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Objective F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. Methods We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. Results F13A1 mRNA showed significant increase in adipose tissue (p 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. Conclusions F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

Context/Objective Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D. Design/Patients Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging. Results T2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P Conclusions Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.

Integrase inhibitors appear to increase body weight, but paradoxically some data indicate that raltegravir (RAL) may decrease liver fat. Our objective was to study the effects of switching from a protease inhibitor (PI) or efavirenz (EFV) to RAL on liver fat, body composition, and metabolic parameters among people living with HIV (PLWH) with high risk for nonalcoholic fatty liver disease (NAFLD). We randomized overweight PLWH with signs of metabolic syndrome to switch a PI or EFV to RAL (

Objective: Obesity may alter serum steroid concentrations and metabolism. We investigated this in healthy young women with increased body fat and their leaner co-twin sisters. Design: Age and genetic background both strongly influence serum steroid levels and body composition. This is a cross-sectional study of 13 female monozygotic twin pairs (age, 23-36 years), ten of which were discordant for body mass index (median difference in body weight between the co-twins, 19 kg). Methods: We determined body composition by dual energy X-ray absorptiometry and magnetic resonance imaging, serum androgens by liquid chromatography-tandem mass spectrometry, and mRNA expression of genes in subcutaneous adipose tissue and adipocytes. Results: The heavier women had lower serum dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) (P

Adipose tissue is a central regulator of metabolic health and its failure in obesity is a major cause of weight associated comorbidities, such as type 2 diabetes. Many extracellular matrix proteins, represented by matrisome, play a critical role in balancing adipose tissue health and dysfunction. Extracellular matrix components, produced by different cell types of adipose tissue, can modulate adipocyte function, tissue remodeling during expansion, angiogenesis, and inflammation and also form fibrotic lesions in the tissue. In this study, we investigated changes in matrisome of whole adipose tissue and adipocytes in human obesity. We investigated further the networks and biological pathways of the genes related to the changes and their association to development of metabolic dysfunction linked to type 2 diabetes. We used transcriptome data and clinical metabolic parameters from a rare weight-discordant MZ twin cohort. The Heavy-Lean differential matrisome gene expression (Δmatrisome) and differential metabolic parameters reflect changes in adipose tissue upon weight gain and changes in whole body glucose, insulin metabolism, as well as lipid status. We report that obesity Δmatrisome shows high specificity with 130 and 71 of the 1068 matrisome genes showing altered expression in the adipose tissue and adipocytes of heavier co-twin, respectively. The Δmatrisome differs considerably between adipose tissue vs adipocytes which reflects inflammation of hypertrophic adipocytes and the remodeling activity of the rest of the tissue resident cells. The obesity Δmatrisome is discussed extensively in the light of existing evidence and novel significant associations to obesity are reported to matrisome genes; cathepsin A, cathepsin O, FAM20B and N-glycanase1.

Background: \ud Renewed interest in triglyceride-rich lipoproteins as causative agents in cardiovascular disease mandates further exploration of the integrated metabolism of chylomicrons and very low-density lipoproteins (VLDL).\ud \ud Methods: \ud Novel tracer techniques and an integrated multi-compartmental model were used to determine the kinetics of apoB48- and apoB100-containing particles in the chylomicron and VLDL density intervals in 15 subjects with a wide range of plasma triglyceride levels.\ud \ud Results: \ud Following a fat-rich meal, apoB48 appeared in the chylomicron, VLDL1 and VLDL2 fractions in all subjects. Chylomicrons cleared rapidly from the circulation but apoB48-containing VLDL accumulated, and over the day were 3-fold higher in those with high versus low plasma triglyceride. ApoB48-containing particles were secreted directly into both the chylomicron and VLDL fractions at rates that were similar across the plasma triglyceride range studied. During fat absorption, whilst most triglyceride entered the circulation in chylomicrons, the majority of apoB48 particles were secreted into the VLDL density range.\ud \ud Conclusion: \ud The intestine secretes apoB48-containing particles not only as chylomicrons but also directly into the VLDL1 and VLDL2 density ranges both in the basal state and during dietary lipid absorption. Over the day, apoB48-containing particles appear to comprise about 20–25% of circulating VLDL and, especially in those with elevated triglycerides, form part of a slowly cleared ‘remnant’ particle population, thereby potentially increasing CHD risk. These findings provide a metabolic understanding of the potential consequences for increased CHD risk when slowed lipolysis leads to the accumulation of remnants, especially in individuals with hypertriglyceridemia.

