic address:

Background: Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored.

Methods: An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue.

Findings: We found that rs11614913, a SNP within pre-miR-196a-2 at the HOXC locus, is an eQTL for miR-196a expression in abdominal subcutaneous adipose tissue (ASAT). Observations in large cohorts showed that rs11614913 increased waist-to-hip ratio, which was driven specifically by an expansion in ASAT. In further experiments, rs11614913 was associated with adipocyte size. Functional studies and transcriptomic profiling of miR-196a knock-down pre-adipocytes revealed a role for miR-196a in regulating pre-adipocyte proliferation and extracellular matrix pathways.

Interpretation: These data identify a role for miR-196a in regulating human body fat distribution. FUND: This work was supported by the Medical Research Council and Novo Nordisk UK Research Foundation (G1001959) and Swedish Research Council. We acknowledge the OBB-NIHR Oxford Biomedical Research Centre and the British Heart Foundation (BHF) (RG/17/1/32663). Work performed at the MRC Epidemiology Unit was funded by the United Kingdom's Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1.
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http://dx.doi.org/10.1016/j.ebiom.2019.05.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607082PMC
June 2019
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