1H‐MR spectroscopy of skeletal muscle provides insight into metabolism that is not available noninvasively by other methods. The recommendations given in this article are intended to guide those who have basic experience in general MRS to the special application of 1H‐MRS in skeletal muscle. The highly organized structure of skeletal muscle leads to effects that change spectral features far beyond simple peak heights, depending on the type and orientation of the muscle. Specific recommendations are given for the acquisition of three particular metabolites (intramyocellular lipids, carnosine and acetylcarnitine) and for preconditioning of experiments and instructions to study volunteers., The recommendations are intended to guide those who have basic experience in general MRS to the special application of 1H‐MRS in skeletal muscle. The structure of skeletal muscle leads to effects that change spectral features far beyond simple peak heights, depending on the type and orientation of the muscle. Specific advice is given for three particular metabolites (intramyocellular lipids, carnosine and acetylcarnitine) and for preconditioning of experiments and instructions to study volunteers.

Background and aims: Obesity and metabolic syndrome (MetS) are risk factors of atrial fibrillation (AF), but limited data exist on their effect on left atrial (LA) function. The aim of the study was to evaluate the effects of cardiac, hepatic and intra-abdominal ectopic fat depots and cardiometabolic risk factors on LA function in non-diabetic male subjects. Methods and results: Myocardial and hepatic triglyceride contents were measured with 1.5T H-1-magnetic resonance spectroscopy and LA and left ventricular function, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), epicardial and pericardial fat by magnetic resonance imaging (MRI) in 33 men with MetS and 40 men without MetS. LA volumes were assessed using a novel three-chamber orientation based MRI approach. LA ejection fraction (EF) was lower in MetS patients than in the control group (44 +/- 7.7% in MetS vs. 49 +/- 8.6% in controls, p = 0.013) without LA enlargement, indicating LA dysfunction. LA EF correlated negatively with waist circumference, body mass index, SAT, VAT, fasting serum insulin, and homeostasis model assessment of insulin resistance index, and positively with fasting serum high-density lipoprotein cholesterol. VAT was the best predictor of reduced LA EF. Conclusions: MetS associates with subclinical LA dysfunction. Multiple components of MetS are related to LA dysfunction, notably visceral obesity and insulin resistance. Further studies are needed to elucidate the role of mechanical atrial remodeling in the development of AF. (C) 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Adipose tissue and liver are central tissues in whole body energy metabolism. Their composition, structure, and function can be noninvasively imaged using a variety of measurement techniques that provide a safe alternative to an invasive biopsy. Imaging of adipose tissue is focused on quantitating the distribution of adipose tissue in subcutaneous and intra-abdominal (visceral) adipose tissue depots. Also, detailed subdivisions of adipose tissue can be distinguished with modern imaging techniques. Adipose tissue (or adipocyte) accumulation or infiltration of other organs can also be imaged, with intramuscular adipose tissue a common example. Although liver fat content is now accurately imaged using standard magnetic resonance imaging (MRI) techniques, inflammation and fibrosis are more difficult to determine noninvasively. Liver imaging efforts are therefore concerted on developing accurate imaging markers of liver fibrosis and inflammatory status. Magnetic resonance elastography (MRE) is presently the most reliable imaging technique for measuring liver fibrosis but requires an external device for introduction of shear waves to the liver. Methods using multiparametric diffusion, perfusion, relaxometry, and hepatocyte-specific MRI contrast agents may prove to be more easily implemented by clinicians, provided they reach similar accuracy as MRE. Adipose tissue imaging is experiencing a revolution with renewed interest in characterizing and identifying distinct adipose depots, among them brown adipose tissue. Magnetic resonance spectroscopy provides an interesting yet underutilized way of imaging adipose tissue metabolism through its fatty acid composition. Further studies may shed light on the role of fatty acid composition in different depots and why saturated fat in subcutaneous adipose tissue is a marker of high insulin sensitivity.

Purpose This study aims to investigate 1) how monozygotic (MZ) twin pairs who are discordant for body mass index (BMI) differ for objectively and subjectively measured physical activity (PA) and cardiorespiratory fitness (VO2max), and 2) associations of PA and VO2max with adiposity and measures of metabolic health, in individual twins and independent of genetic and shared environmental effects within twin pairs. Methods We examined 27 BMI-discordant and 14 BMI-concordant MZ twin pairs. Fat and fat free mass (ffm) were measured by dual energy x-ray absorptiometry and VO2max by spiroergometry. PA was measured objectively by accelerometers using ActiGraph GT1M for daytime activity and Actiwatch AW7 for 24h/day. Self-reported PA was obtained through the Baecke and IPAQ long-form questionnaires. Results Objectively measured moderate to vigorous PA (MVPA, min/day), steps/day and VO2max/kg were significantly lower, by 30%, 21% and 14% respectively in the heavy compared with the lean co-twins of the BMI-discordant twin pairs. There were no significant differences in self-reported PA or VO2max/ffm. As expected, PA and VO2max/ffm were similar in the BMI-concordant co-twins. Furthermore, the 24-h recording of activity suggested that the heavier co-twins had more restless sleep during the night, whereas the leaner co-twins were more active during the day. Within all twin pairs, higher MVPA and steps per day were associated with lower fat percentage and improved metabolic health measures. Conclusion Objectively, but not subjectively measured PA is associated with lower adiposity and better metabolic health, independent of genetic and shared environmental factors. This article is protected by copyright. All rights reserved.

Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n = 18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22-36 kg/m(2)] included 9 male MZ twin pairs discordant for BMI [infra-pair difference (Delta) in BMI >= 3 kg/m(2)]. Sex steroid concentrations were determined by liquid chromatography-tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean Delta BMI = 5.9 kg/m2), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P = 0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P = 0.021) and cortisol-producing HSD11B1 (P = 0.008) higher in the heavier compared to the leaner co-twins. Serum free 17 beta-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P = 0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P = 0.006; and 123 (43) vs. 105 (27) pmol/l, P = 0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone-binding globulin (SHBG) concentrations (P

Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics.We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI3 kg mWe found 2108 genes differentially expressed (false discovery rate (FDR)0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P0.05) and upregulation of inflammation pathways (P0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P0.05).This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

Objectives There is a discrepancy between studies suggesting that higher bone marrow fat saturation is associated with impaired health, and studies suggesting that erythropoiesis increases red bone marrow (RBM) fat saturation in young healthy individuals. Here, we seeked to elucidate these discrepancies by using long TE magnetic resonance spectroscopy (MRS) to study both yellow bone marrow (YBM) and RBM in the femur of healthy volunteers. Materials and methods Thirty-three young healthy volunteers (17 females), age range 20-31 years, underwent long TE H-1 MRS at 3.0 T of RBM and YBM fat composition in the left femur. The water content of the bone marrow depots was measured using short TE MRS. Results The female participants displayed a lower unsaturation in the sampled RBM volume (RBMV) than the males (P

Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r(g)) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference >= 3 kg/m(2)). Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r(g) = 0.40), glycoprotein (r(g) = 0.37), serum triglycerides (r(g) = 0.36), BCAAs (r(g) = 0.30-0.40), HDL particle diameter (r(g) = -0.33) and HDL cholesterol (r(g) = -0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. (C) 2015 Elsevier Inc. All rights reserved.

Context: Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) are 2 important nicotinamide adenine dinucleotide (NAD)+-dependent enzyme families with opposing metabolic effects. Energy shortage increases NAD+ biosynthesis and SIRT activity but reduces PARP activity in animals. Effects of energy balance on these pathways in humans are unknown. Objective: We compared NAD+/SIRT pathway expressions and PARP activities in sc adipose tissue (SAT) between lean and obese subjects and investigated their change in the obese subjects during a 12-month weight loss. Design, Setting and Participants: SAT biopsies were obtained from 19 clinically healthy obese subjects (mean ± SE body mass index, 34.6 ± 2.7 kg/m2) during a weight-loss intervention (0, 5, and 12 mo) and from 19 lean reference subjects (body mass index, 22.7 ± 1.1 kg/m2) at baseline. Main Outcome Measures: SAT mRNA expressions of SIRTs 1–7 and the rate-limiting gene in NAD+ biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) were measured by Affymetrix, and total PARP activity by ELISA kit. Results: SIRT1, SIRT3, SIRT7, and NAMPT expressions were significantly lower, whereas total PARP activity was increased in obese compared with lean subjects. SIRT1 and NAMPT expressions increased in obese subjects between 0 and 5 months, after a mean weight loss of 11.7%. In subjects who continued to lose weight between 5 and 12 months, SIRT1 expression increased progressively, whereas in subjects with weight regain, SIRT1 reverted to baseline levels. PARP activity significantly decreased in all subjects upon weight loss. Conclusions: Calorie restriction is an attractive strategy to improve the NAD+/SIRT pathway and decrease PARPs in SAT in human obesity.

Mitochondrial gene expression in visceral (VAT) and lipogenesis in abdominal subcutaneous adipose tissue (SAT) are lower in insulin resistance (IR). Humans with hormone sensitive lipase (HSL) gene mutations are prone to type 2 diabetes (T2D). SAT is divided into deep (DSAT) and superficial SAT (SSAT). SSAT was speculated to be protective in T2D, but gender specificity is unknown. We hypothesized lower mitochondrial efficiency as well as lower markers of lipogenesis and lipolysis in SSAT only in male T2D patients vs. glucose-tolerant humans (CON), which may characterize dysfunctional SSAT. In 20 T2D and 20 CON matched for sex, BMI and age (female/male: 6/14 per group; 32±1 vs. 31±1 kg/m2, 52±2 vs. 54±2 years), we assessed M-values by euglycemic-hyperinsulinemic clamps, liver fat content (HCL) and VAT by MRS. In biopsies of SSAT, mitochondrial oxidative capacity was measured by respirometry, lipogenesis assessed from stearoyl-CoA desaturase (SCD) mRNA, lipolysis from adipocyte triglyceride lipase (ATGL) and HSL mRNA by RTqPCR. The insulin resistant T2D had 63% and 22% higher HCL (p In conclusion, lower lipogenesis and lipolysis in SSAT of male T2D patients may lead to inadequate lipid storage in SSAT, thereby promoting ectopic fat storage as HCL and VAT. Disclosure K. Bódis: None. J. Lundbom: None. T. Jelenik: None. D.F. Markgraf: None. A. Strom: None. O.P. Zaharia: None. Y. Karusheva: None. V. Burkart: None. K. Müssig: None. Y. Kupriyanova: None. M. Ouni: None. J. Hwang: None. D. Ziegler: None. A. Schuermann: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. J. Szendroedi: None.

Objectives— Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL 1 ) triglycerides. Approach and Results— A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL 1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate ( r =0.44, P r =0.45, P r =0.49, P r =0.55, P 1 -triglycerides and VLDL 1 -apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL 1 -triglycerides ( r =0.56, P 1 -apoB ( r =0.53, P 1 -triglycerides ( r =0.48, P 1 -apoB ( r =0.51, P Conclusions— Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL 1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

High field MR scanners can resolve a metabolite resonating at 2.06 ppm in the in vivo proton-decoupled liver 31P MR spectrum. Traditionally this peak has been assigned to phosphoenolpyruvate (PEP), the key metabolite for gluconeogenesis. However, recent evidence supported the assignment to biliary phosphatidylcholine (PtdCh), which is produced in the liver and stored in the gall bladder. To elucidate the respective contributions of PtdCh and PEP to the in vivo resonance at 2.06 ppm (PEP–PtdCh), we made phantom measurements that confirmed that both biliary PtdCh and PEP resonate approximately at 2 ppm. The absolute quantification of PEP–PtdCh yielded concentrations ranging from 0.6 to 2.0 mmol/l, with mean coefficients of variation of 4.8% for intraday and 7.2% for interday reproducibility in healthy volunteers. The T1 relaxation time of PEP–PtdCh was 0.97 ± 0.30 s in the liver and 0.44 ± 0.11 s in the gallbladder. Ingestion of a mixed meal decreased the concentration of PtdCh-PEP by approximately 12%. In the retrospective analysis, PEP–PtdCh was 68% higher in the liver of subjects with gallbladder infiltration of the volume of interest (VOI) compared with those without gallbladder infiltration. PEP–PtdCh was also significantly higher in the liver of cholecystectomy patients compared with volunteers without gallbladder infiltration, which suggests increased intrahepatic bile fluid as a compensation for gall bladder removal. These results show that liver PtdCh is the major component of the resonance at 2.06 ppm and that careful VOI positioning is mandatory to avoid interference from the gallbladder. Copyright © 2015 John Wiley & Sons, Ltd.

Objectives Obesity increases bone marrow fat (BMF) content. The association between early obesity and bone marrow fatty acid composition is unknown. We measured BMF unsaturation index (UI) in normal-weight and overweight young adults with a known weight status in early childhood and tested the relationship between BMF UI and exercise history, glycemic state, and other clinical characteristics. Methods The study included 18 normal-weight (BMI 2 ; 2 males, 16 females) and 17 overweight (BMI ≥25kg/m 2 ; 9 males, 8 females) young adults aged 15–27 years. BMF UI was assessed with magnetic resonance proton spectroscopy optimized to reduce water interference. Exercise information was obtained with a pedometer accompanied with the history of recent physical activity. Blood samples (insulin, glucose, HbA1c) and body characteristics (BMI, waist-to-hip ratio, body fat composition) were assessed. Results BMF UI was not affected by obesity at the time of study or before age 7years. BMF UI increased with age in normal-weight and overweight subjects (R=0.408, p=0.015) but did not associate with gender, physical activity or body fat composition; a suggestive association was observed with glucose (R=−0.289, p=0.10). Conclusions The association of BMF UI with age in early adulthood may represent normal maturation of bone marrow. There was a trend toward an association with blood glucose, warranting further studies.

Objective Brain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos® on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m2). Methods Heart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation. Results taVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected. Conclusion Non-invasive vagus stimulation by Cerbomed Nemos® does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans., Highlights • Constant hepatic energy metabolism during prolonged fasting. • Vagus stimulation with Cerbomed Nemos® does not alter parasympathetic tone. • Cerbomed Nemos® does not modulate hepatic glucose and energy metabolism in humans.

The objective of this study was to determine the effects of a standardized fat rich meal and subsequent exercise on liver fat content by 1H MRS and on liver adenosine triphosphate (ATP) content by 31P MRS in healthy subjects. Hepatic 1H and proton decoupled 31P MRS were performed on nine healthy subjects on a clinical 3.0 T MR imager three times during a day: after (1) an overnight fast, (2) a following standardized fat rich meal and (3) a subsequent exercise session. Blood parameters were followed during the day to serve as a reference to MRS. Liver fat content increased gradually over the day (p = 0.0001) with an overall increase of 30 %. Also γ-NTP changed significantly over the day (p = 0.005). γ-NTP/tP decreased by 9 % (p = 0.019, post hoc) from the postprandial to the post-exercise state. Our study shows that in vivo MRS can depict short lived physiological changes; entering of fat into liver cells and consumption of ATP during exercise can be measured non-invasively in healthy subjects. The physiological state may have an impact on fat and energy metabolite levels. Hepatic 1H and 31P MRS studies should be performed under standardized conditions.

Objective Ectopic fat accumulation within and around the heart has been related to increased risk of heart disease. Limited data exist on cardiac adiposity in subjects with dilated cardiomyopathy (DCM). The aim of the study was to examine the components of cardiac steatosis and their relationship to LV structure and function in non-diabetic DCM patients. Methods Myocardial and hepatic triglyceride (TG) contents were measured with 1.5 T magnetic resonance spectroscopy (MRS), and LV function, visceral adipose (VAT) and abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by MRI in 10 non-diabetic men with DCM and in 20 controls. Results In face of comparable intra-abdominal fat depots, myocardial TG [0.41% (0.21–2.19) vs 0.86% (0.31–2.24), p=0.038] was markedly lower and epicardial (895 mm 2 ±110 vs 664 mm 2 ±180, p=0.002) and pericardial fat [2173 mm 2 (616–3673) vs 1168 mm 2 (266–2319), p=0.039] depots were larger in patients with DCM compared with controls. In subjects with DCM, the LV global function index was decreased to a greater extent than the LV EF [21%±6 vs 34% (16–40)]. Conclusions Myocardial TG content decreased and epicardial and pericardial fat depots increased in non-diabetic subjects with DCM. Although recognised as a site of ectopic fat accumulation, the derangement of myocardial TG seems to play a specific role in the myocardial energy metabolism in congestive heart failure.

Cardiac steatosis has been related to increased risk of heart disease. We investigated the association between cardiac steatosis, electrocardiographic (ECG) abnormalities, and individual components of the metabolic syndrome (MetS).A 12-lead ECG and laboratory data were examined in 31 men with the MetS and in 38 men without the MetS. Myocardial triglyceride (MTG) content was measured with 1.5 T magnetic resonance (MR) spectroscopy and epicardial and pericardial fat by MR imaging. MTG content, epicardial and pericardial fat depots were higher in men with the MetS compared with subjects without the MetS (p0.001). The heart rate was increased (p0.001), the PR interval was longer (p0.044), the frontal plane QRS axis shifted to the left (p0.001), and the QRS voltage (p0.001) was lower in subjects with the MetS. The frontal plane QRS axis and the QRS voltage were inversely correlated with MTG content, waist circumference (WC), body mass index (BMI), TGs, and fasting blood glucose. High-density lipoprotein cholesterol correlated positively and measures of insulin resistance negatively with the QRS voltage. MTG content and hypertriglyceridemia were determinants of the frontal plane QRS and WC and hyperglycemia were predictors of the QRS voltage.The MetS and cardiac steatosis appear to associate with multiple changes on 12-lead ECG. The frontal plane QRS axis is shifted to the left and the QRS voltage is lower in subjects with the MetS. Standard ECG criteria may underestimate the presence of left ventricular hypertrophy in obese subjects with cardiometabolic risk factors.

Context: The joint effects of cardiorespiratory fitness (CRF) and body composition on metabolic health are not well known. Objective: To examine the associations of CRF, fat-free mass index (FFMI), and fat mass index (FMI) with metabolic health in individual twins and controlling for genetic and shared environmental effects by studying monozygotic intrapair differences. Design, Setting, and Participants: Two cross-sectional samples of healthy adult monozygotic and dizygotic twins were drawn from population-based Danish and Finnish national twin registries (n = 996 and n = 309). Main Measures: CRF was defined as VO2max divided by fat-free mass. Insulin sensitivity and acute insulin response indices were derived from an oral glucose tolerance test. A continuous metabolic syndrome score was calculated. Visceral and liver fat were measured in the Finnish sample. Associations were analyzed separately in both cohorts with multivariate linear regression and aggregated with meta-analytic methods. Results: Insulin sensitivity, acute insulin response, metabolic syndrome score, visceral, and liver fat amount had strong and statistically significant associations with FMI (|β| 0.53 to 0.79), whereas their associations with CRF and FFMI were at most weak (|β| 0.02 to 0.15). The results of the monozygotic intrapair differences analysis showed the same pattern. Conclusions: Although FMI is strongly associated with worsening of metabolic health traits, even after controlling for genetic and shared environmental factors, there was little evidence for the effects of CRF or FFMI on metabolic health. This suggests that changing FMI rather than CRF or FFMI may affect metabolic health irrespective of genetic or early environmental determinants.

Background. Obese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non-invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. Methods. MRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. Results. In accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2 +/- 1.0% vs. 14.4 +/- 1.5%, P = 0.024) and associated with SAT volume (R = 0.672, P = 0.001). DSAT unsaturation did not differ between twins (11.4 +/- 0.8 vs. 11.0 +/- 1.0, P = 0.267) and associated inversely with IMCL content (R = -0.462, P = 0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R = -0.641, P = 0.025) and for the repeated sampling at random of one person (R = -0.765, P = 0.027). Conclusions. DSAT and SSAT FA unsaturation shows distinct associations with obesity and IMCL in MZ twins, reflecting compartment-specific metabolic activities. The FA unsaturation in the DSAT depot associates inversely with IMCL content, which raises the possibility of cross talk between the DSAT depot and the rapid turnover IMCL depot. (C) 2016 Elsevier Inc. All rights reserved.

Low mitochondrial activity in adipose tissue is suggested to be an underlying factor in obesity and its metabolic complications. We aimed to find out whether mitochondrial measures are downregulated in obesity also in isolated adipocytes. We studied young adult monozygotic (MZ) twin pairs discordant (n = 14, intrapair difference ΔBMI ≥ 3 kg/m2) and concordant (n = 5, ΔBMI

IF 5.531; International audience; Context: The metabolism of high-density lipoprotein (HDL) is severely impaired in individuals with abdominal obesity. However, the specific metabolism of apolipoprotein (apo)-A-II, the second major apolipoprotein of HDL, remains poorly known. The relationships between HDL apoA-II catabolism and other metabolic variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, remain to be investigated.Objectives: Our aim was to study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I.Design: We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity.Results: In a univariate analysis, apoA-II FCR was positively correlated with body mass index, sc fat, liver fat, apoA-I FCR, apoA-I production rate (PR), apoA-II pool, apoA-II PR, VLDL1-triglyceride PR, VLDL2-triglyceride PR, VLDL2-triglyceride (TG) FCR, and VLDL2-apoB FCR and negatively with HDL cholesterol to apoA-I ratio. After adjustment for apoA-I FCR, a strong positive correlation between apoA-II FCR and VLDL1-TG indirect FCR was observed (r = 0.520, P < .0001). In a multivariate analysis, apoA-II FCR was independently and positively associated with apoA-I FCR (P < .0001) and VLDL1-TG indirect FCR (P < .0001). Both variables explained 59.7% of the variability in apoA-II FCR.Conclusions: We show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR. These data suggest that, in a condition of delayed VLDL1 catabolism, such as abdominal obesity, retention of apoA-II in the VLDL1 pool may occur, with an effect on apoA-II catabolism. The consequences of this link between VLDL1 catabolism and apoA-II catabolism remain to be determined.

Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-2H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy (31P/1H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases.

Objective— Obesity increases the risk of cardiovascular disease and premature death. However, not all obese subjects develop the metabolic abnormalities associated with obesity. The aim of this study was to clarify the mechanisms that induce dyslipidemia in obese subjects. Methods and Results— Stable isotope tracers were used to elucidate the pathophysiology of the dyslipidemia in hypertriglyceridemic ( n =14) and normotriglyceridemic ( n =14) obese men (with comparable body mass index and visceral fat volume) and in normotriglyceridemic nonobese men ( n =10). Liver fat was determined using proton magnetic resonance spectroscopy, and subcutaneous abdominal and visceral fat were measured by magnetic resonance imaging. Serum triglycerides in obese subjects were increased by the combination of increased secretion and severely impaired clearance of triglyceride-rich very-low-density lipoprotein 1 particles. Furthermore, increased liver and subcutaneous abdominal fat were linked to increased secretion of very-low-density lipoprotein 1 particles, whereas increased plasma levels of apolipoprotein C-III were associated with impaired clearance in obese hypertriglyceridemic subjects. Conclusion— Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects with similar levels of visceral adiposity. The results emphasize the clinical importance of assessing hypertriglyceridemic waist in obese subjects to identify subjects at high cardiometabolic risk.

The aim of this study was to evaluate use of infrared spectroscopy for measuring adipose tissue triacylglycerols (TAGs) with analysis by multivariate curve resolution (MCR). The mid-infrared spectrum was measured with an attenuated total reflection accessory from a lipid droplet pressed from adipose tissue. The obtained spectra were characteristic of pure TAG spectra and water and protein contamination could be easily identified from specific spectral regions. MCR analysis of the olefinic (CH) stretch (3006 cm−1), resolved the different contributions of monounsaturated (MUFA) and polyunsaturated (PUFA) double bonds. Similar MCR analysis of the trans (HCCH) region (966 cm−1), resolved the differing contributions of isolated trans isomers (transFA) and CLA. The PUFA double bond content of 16 subjects was negatively correlated with concentrations of serum total cholesterol R = −0.498 (p = 0.050) and triacylglycerols R = −0.609, (p = 0.016). The transFA content exhibited a negative, although non-significant, correlation to high-density lipoprotein (HDL)-cholesterol (R = −0.483, p = 0.068). The present study shows that MCR analysis of adipose tissue TAG infrared spectra can be used to estimate differences in the fatty acid (FA) profiles in population studies. Infrared spectroscopy in combination with MCR provides a robust method for assessing a FA profile of human adipose tissue. Practical applications: This study has highlighted the use of MCR to enhance the information obtained from infrared spectra. This new approach provides a robust method for assessing a FA profile of human adipose tissue lipids.

To determine if 3.0-T proton-decoupled phosphorus 31 ((31)P) magnetic resonance (MR) spectroscopy can be used to differentiate between stages of nonalcoholic fatty liver disease (NAFLD) by resolving the components of phosphomonoester (PME) and phosphodiester (PDE) and enabling detection of a greater number of other phosphorus-containing compounds.This study was approved by the ethics committee of Helsinki University Central Hospital, and written informed consent was obtained from all study subjects. A 3.0-T clinical imager was used to obtain proton-decoupled (31)P MR spectra in the liver of control subjects (n = 12), patients with biopsy-proved simple steatosis due to nonalcoholic causes (nonalcoholic fatty liver, n = 13; nonalcoholic steatohepatitis [NASH], n = 9), and patients with cirrhosis (n = 9) to determine PME, phosphoethanolamine (PE), phosphocholine, PDE, glycerophosphocholine (GPC), glycerophosphoryl ethanolamine, uridine diphosphoglucose, nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate, phosphoenolpyruvate, and alpha-, beta- and gamma-nucleotide triphosphate levels. Liver fat was determined with hydrogen 1 MR spectroscopy. Differences between the disease groups were analyzed with one-way analysis of variance.The PME/(PME + PDE), PME/PDE, and PE/(PME + PDE) ratios were higher and the GPC/(PME + PDE) ratio was lower in patients with cirrhosis than in the other study groups (Por = .001, one-way analysis of variance). The NADPH/(PME + PDE) ratio was higher in patients with NASH and those with cirrhosis than in control subjects (P.05, post hoc analyses) and correlated with disease severity (P = .007).NADPH, a marker of inflammation and fibrinogenic activity in the liver, is increased in patients with NASH and those with cirrhosis. Proton-decoupled (31)P 3.0-T MR spectroscopy shows promise in the differentiation of NAFLD stages.

The aim of this study was to investigate the use of 1H-MRS with various echo times to characterize subcutaneous human adipose tissue (SAT) triglyceride composition and to validate the findings with fatty acid (FA) analysis of SAT biopsies by gas chromatography (GC). 1H-MRS spectra were acquired with a 1.5 Tesla clinical imager from the SAT of 17 healthy volunteers, with 10 undergoing SAT biopsy. Spectra were localized with PRESS and a series of echo times; 30,50,80,135,200,300 and 540 ms were acquired with TR = 3000 ms. Prior knowledge from phantom measurements was used to construct AMARES fitting models for the lipid spectra. SAT FA composition were compared with serum lipid levels and subject characteristics in 17 subjects. Long TE (135,200 ms) spectra corresponded better with the GC data than short TE (30,50 ms) spectra. TE = 135 ms was found optimal for determining diallylic content (R = 0.952, p

Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment.14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins.We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity.This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.

Background and aims: Lipid oversupply to cardiomyocytes or decreased utilization of lipids leads to cardiac steatosis. We aimed to examine the role of different circulating metabolic biomarkers as predictors of myocardial triglyceride (TG) content in non-diabetic men. Methods and results: Myocardial and hepatic TG contents were measured with 1.5 T magnetic resonance (MR) spectroscopy, and LV function, visceral adipose tissue (VAT), abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by MR imaging in 76 non-diabetic men. Serum concentration of circulating metabolic biomarkers [adiponectin, leptin, adipocyte-fatty acid binding protein 4 (A-FABP 4), resistin, and lipocalin-2] including beta-hydroxybuturate (beta-OHB) were measured. Subjects were stratified by tertiles of myocardial TG into low, moderate, and high myocardial TG content groups. Concentrations of beta-OHB were lower (p = 0.003) and serum levels of A-FABP 4 were higher (p

Background The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2). Results There were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed. Conclusions The methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0073-5) contains supplementary material, which is available to authorized users.

Background— Nonalcoholic fatty liver disease has emerged as a novel cardiovascular risk factor. The aim of the study was to assess the effect of different ectopic fat depots on left ventricular (LV) function in subjects with nonalcoholic fatty liver disease. Methods and Results— Myocardial and hepatic triglyceride contents were measured with 1.5 T magnetic resonance spectroscopy and LV function, visceral adipose tissue (VAT) and subcutaneous adipose tissue, epicardial and pericardial fat by MRI in 75 nondiabetic men. Subjects were stratified by hepatic triglyceride content into low, moderate, and high liver fat groups. Myocardial triglyceride, epicardial and pericardial fat, VAT, and subcutaneous adipose tissue increased stepwise from low to high liver fat group. Parameters of LV diastolic function showed a stepwise decrease over tertiles of liver fat and VAT, and they were inversely correlated with hepatic triglyceride, VAT, and VAT/subcutaneous adipose tissue ratio. In multivariable analyses, hepatic triglyceride and VAT were independent predictors of LV diastolic function, whereas myocardial triglyceride was not associated with measures of diastolic function. Conclusions— Myocardial triglyceride, epicardial and pericardial fat increased with increasing amount of liver fat and VAT. Hepatic steatosis and VAT associated with significant changes in LV structure and function. The association of LV diastolic function with hepatic triglyceride and VAT may be because of toxic systemic effects. The effects of myocardial triglyceride on LV structure and function seem to be more complex than previously thought and merit further study.

High field MR scanners can resolve a metabolite resonating at 2.06 ppm in the in vivo proton-decoupled liver (31) P MR spectrum. Traditionally this peak has been assigned to phosphoenolpyruvate (PEP), the key metabolite for gluconeogenesis. However, recent evidence supported the assignment to biliary phosphatidylcholine (PtdCh), which is produced in the liver and stored in the gall bladder. To elucidate the respective contributions of PtdCh and PEP to the in vivo resonance at 2.06 ppm (PEP-PtdCh), we made phantom measurements that confirmed that both biliary PtdCh and PEP resonate approximately at 2 ppm. The absolute quantification of PEP-PtdCh yielded concentrations ranging from 0.6 to 2.0 mmol/l, with mean coefficients of variation of 4.8% for intraday and 7.2% for interday reproducibility in healthy volunteers. The T1 relaxation time of PEP-PtdCh was 0.97 ± 0.30 s in the liver and 0.44 ± 0.11 s in the gallbladder. Ingestion of a mixed meal decreased the concentration of PtdCh-PEP by approximately 12%. In the retrospective analysis, PEP-PtdCh was 68% higher in the liver of subjects with gallbladder infiltration of the volume of interest (VOI) compared with those without gallbladder infiltration. PEP-PtdCh was also significantly higher in the liver of cholecystectomy patients compared with volunteers without gallbladder infiltration, which suggests increased intrahepatic bile fluid as a compensation for gall bladder removal. These results show that liver PtdCh is the major component of the resonance at 2.06 ppm and that careful VOI positioning is mandatory to avoid interference from the gallbladder.

Postprandial responses to food are complex, involving both genetic and environmental factors. We studied postprandial responses to a Big Mac meal challenge in monozygotic co-twins highly discordant for body weight. This unique design allows assessment of the contribution of obesity, independent of genetic liability. Comprehensive metabolic profiling using 3 analytical platforms was applied to fasting and postprandial serum samples from 16 healthy monozygotic twin pairs discordant for weight (body mass index difference >3 kg/m2). Nine concordant monozygotic pairs were examined as control pairs. Fecal samples were analyzed to assess diversity of the major bacterial groups by using 5 different validated bacterial group specific denaturing gradient gel electrophoresis methods. No differences in fecal bacterial diversity were detected when comparing co-twins discordant for weight (ANOVA, P

The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood.We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content.We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%).We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine.BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance.

The objective of this study was to determine the effects of a standardized fat rich meal and subsequent exercise on liver fat content by ¹H MRS and on liver adenosine triphosphate (ATP) content by ³¹P MRS in healthy subjects.Hepatic ¹H and proton decoupled ³¹P MRS were performed on nine healthy subjects on a clinical 3.0 T MR imager three times during a day: after (1) an overnight fast, (2) a following standardized fat rich meal and (3) a subsequent exercise session. Blood parameters were followed during the day to serve as a reference to MRS.Liver fat content increased gradually over the day (p = 0.0001) with an overall increase of 30 %. Also γ-NTP changed significantly over the day (p = 0.005). γ-NTP/tP decreased by 9 % (p = 0.019, post hoc) from the postprandial to the post-exercise state.Our study shows that in vivo MRS can depict short lived physiological changes; entering of fat into liver cells and consumption of ATP during exercise can be measured non-invasively in healthy subjects. The physiological state may have an impact on fat and energy metabolite levels. Hepatic ¹H and ³¹P MRS studies should be performed under standardized conditions.

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45–80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.